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A.T. Portman

PARKINSON'S DISEASE:

DEEP BRAIN STIMULATION

AND FDOPA-PET

PARKINSON'S DISEASE:

DEEP BRAIN STIMULATION

AND FDOPA-PET

Parkinson’s Disease: Deep Brain Stimulation and FDOPA-PET

The work described in this thesis was performed at the Department of Neurology,University Medical Center, Groningen (the Netherlands).

© A.T. Portman

ISBN: 90-367-2390-6

Print: Stichting Drukkerij C. Regenboog, Groningen.

Cover: Lauwersoog (2004).

Lyrics: “Senses working overtime” by Andy Partridge (1982).

The studies of this thesis were financially supported by the Stichting InternationaalParkinson Fonds (Hoofddorp, the Netherlands).

Publication of this thesis was financially supported by: Ziekenhuis Refaja(Stadskanaal), Boehringer Ingelheim bv, Medtronic, Roche Nederland B.V., BiogenIdec International, Novartis Pharma B.V., TEVA Pharma B.V., UCB Pharma,GlaxoSmithKline B.V., Sanofi-Aventis and Ipsen Farmaceutica.

Rijksuniversiteit Groningen

Parkinson’s Disease: Deep Brain Stimulation and FDOPA-PET

Proefschrift

ter verkrijging van het doctoraat in deMedische Wetenschappen

aan de Rijksuniversiteit Groningenop gezag van de

Rector Magnificus, dr. F. Zwarts,in het openbaar te verdedigen op

woensdag 2 november 2005om 16.15 uur

door

Axel Tiddo Portmangeboren op 30 januari 1965

te Groningen

Promotores: Prof. dr. K. L. LeendersProf. dr. M. J. Staal

Copromotor: Dr. T. van Laar

Beoordelingscommissie: Prof. dr. R. A. C. RoosProf. dr. J. H. A. de Keyser

Prof. dr. J. J. A. Mooij

“And all the world is football-shaped

it’s just for me to kick in space

And I can see, hear, smell, touch, taste

and I’ve got one, two, three, four, five

Senses working overtime

trying to take this all in”

Contents

Preface and outline of the thesis 1

Chapter 1 General introduction and aims of the thesis 3

Chapter 2 Study design and patient population 33

Chapter 3 Chronic stimulation of the subthalamic nucleus increases

daily on-time without dyskinesia in advanced Parkinson’s

Disease 37

Chapter 4 Striatal FDOPA uptake and cognition in advanced

non-demented Parkinson’s Disease: a clinical and

FDOPA-PET study 51

Chapter 5 Disease progression continues in patients with advanced

Parkinson’s Disease and effective subthalamic nucleus

stimulation 65

Chapter 6 Presurgical FDOPA-PET and motor outcome of

subthalamic nucleus stimulation in Parkinson’s Disease 81

Chapter 7 Summary and conclusions 93

Chapter 8 Samenvatting en conclusies 97

Appendices 101

Dankwoord 109

Curriculum Vitae 113

1

Preface and outline of the thesis

Parkinson’s Disease (PD) is a common neurodegenerative disorder of unknown etio-

logy, characterised by a progressive loss of dopaminergic and other neurons in the

mesencephalon. In addition to the “classical” treatment strategies in PD, which are

mainly focussed on motor symptom control, a major therapeutic aim nowadays is hal-

ting the disease process itself. In recent years advances in the understanding of the

cause and pathogenesis of PD have permitted the rational selection of putative neuro-

protective drugs for study in PD. However, thus far study results have been disap-

pointing. The introduction of Deep Brain Stimulation (DBS) of the subthalamic nucle-

us (STN) in the late 1990s offered long-term motor benefit for PD patients with

advanced disease. Clinical, experimental and pathophysiological considerations gave

rise to expectations that DBS of the STN might even offer a novel neuroprotective

approach in PD. The clinical introduction of bilateral STN-DBS in our hospital in 1999

brought the possibility to start a study on disease progression in STN stimulated PD

patients, and to investigate the relationship between striatal dopaminergic activity and

clinical responses of PD patients to DBS. In this study nigrostriatal dopaminergic

integrity was monitored by Positron Emission Tomography (PET) using the ligand

FDOPA. All clinical and PET study data in this thesis were collected between 1999 and

2004.

In Chapter 1 the reader is provided with the current knowledge on etiology, patho-

physiology, and treatment options in PD. The pivotal role of the STN and the potential

of STN-DBS to attenuate dopaminergic cell decline in PD are emphasised. In Chapter

2 we present the employed study design and recruitment of study population in the

University Medical Center Groningen. Chapter 3 shows the results of STN-DBS on

motor function in advanced PD, while Chapter 4 presents data on the nature of the

relationship between striatal dopamine depletion and cognitive function in PD.

Chapter 5 shows the results of a prospective two-center study on disease progression

after successful STN-DBS in PD, and in Chapter 6 the predictive value of the nigrostri-

atal dopaminergic status on the efficacy of STN-DBS in advanced PD is discussed.

Finally, in Chapters 7 and 8 all study results are reviewed and summarised, and the

conclusions of this thesis are stated.

2

Preface and outline of the thesis

In 1817 James Parkinson wrote his, by now, famous “Essay on the Shaking Palsy”, but

he already debuted scientifically in the field of medicine 30 years earlier. On February

4th 1787 he read a paper at the meeting of the Medical Society in London, concerning

the effects of lightning on the physical health of men. Nowadays it may seem that

Parkinson reached full circle realising that he himself was also interested in the stri-

king effect of “electric stimulation” of the brain.

Chapter 1

General introduction and aims of the thesis

3

1. General introduction

A M. Parkinson

I Introduction

James Parkinson (1755-1824) was born in Shoreditch, Middlesex (GB), where he spent

his entire life. He was the oldest son of an apothecary, and in 1771 he started his

apprenticeship to his father. Within 5 years he became a “dressing pupil” at the

London Hospital and in 1784 he was awarded the Membership of the Company of

Surgeons 1

. During his life he made major scientific contributions in medicine, geolo-

gy and palaeontology, and he also was a prominent political reformer. His first contri-

bution to the medical literature was entitled “Some Accounts of the Effects of

Lightening”, which he read at a meeting of the Medical Society in London in 1787 1

. In

1817 his “Essay on the Shaking Palsy” was published 2

. In 5 brief chapters, Parkinson

described a previously unrecognised nervous system disorder in six human cases (of

whom 3 were even not his patients: he had merely observed them during his walks in

the streets), of which a “tremulous motion” seemed one of its hallmarks. Parkinson,

lacking cerebral autopsy material, predicted that the lesions of his patients would be

located in the cervical spinal cord 3

. For many years the work of James Parkinson was

almost forgotten. After his death in 1824 (he suffered from a stroke), the medical pro-

fession failed to recognise the disease James Parkinson had described in his essay.

However, when William Gowers in 1886 published “A manual of Diseases of the

Nervous System”, it contained an article on “shaking palsy” or, erroneously, “paraly-

sis agitans” 1

. Subsequently, it was the French neurologist Jean Martin Charcot who

preferred the eponym of “Parkinson’s Disease” (PD). In the following decades succes-

sive pathological studies (e.g. Lewy, 1914) of patients with PD showed characteristic

brain abnormalities, especially neuronal degeneration in the substantia nigra 4

. It las-

ted until 1960s that Hornykiewicz discovered that PD patients suffered from extensive

dopamine depletion in the striatum 5

. In 1967 the “levodopa era” started when Cotzias

showed that orally administered levodopa had a dramatic and sustained effect on the

cardinal motor features of PD: tremor, rigidity and bradykinesia 6

.

II Motor and non motor features

Since there is no diagnostic biological marker for PD, the clinical diagnosis is entirely

based on the presence of its characteristic motor features 7

. Thus far few attempts have

been made to develop explicit diagnostic criteria, including features as proposed by

the Parkinson’s Disease Society Brain Bank 8

. These include bradykinesia (slowness of

initiation of movement with progressive reduction in speed and amplitude of repeti-

Chapter 1

4

tive actions), and at least one of the following motor features: rigidity, 4-6 Hz rest

tremor and postural instability. Additional supportive criteria for the clinical diagno-

sis PD are a persistent asymmetry of motor features affecting one side most, and an

excellent response to levodopa. Before the appearance of these classic motor features,

there may be a prodromal period in which symptoms and signs occur but do not

specifically indicate PD; these symptoms include depression, musculoskeletal pain,

sensory dysfunction and autonomic disturbance 9

. Olfactory dysfunction may also be

an early symptom of PD. A recent study on odour discrimination showed that PD

patients could be discriminated from healthy controls with a sensitivity of 88 % and a

specificity of 83 % 10

. As depression is the most common psychiatric symptom in PD, a

subgroup of patients presents with a depression as the initial disease manifestation 11

.

Autonomic dysregulation is the most common non motor feature of PD. Orthostatic

hypotension and gastrointestinal complaints are the most common vegetative symp-

toms in PD. Data on the incidence vary between 14-80 % depending on the population

studied and the method used 12

. Cognitive impairment occurs in 25-40 % to over 90 %

of patients with PD 13-15

, and dementia is increasingly recognised as an important non-

motor feature of PD, especially in the elderly 6

. Mental decline in PD is often being

characterised by cognitive slowing, impaired abstract thinking and difficulties with

reasoning. In addition, attentional deficits, visuospatial and executive dysfunction and

memory impairments can be affected even at the early stages of the disease.

III Diagnosis

The combination of asymmetry of symptom onset, the presence of a typical resting

tremor, and an excellent response to levodopa best differentiates (idiopathic) PD from

parkinsonism due to other, more seldom, causes 6

. Although many signs and symp-

toms are present in all parkinsonian syndromes, they specifically start at different

stages of the disease. These differences in the dynamics of time course become evident

when comparing PD with other, more “atypical” parkinsonian syndromes (e.g.

Multiple System Atrophy, Progressive Supranuclear Palsy), with the latter having a

more rapid functional deterioration 16

.

In clinical practice the differential diagnosis of PD thus primarily includes other pri-

mary inherited or sporadic neurodegenerative syndromes featuring parkinsonism,

parkinsonian syndromes associated with defined diseases, symptomatic parkinsonian

syndromes and monogenetically inherited forms of PD 17

(see table 1).

Despite application of explicite diagnostic criteria only 60-70 % of clinical diagnosis of

PD are confirmed by autopsy 8;14

. Recently 800 patients with clinically PD were

prospectively followed up with repeated clinical assessments; after 6 ± 1.4 years, 8.1 %

of patients initially diagnosed as having PD were found to have an alternate diagno-

sis 7

.


5

Chapter 1

6

Table 1 Differential diagnosis of parkinsonism

Primary neurodegenerative disorders with parkinsonism

Inherited:

1. Parkinson’s Disease (α-synuclein, Parkin, Park 3-10, NR4A2)

2. M. Alzheimer

3. M. Huntington

4. Spinocerebellar atrophies

5. Neuro-acanthocytosis

6. Dopa-responsive dystonia

7. Dentato Rubral Pallidal Luysian atrophy

8. Pantothenate kinase-associated neurodegeneration

9. Familial depression, alveolar hypoventilation and parkinsonism

10. Neuronal intranuclear inclusion disease

Sporadic:

1. (idiopathic) Parkinson’s Disease

2. Parkinson “plus” syndromes

* Progressive Supranuclear Palsy

* Multiple System Atrophy

* Cortical Basal Ganglionic Degeneration

* Dementia with Lewy Bodies

* M. Alzheimer

* M. Pick

* ALS-Parkinsonism-dementia of Guam

* Hemiparkinsonism with hemiatrophy

Secondary disorders with parkinsonism

Inherited:

1. M. Wilson

2. M. Gaucher

3. GM1 gangliosidosis

4. Chediak-Higashi syndrome

Sporadic:

1. Toxic (CO, CS2 , manganese)

2. Hepatocerebral degeneration (non-Wilsonian)

3. Endocrine (hypothyroidism, hypoparathyroidism)

4. Mass lesions (AV-malformations, neoplasm)

5. Vascular (vasculitis, infarction, lacunar state)

6. Trauma

7. Autoimmune or inflammatory disease

8. Lack of substrate (hypoxia, hypoglycaemia)

Others:

1. Medication induced (direct or withdrawal)

2. Normal pressure hydrocephalus

Routine imaging of the brain seems not helpful in confirming the clinical diagnosis of

PD, although occasionally PD patients show an increased signal from the substantia

nigra on conventional T2-weighted MRI sequences 18

. Functional imaging techniques,

like Positron Emission Tomography (PET), provides a means of assessing dopamine

terminal functioning or specific cerebral glucose metabolism in vivo, and allows to

detect preclinical and clinical PD 19;20

. Several biochemical markers have been tested as

indicators for dopamine deficiency, mostly in the cerebrospinal fluid (CSF). Overall,

the sensitivity and specificity of homovanillic acid (HVA), noradrenaline and 3-

methoxy-4-hydroxyphenylethylglycol in cerebrospinal fluid, and HVA in serum are

too low to use as preclinical or clinical markers for PD 9

.

IV Prevalence and incidence

PD is the commonest neurodegenerative disease after M. Alzheimer, and it is estima-

ted that in the Netherlands approximately 40.000 people suffer from PD. However,

prevalence estimates of PD in the literature vary widely, merely because of differences

in diagnostic criteria and in the age distribution of the study population 21

, and ranges

from 150-300 per 100.000 population 22;23

.

A population-based cohort study in a general elderly population in the Netherlands

showed increasing prevalence of PD with age, being 1.0 % for those over 65 to 4.3 % in

those over 85 years of age 21

. Recently the results of 7 population-based studies were

examined separately and pooled to obtain estimates of PD prevalence. The overall

prevalence in persons 65 to 89 years ranged from 1.8-2.6 % 24

, being the lowest among

Asians and African blacks and highest among whites. PD occurs throughout the world

in all ethnic groups and affects both sexes almost equally 6

. An overall estimated annu-

al incidence of PD is 12 cases per 100.000 23

.

V Etiology and pathophysiology

PD is characterised by the progressive death of selected heterogeneous populations of

neurons, including dopaminergic neurons in the substantia nigra pars compacta

(SNpc) 6

. The loss of dopamine-containing neurons in PD affects different parts of the

nigral complex to different degrees, the most severe loss occurring in the ventrolate-

ral part of the SNpc 25

. Nigrostriatal degeneration leads to (severe) dopamine deficit in

the striatum, and this process follows two regular characteristic inter- and subregio-

nal patterns: first the putamen loses considerably more dopamine than the caudate,

and within the putamen the caudal portions are more depleted of dopamine than the

rostral portions. In the caudate this rostrocaudal gradient goes in the opposite direc-

tion26

. It is estimated that at least 30-50 % of nigral cell loss has occurred at the onset of

PD symptomatology 6

, which percentage exceeds over 80 % in the advanced disease

state26

.


7

Being a widespread degenerative illness, PD affects the central, peripheral, and enteric

nervous systems. Components of the limbic system and the motor system have been

shown to be particularly vulnerable to severe destruction. This damage is consistently

accompanied by extranigral alterations, with predilection sites includes the entorhinal

region, the second sector of the Ammon’s horn, and important subnuclei of the amyg-

dala. In addition, the nucleus of the stria terminalis, components of the hypothalamus,

all of the non-thalamic nuclei with diffuse projections to the cerebral cortex, and most

of the centers regulating autonomic functions exhibit severe lesions. Afflicted neurons

eventually produce Lewy bodies (neuronal cell bodies, the histological hallmark of

PD) in their perikarya and Lewy neurites in their neuronal processes 27

.

The precise mechanisms responsible for progressive cell death in PD are largely

unknown. Several mechanisms have been proposed, including oxidative stress and

free radical damage, mitochondrial (complex I) deficiency, glutamate excitotoxicity

and inflammatory responses 6;22;23

. Cells may die by necrosis, involving the disintegra-

tion of a cell and its organelles and subsequent removal by phagocytosis 22

. Increasing,

but controversial, evidence suggests that neuronal death may result from apoptosis,

characterised by chromatin condensation, DNA fragmentation and cell shrinkage

without an inflammatory response, which may be programmed or occurs in response

to a toxic stimulus 23

. Further research into the etiology of PD is likely going to show

that multiple environmental and genetic factors are involved, and that PD results from

the combined effect of environmental exposure, genetic susceptibility and complex

genetic-environmental interactions 23

. Most epidemiological studies support the role of

pesticide exposure in PD, whereby rural living, drinking well water and farming acti-

vity may be compound risk factors. Also an inverse relationship between smoking and

the risk of PD is suggested, although such an association is not confirmed in all stu-

dies 23

. Finally, there is increasing evidence for a genetic component in the cause of PD,

and the recent identification of several genes and additional loci associated with inhe-

rited forms of PD suggest that genetic factors can influence the susceptibility to the di-

sease 28;29

. By now at least 8 defined genetic loci are associated with autosomal domi-

nant or recessive, familiar, PD, wherein thus far 5 causative mutations have been iden-

tified30

. The first protein implicated in familial PD was α-synuclein, a brain protein of

unknown function 31

. Since α-synuclein aggregates in Lewy bodies, and these inclusion

bodies are present in sporadic and familial PD, this protein may play a substantial role

in both genetic and sporadic forms of the disease. However, mutations in the gene

encoding α-synuclein (which is localised on chromosome 4q21) are a very rare cause

of sporadic PD. Finally these findings have led to a general hypothesis that the patho-

genesis of PD involves the abnormal folding, aggregation and deposition of α-synucle-

in as key steps in mediating neuronal dysfunction and degeneration 32

.

VI The basal ganglia: a pathophysiologic PD model

The basal ganglia (striatum, pallidum, subthalamic nucleus and substantia nigra) are

crucial to function in the motor and cognitive domains, and are usually regarded as

Chapter 1

8

9

components of several largely segregated basal ganglia-thalamo-cortical circuits ser-

ving motor, oculomotor and cognitive functions 33

. In models of basal ganglia function

in PD (see figure 1), loss of dopamine leads to a shift of balance within these circuits:

in the “motor circuit” modulation via dopamine D1 and D2 receptors within the stria-

tum (putamen) leads to overactivity of the subthalamic nucleus (STN) and finally

results in decreased activity of thalamocortical projection neurons 34

. It is postulated

that this results in decreased facilitation of cortical motor areas and subsequent deve-

lopment of akinesia and bradykinesia in PD. However, these models do not account

for a variety of anatomical, physiological, experimental and clinical findings 35

.

Figure 1 Influence of dopamine on striatal output pathways


Acb = nucleus accumbens; Caud = nucleus caudatus; GPe = external pallidum; GPi = internal pallidum; MC= primary motor cortex; MD = nucleus mediodorsalis; MEA = midbrain extrapyramidal area; O = occipitalcortex; P = parietal cortex; PFC = prefrontal cortex; Put = putamen; sc = sulcus centralis; SNC = substantianigra pars compacta; SNR = substantia nigra pars reticulata; STN = nucleus subthalamicus; T = temporal cor-tex; VA = nucleus ventralis anterior; VL = nucleus ventralis lateralis; VP = ventral pallidum; VTA = ventraltegmental area

From: Groenewegen HJ. Bewegingsstoornissen. Wolters EC, van Laar T (eds.). VU Uitgeverij, Amsterdam, 2002. Bypermission of VU Uitgeverij.

10

Chapter 1

B Treatment of M. Parkinson

I Introduction

Current strategies on treatment of PD are basically focussed on control of motor symp-

toms of the disease and prevention or treatment of the complications of symptomatic

agents. Symptomatic treatment of PD mainly includes replacement or mimicking of

dopamine (dopaminergic therapy) and functional (stereotactic) neurosurgery36

.

However, since PD progresses over time a major therapeutic aim nowadays is the li-

miting or halting of the disease process37

. Neuroprotective therapies in PD can be

defined as those medical or surgical interventions that favourable alter the underlying

etiology or pathogenesis and thus delay the onset or slow dopaminergic decline38

.

Neuroregeneration, the salvage of dying dopaminergic neurons, may be part of the

process of neuroprotection. Finally, neurorestauration is the process of increasing the

numbers of dopaminergic neurons by cell implantation or the use of nerve growth fac-

tors38

.

II Dopaminergic therapy

Current drug therapy in PD is symptomatic and primarily aimed at restoring

dopaminergic function in the striatum 39

. Levodopa, in combination with a peripheral

decarboxylase inhibitor, is the single most effective drug for the symptomatic treat-

ment of PD 40

and its use is associated with decreased morbidity and mortality 41

.

Levodopa is most successful during the first years of treatment, and this period is

known as the levodopa “honeymoon” 42

. Although usually well tolerated initially, the

chronic administration of oral levodopa is often associated with significant motor com-

plications like response fluctuations43

. Major subtypes of these fluctuations include

“wearing off” (shrinkage of duration of levodopa dose-induced benefit), “on-off “

(sudden, unpredictable loss of levodopa effect) and “on-dyskinesia” (chorea at peak

dose of dopamine concentration) 44

. The prevalence of these motor features increases

with the duration of exposure to levodopa, occurring in approximately 50 % of PD

patients who received levodopa for more than 5 years. It is believed that these motor

phenomena may be caused by a complex combination of central pharmacodynamic

(loss of dopamine storage sites as PD progresses) and peripheral pharmacokinetic

(delayed absorption of levodopa in the duodenum and pulsatile levodopa administra-

tions) mechanisms 45

. Prescribing controlled-release levodopa has shown to be associ-

ated with a lower incidence of motor fluctuations and dyskinesia 46

. Despite major

advantages, levodopa has no impact on several motor features, including speech, gait,

posture and balance, and tends to aggravate non motor features like hallucinations,

cognitive impairment and orthostatic hypotension 42

.

11


Dopamine agonists exert their antiparkinsonian effects by acting directly on postsy-

naptic dopamine receptors and mimic the endogenous neurotransmitter39

.

Apomorphine was the first dopaminergic agonist synthesised in the 19th century, and

in 1951 Schwab noted that apomorphine injections caused marked improvement in PD

patients 5

. In 1974 Calne et al. reported the beneficial effects of bromocriptine, an ergot

derivate, as add-on therapy to levodopa in PD 47

, and in 1982 pergolide, also an ergot

derivate, proved to be effective as levodopa adjunct in PD patients with motor compli-

cations 48

. In 1997 another 2, non ergot, dopamine agonists were introduced in Europe

as potent antiparkinsonian drugs: pramipexole and ropinirole 49

. Nowadays dopamine

agonists are basically used as monotherapy (especially in de novo patients) 50;51

and as

adjunct to levodopa 52

. For PD patients requiring initiation of symptomatic therapy,

either levodopa or a agonist can be used, although levodopa provides superior motor

benefit but seems associated with a higher risk of dyskinesia 53

.

Despite the initial outstanding benefit, long-term levodopa and dopamine agonist

therapies do not solve all the problems faced by PD patients. Especially in advanced

disease not all parkinsonian motor features can adequately be controlled with

dopaminergic medication 54

. Furthermore, PD is not just a motor disorder. Dysfunction

of autonomic, cognitive and psychiatric systems frequently accompany PD and these

non motor features tend to be poorly responsive to dopaminometica or may even be

worsened by antiparkinsonian medication 42

.

III Surgical treatments

History and targets

Surgical treatments as possible therapy for PD have been performed since the begin-

ning of the 20th

century. The first neurosurgical operation for relief of parkinsonism

was performed by the Frenchman Leriche in 1912 55

. By performing a bilateral posteri-

or rhizotomy of lower cervical radices moderate tremor suppression was achieved.

Since an unwanted but associated loss of voluntary motor function accompanied this

treatment, it soon was abandoned. After Bucy and Case in 1939 extirpated the

Brodmann’s areas 4 and 6 in a patient with posttraumatic rest and intention tremor 56

,

neurosurgeons started to perform cortical ablations. Meyers became the first to per-

form an operation in the basal ganglia in 1939 by extirpating the almost entire head of

the caudate nucleus in a postencephalitic parkinsonian patient 57

. In addition he pla-

ced lesions in other extrapyramidal structures like the pallidofugal fibers, which relie-

ved tremor and rigidity in 60 % of PD patients. The development of stereotactic instru-

ments, which already had been designed initially by Clarke and Horsley in 1906 58

, and

stereotaxis atlases, first introduced by Spiegel and Wycis in 1952 59

, permitted more

accurate target localisation and fewer side effects and subsequently the application for

stereotactic surgery increased. Were initially the inner segment of the globus pallidus

12

Chapter 1

and the ansa lenticularis the main targets for surgery, several groups (e.g. Leksell) pre-

ferred attacking the posteroventral pallidum 60

. Since Cooper in 1958 noted that lesi-

ons placed within the thalamus provided similar effects and less side effects, thalamo-

tomy became the favourite surgical procedure in relieving PD tremor in the late 1950s

and 1960s 61

.

With the introduction of levodopa in 1969 the demand for surgery declined. In the

1970s and 1980s surgical procedures were rarely performed, but because of insufficient

relief of tremor by levodopa, thalamotomy regained popularity as surgical target 62

.

Advancements in understanding of the pathophysiology of PD, based on models of

basal ganglia function 63

, led to renewed surgical procedures in the 1990s. In 1992

Laitinen described 38 PD patients in whom he had performed a lesion of the pos-

teroventral region of the internal part of the pallidum (GPi), following the original con-

cept of Leksell 64

. Based on these results several groups began to perform posteroven-

tral GPi pallidotomy in PD 65;66

. The most consisted finding in these studies has been

the dramatic improvement in contralateral dyskinesia, while results with respect to

parkinsonism were less striking. In addition, side-effects of bilateral pallidotomy

largely restricted surgery to unilateral procedures 67

, and long term results of pallido-

tomy on persistent benefit are variable 68

.

Deep Brain Stimulation (DBS), introduced by Heath et al in 1950 69

, was based on the

common effect of tremor suppression during high-frequency testing of the target site

during ablative surgery with the electrode to confirm proper placement. DBS as a

treatment for PD was introduced by Benabid et al in 1987 70

and was first tested in the

ventral intermediate (VIM) nucleus of the thalamus in patients with tremor dominant

disease 71

. Although DBS of the VIM has now been shown to dramatically ameliorate

contralateral tremor 72

, most studies have not found significant benefit in other PD

symptoms. The major advantages to DBS is that, unlike ablative surgery, it permits a

bilateral procedure, its side-effects associated with stimulation are reversible, and

adjustment of stimulation parameters maximises benefits and minimises adverse

events 73

. Because clinical efficacy of thalamus-DBS in PD was limited to tremor sup-

pression only, interest in the late 1990s shifted to DBS of the GPi and the subthalamic

nucleus (STN). Based on extensive electrophysiological and metabolic studies indica-

ting overactivity of GPi and STN in animal PD models and PD patients 74;75

, DBS of

these structures offered an opportunity to functionally inhibit their overactivity with-

out making a destructive lesion. In addition, high-frequent stimulation of the STN in

an animal model of PD, the MPTP-lesioned monkey, decreased tremor, rigidity and

akinesia successfully. Since then several studies on bilateral GPi-DBS showed allevia-

tion of all PD motor symptomatology 76;77

. Limousin et al (1995) were the first to

describe the beneficial efficacy of STN-DBS in 3 PD patients with advanced disease 78

.

Like GPi-DBS, STN-DBS improved all cardinal motor features of PD, but no ran-

domised, blinded clinical trial has shown superiority of one target over the other yet79

.

13


By now, the precise mechanism as to how DBS exactly works is not known 73

. It is

believed that DBS suppresses the neuronal firing pattern in the target area either

directly or by inducing the release of inhibitory transmitters; other possibilities include

back firing, “jamming” and depolarisaton blockade 80

.

Chronic stimulation of the subthalamic nucleus

A. The subthalamic nucleus

The subthalamic nucleus (STN) was “discovered” by the French investigator Jules

Bernard Luys 81

, and subsequently he published his knowledge in his book “Studies on

the structure, functions and diseases of the nervous sytem” in 1865. The STN is a small

biconvex-shaped structure surrounded by dense bundles of myelinated fibers (see fi-gure 2). Its anterior and lateral borders are adjacent to the internal capsule and rostro-

medially the STN lies adjacent to the Fields of Forel. Posteromedial it is adjacent to the

red nucleus and its ventral limits are the cerebral peduncle and the ventrolateral sub-

stantia nigra 82

. Dorsally the STN is limited by the fasciculus lenticularis and zona

incerta. The volume of the STN is approximately 175 mm3

in humans (Levesque, 2005).

Figure 2 Coronal brain section representing the major anatomical structures and fibre tracts

associated with the subthalamic nucleus

AL = ansa lenticularis; CP = cerebral peduncle; FF = Fields of Forel; GPe = globus pallidus externus; GPi =globus pallidus internus; H1 = H1 Field of Forel (thalamic fasciculus); IC = internal capsule; LF = lenticularfasciculus (H2); PPN = pedunculopontine nucleus; Put = putamen; SN = substantia nigra; STN = subthala-mic nucleus; Thal = thalamus; ZI = zona incerta.

From: Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano AM. The subthalamic nucleus in the context of movementdisorders. Brain 2004;127:4-20. By permission of Oxford University Press.

Functionally the STN is subdivided into a limbic and associative part (the medial por-

tion of the rostral two-thirds) and a portion related to motor circuits (dorsal part of the

lateral portion of the rostral two-thirds) within the basal ganglia 83

. Most of the cortical

afferents to the STN arise from the primary motor cortex, (pre-) supplementary motor

area and the dorsal and ventral pre-motor cortices and predominately innervate the

dorsal part. The ventromedial portion of the STN receives afferents from the frontal

eye field (area 8) and the supplementary frontal eye field 82

. However, its major affe-

rents comprises the projection from the external pallidum, and, to a lesser extent, tha-

lamus (parafascicular and centromedian nuclei) and brainstem (substantia nigra,

pedunculopontine nucleus, tegmental nuclei, dorsal raphe nucleus). The major effe-

rent projections from the STN are mainly directed to both segments of the globus pal-

lidus, substantia nigra and striatum. The STN innervates both components of the sub-

stantia nigra: although most fibers innervate the SNpr, some ascend and reach the

SNpc, comprising one mechanism responsible for the regulation of dopamine release84

.

The main excitatory drive to the STN is provided by excitatory amino acids, and

NMDA and AMPA receptors have been described in STN neurons 85

. It is believed that

these multiple glutamate receptor subtypes mediate a complex signalling pathway in

the STN 86

. GABAergic activity also has a major role in aspects of STN physiology by

modulating its firing rate and pattern of neuronal activity. The impact of GABA on the

STN is related to the initial membrane potential of the cells, which is strongly dictated

by pallidal afferents 86

. It is estimated that in vivo 55-65 % of the STN neurons fire irre-

gularly, whereas 15-25 % fire regularly and 15-50 % present bursting activity in non-

human primates, and the average firing rate of STN neurons is 18-25 Hz 87;88

. 30-50 %

of STN neurons are related to movement, and most of them are localised in the dorsal

half of the nucleus and are activated by passive or active movement of contralateral

joints 87

. In addition, 20 % of the neurons are responsive to eye fixation or visual sti-

muli, and these are primarily found in the ventral STN 89

. The STN is currently thought

to play a prominent role in the pathophysiology of PD 63

. Metabolic, electrophysiolo-

gical and behavioural studies performed mainly in the MPTP monkey model of PD

revealed an increase in neuronal activity of the STN and its main output basal ganglia

nuclei. In the current model of the basal ganglia in PD, STN hyperactivity has been

attributed to the underactivation of the globus pallidus externus (GPe) due to abnor-

malities in the indirect pathway elicited by dopamine depletion in the striatum.

However, recent studies suggest that other brain regions, e.g. the cerebral cortex and

thalamus, may also be responsible for increased STN activity in PD 90

. The pathologi-

cal STN drive thereby modifies the overall activity in output structures like SNr, GPi,

GPe and PPN, and disrupts the normal physiology of the basal ganglia. In the SNpc,

STN glutamatergic overactivity is predicted to enhance bursting activity and increa-

ses the release of dopamine. Although this has been considered an initial compensa-

tory mechanism after dopamine depletion, this excessive glutamate release may lead

to excitotoxic damage within the SNpc and could promote a further loss of dopami-

nergic neurons91

.

14

Chapter 1

15


B. Chronic bilateral STN-DBS

Limousin et al were the first to describe the clinical efficacy of bilateral STN-DBS in 3

advanced PD patients, suffering from unpredictable motor fluctuations 78

. At 3 months

follow up, the UPDRS motor subscore (part III) in off-medication condition had

improved by 84 %, 75 % and 42 % respectively. The individual levodopa dosage could

be reduced by 50 % and 40 % in the first 2 patients, and was withdrawn in the third in

the following months postoperatively. They subsequently extended their data set and

in 1998 published the results of bilateral STN-DBS in 24 patients with advanced PD,

suffering from disabling motor fluctuations 92

. After 1 year of STN-DBS the motor

scores (as examined by the UPDRS part III in off- medication condition) improved by

60 %, including subscores on akinesia, tremor, rigidity and gait. The mean dosage of

dopaminergic drugs was reduced by half, and, consequently, levodopa induced dys-

kinesia significantly diminished. On average, neuropsychological assessment showed

no change after surgery, despite worsening of cognitive impairment in 1 patient. The

most serious adverse event was an intracerebral hematoma (1 patient) and a subcuta-

neous infection developed at the site of the extension lead in 1 patient. In 8 patients

transient adverse effects on mental status (hallucinations, confusion) developed after

surgery, which lasted for a maximum of 2 weeks.

Since then several institutions published their beneficial results on bilateral STN-DBS

in PD, of which the main results are emphasised in table 2.

It can be concluded that bilateral STN-DBS substantially improves all levodopa

responsive PD motor features significantly 93

up to (at least) 5 years after surgery 94

.

Since STN-DBS mimicks the effect of levodopa 95

, it allows dopaminergic therapy to be

(partially) discontinued postsurgically. All studies have shown a significant improve-

ment of time spent with disabling dyskinesia or diminishing of severity of dyskinesia93

.

In addition, the improvement in on-period dyskinesia might be mainly due to this

decrease in levodopa daily dose 96

, although a specific effect of stimulation on motor

fluctuations itself is also argued 93

. Since DBS is an elective procedure, the disability of

the patient must be profound to justify the risk of surgery (permanent morbidity and

mortality of STN-DBS: 1-3 %) 93

. Most important side effects of the STN-DBS procedure

are mild and transient, and consist of direct surgical complications (e.g. asymptomatic

intracerebral bleeding detected on MRI, wound healing problems) or postoperative

confusion 94

. Persistent body weight gain has consistenly been reported after STN-

DBS97

, and in some patients the procedure can induce cognitive decline 98

or behaviou-

ral changes 99-101

. The latter is probably caused by direct stimulation effects of DBS on

the STN or its adjacent structures, which have strong connections with limbic struc-

tures 102

. As a result, demented patients and patients suffering from depression or le-

vodopa-induced psychosis are considered not to be suitable candidates for STN-DBS,

although clear-cut studies are lacking 93

.

16

Chapter 1

Finally, there is much debate about as to how STN-DBS exerts its efficacy. The imme-

diate reduction of patients’ rigor and rest tremor is believed to result from a depola-

rization block of the neurons surrounding the electrode tip or from a disruption of

pathologically synchronised neural firing pattern by additional high-frequent stimuli

(neural jamming)80

. In contrast, the amelioration of akinesia and the induction of dys-

kinesia by STN-DBS takes minutes up to hours or even weeks to occur. This observa-

tion, as well as the clinicial experience that motor improvement achieved by STN-DBS

resembles those achieved after levodopa, raised questions about a delayed increase of

striatal dopaminergic transmission following DBS. In addition, the area encompassing

the dorsal STN and the axons dorsal to the STN seems the most effective target for the

amelioration of PD symptoms after successful STN-DBS 103

. Since the nigrostriatal tract

Authors Patients Follow up* UPDRS III-off#

Medication+

Limousin (1998), Grenoble 24 12 60 50

Moro (1999), Rome 7 16 42 65

Kleiner (1999), Toronto 25 24 48 38

Houeto (2000), Paris 23 6 67 61

Rodriquez (2000), Pamplona 15 12 74 55

Molinuevo (2000), Barcelona 15 6 66 80

Volkmann (2001), Düsseldorf 16 12 60 65

Obeso (2001), multi center 96 3 49 47

Vingerhoets (2002), Lausanne 20 21 45 79

Østergaard (2002), Aarhus 26 12 64 22

Thobois (2002), Lyon 18 6 55 66

Herzog (2003), Kiel 48 6 51 49

Krack (2003), Grenoble 49 60 54 63

Esselink (2004), Amsterdam 34 6 59 33

Ford (2004), New York 30 12 29.5 30

* in months# reduction in % (in off- medication on-stimulation condition) of pre-operative score+ reduction in % of pre-operative dopaminergic therapy

Table 2 The efficacy of STN-DBS in PD

17


runs in close apposition to this dorsal surface of the STN, it also is subject to the effects

of DBS. It is hypothized that one possible effect of DBS could be the activation of those

nigrostriatal axons arising from the SNpc, with the release of endogenous dopamine

in the striatum 104

. However, recent Positron Emission Studies successively failed to

show a substantial increase of striatal dopamine release after STN-DBS in PD 104-106

.

IV Neuroprotective, neurorestaurative and neuroregenerative therapy

In the absence of an identified biological marker in sporadic PD, prevention of dopa-

minergic cell decline is aimed at slowing, stopping or reversing neuronal death 37

. It is

obvious that any neuroprotective therapy for PD should ideally be introduced before

the onset of clinical manifestation, or at least as soon as possible when clinical features

of PD become manifest.

The first drugs to be studied in PD were antioxidants. In 1993 the DATATOP study

evaluated the antioxidant vitamin E and the MAO-B inhibitor deprenyl as putative

neuroprotective therapy in PD 107

. While no beneficial effect of vitamin E was detected,

deprenyl seemed to slow disease progression. However, since deprenyl also exerted

symptomatic efficacy, interpretation of the study results seemed confounded; subse-

quently, an additional study on deprenyl versus placebo showed confounding results

too108

. In a double-blind placebo-controlled pilot study coenzyme Q10 (an enhancer of

ATP production and antioxidant) was studied as a putative neuroprotective agent in

PD in 2002 109

. Although a reduced rate of deterioration of patients’ motor function du-

ring the study course was noticed, again an unexpected symptomatic effect of the drug

confounded study interpretation. Dopamine agonists also exhibit neuroprotective

potency as antioxidants, and in addition decrease dopamine turnover and thereby

reduce the generation of free radicals. In laboratory studies dopamine agonists pro-

tected dopaminergic and nondopaminergic neurons from toxins in PD models 110

.

Thus far 2 neuroimaging studies (CALM-PD and REAL-PET) on 2 dopamine agonists

(pramipexole and ropinirole) have been performed testing the capacity of these ago-

nists to modify disease progression in PD 111;112

. Both studies demonstrated that

dopamine agonists were associated with a significant delay in the rate of tracer uptake

decline, but, however, neither study showed a corresponding clinical benefit. Also

pharmacological differences in the capacity of these drugs to regulate neuroimaging

tracer dynamics have made the interpretation of study results controversial 113

.

The first promising attempt to treat PD patients by use of cell transplantation in 1985

involved striatal infusion of autologous adrenal medullary cells 114

. However, later stu-

dies showed poor results with no improvement in patients’ motor disability 115;116

.

Following several unblinded but promising case series of human foetal cell transplan-

tation, in 2001 Freed published results on fetal nigral cell transplantation versus sham

surgery in 40 PD patients 117

. Again, no significant improvement was established,

although younger patients showed a small benefit. A double-blind controlled trial of

18

Chapter 1

bilateral fetal nigral transplantation in PD by Olanow 118

in 2003 showed similar disap-

pointing results. A small, unblinded study using xenogenic neural transplants of

embryonic porcine ventral mesencephalic cells in PD showed small motor benefit in

study patients 119

. Controlled trials with larger graft doses are needed to assess this pro-

cedure’s efficacy in the future. Studies on embryonic-stem-cell transplantation are in

the early stages of development.

The use of neural trophic factors has been proposed as a method of promoting the

restauration and maintenance of degenerating dopaminergic cells. A large double-

blind, placebo controlled trial of intraventricular infusion of glial-cell-derived neu-

rotrophic factor showed no benefit at 8 months follow-up 120

. However, since autopsy

results suggested that the neurotrophic factor had not reached the target area in this

study, direct infusion of glial-cell derived neurotrophic factor into the putamen

showed indeed a modest motor benefit in patients in another study 121

. Recently a ran-

domised, double blind, placebo-controlled phase II study has been stopped because of

lack of efficacy (Amgen Inc., 2004).

C STN-mediated excitotoxicity in PD: a target for neuroprotection

I Introduction

Essential to the concept that the STN might contribute to neurodegeneration in PD is

the existence of a glutamatergic pathway between the STN and the SNpc. Anatomical

studies clearly demonstrated these glutamatergic projection in several animal models

of PD 122

. In addition, electrophysiologic studies confirm that the STN exerts an excita-

tory effect on dopamine neurons in the SNpc, which is mediated by glutamate acting

on NMDA receptors 123

. Theoretically, increased STN activity in PD may result from

reduced inhibition, increased excitation or both. It is believed that a loss of inhibitory

drive of the external pallidum (GPe), secondary to dopamine depletion, to the STN is

the major mechanism responsible for excess firing of the STN in PD 124

. Because STN

neurons use glutamate as a neurotransmitter, there is reason for concern that excess

neuronal firing in the STN might lead to excitotoxic damage in its target structures,

especially the SNpc. Although the precise molecular mechanisms involved in this pro-

ces are unresolved, excitotoxicity primarily involves an NMDA-mediated rise in in-

tracellular Ca2+ 125

. In normal neurons there is an ATP-dependent Mg2+

blockade of

NMDA channels. As a result, physiologic concentrations of glutamate do not excessi-

vely activate NMDA receptors or promote calcium influx. However, in PD the release

of high concentrations of glutamate could overcome this blockade and stimulate

NMDA receptors inducing an alteration in calcium influx. In addition, a bioenergetic

cellular defect due to primary mitochondrial (complex I) dysfunction 126

in PD results

in a loss of the voltage dependant Mg blockade of NMDA receptors and permits even

physiologic concentrations of glutamate to induce excitotoxicity 127

. Finally, lesions of

19


the STN have shown to be neuroprotective in several experimental models of PD.

Piallet et al (1996) showed that chemical ablation of the STN prevented dopaminergic

nigral degeneration in 6-OHDA lesioned rats 128

. In their study the number of tyrosine

hydroxylase-immunoreactive cells in the SNpc was not significantly different on the

STN-lesioned side compared to the control side. In 1999, Nakao et al showed an atte-

nuated progressive loss of nigral TH-positive neurons after chemical STN ablation in

3- nitropropionic lesioned rats 129

.

II The excitotoxic hypothesis in PD

Rodriquez et al speculated that the STN plays a major role in the pathogenesis of PD

according to the following sequence of events 124

:

1. An inherited or acquired mitochondrial defect and / or oxidant stress make

dopaminergic SNpc neurons susceptible to noxious stimuli and vulnerable to

degeneration or even apoptosis; as a result a small portion of these cell actually

degenerate

2. The loss of dopaminergic neurons causes a reduction in striatal dopamine, which

results in a reduced dopaminergic inhibition of D2 striatal neurons, increased inhi-

bition of the GPe, and finally disinhibition of the STN, with increased activity in

excitatory STN neurons

3. Enhanced STN neuronal firing produces excessive glutamate release in the SNpc

4. Increased glutamate release in the SNpc leads to a further loss of dopaminergic

neurons and reduction in striatal dopamine

5. Increased degeneration of SNpc neurons and dopamine depletion induces further

disinhibition of the STN

6. Finally, a vicious cycle is created in which dopamine neuronal degeneration in the

SNpc leads to further STN disinhibition, and STN overactivity leads to excitotoxic

damage in remaining SNpc neurons

7. When degeneration of SNpc neurons and loss of striatal dopamine reach a critical

level, the signs and symptoms of PD emerge

This hypothetic model illustrates how disinhibition of the STN and resultant exci-

totoxicity could contribute to the neurodegenerative process in PD, regardless of

the specific, and yet unknown, etiology. A consequence of this hypothesis is the aim

of providing a neuroprotective therapy in PD that slows the rate of disease progres-

sion by reducing STN overactivity. Since it is estimated that approximately 30-50 %

of dopamine neurons already have degenerated by the time the first signs and

symptoms of PD appear 130

, any “protective” treatment should be introduced as

early as possible in the course of the disease. Theoretically, such a treatment could

involve dopamine agonists (by restoring dopaminergic tone), agents that inhibit

glutamate release, selective NMDA receptor antagonists (to block glutamate

release) and surgical interventions that inhibit neuronal firing of the STN.

20

Chapter 1

Since all pharmacological therapies thus far have failed to show a neuroprotective

effect in PD in vivo, surgical treatments that inhibit STN firing represent an addi-

tional and promising option to attenuate progressive dopaminergic cell decline. In

addition, the clinical introduction of DBS of the STN in PD has yet provided an

opportunity to functionally inhibit the STN.

D FDOPA-PET and M. Parkinson

I Positron Emission Tomography

Positron Emission Tomography (PET) is an imaging method used to track the regio-

nal distribution and kinetics of chemical compounds labelled with short-lived-

positron-emitting isotopes in the living body 131

. Positron imaging was initially sug-

gested by Wrenn et al in 1951 132

. At that time, cyclotrons became available for the pro-

duction of short-lived radioisotopes and initial studies with carbon-11 (11

C), nitrogen-

13 (13

N) and fluorine-18 (18

F) were performed. PET studies are carried out by admini-

stering a tracer labelled with a positron-emitting isotope with a short half-life genera-

ted by a cyclotron. The tomographic image in PET is formed by recording of two 511

keV photons emitted in positron decay with a circumferential array of radiation detec-

tors. Since these photons are simultaneously emitted 1800

apart, a special coincidence

technique is used to define the origin of emission. These data are processed through a

conventional reconstruction algorithm to form the tomographic images of the tracer

concentration in tissue. While the first PET scanner (PETT II) provided a single tomo-

graphic image plane with restricted spatial resolution, modern scanners have multiple

rings of detectors to allow the simultaneous collection of multiple planes of imaging133

.

In addition to conventional datasets of regional tracer uptake collected in two-dimen-

sional (2-D) mode, nowadays software is available allowing PET data to be acquired in

a 3-D mode, which have led to a further increase in spatial resolution 134

.

The integrity of the presynaptic nigrostriatal dopaminergic projection can be studied

in vivo with radiotracers whose striatal uptake reflects a measure of structural as well

as the biochemical integrity of the dopaminergic nerve terminals (FDOPA) or

dopamine transporter density (FP-CIT, β-CIT) 135

.

II FDOPA-PET

PET was the first technology that enabled direct measurement of components of the

dopamine system in the living human brain 131

. In 1983 Garnett et al reported on the

successful application of 6-[18

F]fluoro-L-3, 4-dihydroxyphenylalanine (FDOPA) for

PET studies of nigrostriatal dopaminergic neurons in living man136

, while in 1986

Leenders et al administered FDOPA in trace amounts to healthy controls and PD

patients 137

.

21


Since then FDOPA-PET has provided an objective means of assessing the functional

integrity of the presynaptic nigrostriatal dopaminergic projections in vivo 138

. It esti-

mates the rate of enzymatic decarboxylation of FDOPA to 18

F-dopamine as well as its

storage in dopaminergic nerve terminals. Although striatal FDOPA uptake is not a

measurement of endogenous dopamine synthesis, it is highly correlated with

dopamine cell counts measured in post mortem specimens 139

. FDOPA-PET can sensi-

tively discriminate PD from normal populations, and several studies reported a

marked decrement of striatal FDOPA uptake in PD, which is specifically more pro-

nounced in the putamen than in the caudate 20;140

. Various studies have demonstrated

that specific FDOPA uptake in the putamen of PD patients is on average 40 % of con-

trol values and in caudate 60 % 141

. In early PD these values can be considerably high-

er and for caudate will often be normal. At very late stages of the disease a 60-70 % or

more drop in striatal uptake in PD may be observed, caudate being less severely affec-

ted than putamen with however a significant uptake decrement in advanced stages of

the disease. Initially, FDOPA-PET has also been used to differentiate among parkin-

sonian syndromes (e.g. Multi System Atrophy, Progressive Supranuclear Palsy).

Subsequent studies have shown that differences on the presynaptic dopaminergic

level are not sufficiently precise to categorise individual cases of disease 138

.

III FDOPA-PET studies on the rate of PD progression

FDOPA-PET provides a potential means of objectively monitoring disease progression

in PD. The first reported PET study was by Bhatt (1991) who measured striatal FDOPA

uptake on 2 occasions over 3 years in groups of 9 PD patients and 7 normal subjects 142

.

The mean interval between the scans was 3.3 years for the group with idiopathic

parkinsonism and 3.9 years for the control subjects. Both groups showed a statistical-

ly significant 5 % reduction of striatal FDOPA uptake over the study interval and the

rate of decrease was almost identical in each group. They inferred that the usual rate

of loss of integrity of the dopaminergic nigrostriatal pathway in PD patients was slow

and the rate of change between the two groups was comparable. A follow-up study

was performed by Vingerhoets et al 143

. They performed FDOPA-PET on two occasions,

7 years apart, on 16 patients with PD (mean age 51 years, mean disease duration 4.5

years) and 10 normal controls (mean age 54 years). Their PET index ((striatal-occipi-

tal)/occipital ratio) dropped by 1.7 % per year versus the normals’ ratio 0.3 %, and in

addition the ratios in the PD group progressed significantly faster than the controls.

However, one problem with the interpretation of study results was that large whole

striatal Regions Of Interest were employed to analyse disease progression whereas the

PD pathology primarily targets dopamine storage in the putamen only.

Morrish et al, using an FDOPA influx constant (Ki), studied PD disease progression in

a group of 10 patients with recent onset PD (mean age 53.7 years, mean disease dura-

tion 18 months), and a group of seven patients with established PD (mean age 60 years,

22

Chapter 1

mean disease duration 71 months), using both clinical assessment and FDOPA-PET 144

.

Results were compared with those of a group of 10 normal subjects (mean age 66

years). The mean annual rate of reduction in mean putamen Ki in the PD patients was

12.5% per annum, whereas the control group showed no significant change in Ki over

a mean of 32 months follow up. The rate of progression was more rapid in the recent

onset compared with the established disease group but this did not reach statistical

significance. Assuming a linear progression for the entire group they additionally esti-

mated PD symptom onset with a mean preclinical period of 3.1 years. They successive-

ly extended their study in 1998 on 32 PD patients with PD (mean age 58 years, mean

disease duration 39 months) using graphical (Ki) and ratio methods of analysis 145

. The

mean annual rate of deterioration in specific putamen FDOPA uptake was 9 % from

baseline scan (or 4.7% of normal mean). Extrapolation of these data suggested that

symptom onset occurred after a 30 % loss of dopaminergic terminal function and the

estimated preclinical window was estimated to be 6 ± 3 years.

Finally, in 2001 Nurmi et al investigated the rate of progression in PD using FDOPA-

PET in 21 PD patients 146

. FDOPA-PET was carried out twice at an approximately 5-

year interval. The FDOPA uptake declined by the time of the second PET scan and the

calculated annual rate of decline was 8.3 % of the baseline mean in the anterior puta-

men, and 10.3 % in the posterior putamen. In the caudate nucleus, FDOPA uptake

decreased by 5.9 % of the baseline mean per year. They successively estimated the pre-

clinical PD period being longest for the posterior putamen (6.5 years). In healthy con-

trols no significant decline in FDOPA uptake in any striatal subregion was established.

23


Aims of the thesis

Since glutamate-mediated excitotoxicity is suggested to contribute to nigrostriatal

degeneration in PD, the clinical introduction of STN-DBS in PD provided an opportu-

nity to functionally inhibit STN activity and therefore decrease disease progression.

The primary aim of this thesis was to prospectively determine disease progression in

a population of PD patients after STN-DBS by means of repetitive FDOPA-PET. Is

STN-DBS really “neuroprotective” in PD?

In addition, we studied the clinical efficacy of STN-DBS on motor features in PD. Does

STN-DBS “work” in our own PD study population?

We also investigated the nature of the relationship between striatal dopamine deple-

tion and cognitive functioning in PD. Does FDOPA-PET reveal the nature of basal gan-

glia dysfunction in patients’ cognitive impairment?

Finally, we sought to determine the predictive value of the patients’ presurgical nigro-

striatal status on motor efficacy of STN-DBS in PD using FDOPA-PET. Is the nigrostri-

atal dopaminergic deficit in PD related to surgical outcome?

24

Chapter 1

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Chapter 2

Study design and patient population

33

Study patient recruitment

All patients were recruited from our outpatients’ Movement Disorder Unit of the University

Medical Center Groningen (UMCG) between 1999 and 2003. All patients were selected from

an existing population of PD patients, who on clinical criteria already were selected for bilate-

ral DBS of the STN (or thalamus-DBS, see chapter 4). In 2004 the study results concerning PD

progression after STN-DBS (see chapter 5) were combined with the study data of the Medical

University of Cologne (dr. R. Hilker).

Patients eligible for functional stereotactic surgery had to satisfy the following preoperative

inclusion criteria, according to the Core Assessment Program for Surgical Interventional

Therapies in Parkinson’s Disease (CAPSIT-PD; Defer et al, 1999):

1. Preoperative dopaminergic responsiveness confirmed by a pharmacological test (levodopa

“challenge”) which should induce at least a 30 % decrease in the Unified Parkinson’s

Disease Rating Scale (UPDRS) part III score

2. At least bradykinesia or resting tremor as a prominent clinical sign

3. No depression (Montgomery and Asberg Depression Rating Scale, score < 19) or recent

psychiatric illness

4. No dementia (Mattis Dementia Rating Scale, score > 130)

Exclusion criteria were:

- Abnormalities on cerebral Magnetic Resonance Imaging (MRI) suggestive of atypical

parkinsonism, nor prominent cortical atrophy or extensive white matter lesions

- Any clinical suggestion of atypical parkinsonism (e.g. Progressive Supranuclear Palsy,

Multiple System Atrophy)

- Parkinsonism due to trauma, brain tumour, cerebrovascular disease, or due to the intake of

anti-dopaminergic drugs or other known chemicals or toxins

Neurosurgical and clinical procedure

In all patients stereotactic surgery was performed by the same neurosurgeon following proto-

collar procedures. All peroperative semi-micro electrode recording was performed by the same

neurophysiologist. All peroperative- and postoperative clinical assessments and DBS adjust-

ments were performed by the neurologists involved in the studies.

Diagnostic evaluation and collection of clinical data

All patients were clinically evaluated during a short hospitalisation at the Neurology

Department, according to the CAPSIT-PD recommendations and time schedule: 3-6 months

before planned stereotactic surgery, and 6, 12 and (for a smaller part of the study population)

24 months after surgery.

Chapter 2

34

Motor assessment

The following assessments were obtained in the medication-off / medication-on condition, and

in stimulator-on condition after surgery, and presented in the studies:

1 Unified Parkinson’s Disease Rating Scale part III (Motor Examination) (see appendix 1)

2 Modified Hoehn & Yahr Staging (see appendix 2)

3 Schwab and England Activities of Daily Living Scale (see appendix 3)

4 Clinical Dyskinesia Rating Scale (see appendix 4)

All patients (and family members or caretakers) were instructed in the identification of the 4

different patient diary motor states.

Neuropsychological assessment

All tests were performed in the medication-on condition, and in stimulator-on condition after

surgery, at the UMCG Neuropsychological Department. Assessments were performed accor-

ding to CAPSIT-PD recommendations. They consisted of:

1 Montgomery and Asberg Depression Rating Scale

2 Mattis Dementia Rating Scale

3 Dutch Adult Reading Test

4 Groningen Intelligence Test

5 Alternating Category Fluency

6 Alternating Letter Fluency

7 Boston Naming Test

8 Dutch Verbal Learning Test

9 Trailmaking Test

10 Stroop Color Word Test

11 Odd Man Out Test

12 Paced Auditory Serial Addition Task 3.2 and 2.8

In addition, both the patient and a close relative completed questionnaires on memory com-

plaints and cognitive dysexecutive problems.

PET Assessment

FDOPA-PET data acquisition was performed at the UMCG PET Center at (approximately) 3-6

months before planned surgery (baseline PET), and follow-up scans were performed 12-24

months after surgery in the stimulator (DBS)-on condition, following a “stereotactic” scanning

protocol. PET data analysis was performed by the same rater, who was unaware of the clinical

condition of all patients, and following a standardised protocol.

Study design and patient population

35

Chapter 2

36

Chapter 3

Chronic stimulation of the subthalamic nucleus increases daily on-time without dyskinesia in advanced Parkinson’s Disease

Portman AT1

, van Laar T1

, Staal MJ2

, Rutgers W3

, Journee HL2

, Leenders KL1

1 Department of Neurology, University Medical Center, Groningen,

the Netherlands

2 Department of Neurosurgery, University Medical Center, Groningen,

the Netherlands

3 Department of Neurology, Martini Ziekenhuis, Groningen, the Netherlands

Accepted for Parkinsonism & Related Disorders

37

Abstract

We assessed the efficacy of chronic stimulation of the subthalamic nucleus (STN-DBS)

in 20 patients with Parkinson’s Disease (PD) by means of clinical assessments and

patient diaries 12 months after surgery.

STN-DBS reduced the UPDRS part III off-medication score by 33 %, and successively

improved complete daily on-time without dyskinesia at 12 months significantly.

In conclusion, our study demonstrates the efficacy of chronic STN-DBS on motor fea-

tures in a selected population of advanced PD patients. In addition to clinical assess-

ments, patients’ diaries serve as an essential tool to evaluate the functional motor sta-

tus after STN-DBS.

Chapter 3

38

Introduction

Since lesioning and high-frequency Deep Brain Stimulation of the subthalamic nucle-

us (STN-DBS) in animal models of Parkinson’s disease (PD) gave rise to marked

improvement of parkinsonian motor features 1

, STN-DBS in PD patients has been

applied successfully to this target worldwide.

In 1995 the first PD patients having bilateral STN-DBS were described 2

, and currently

bilateral STN-DBS is considered the most effective surgical treatment for PD patients

suffering from severe motor fluctuations after long-term medical treatment 3-5

.

To date the efficacy of STN-DBS in PD is almost exclusively estimated by means of

clinical assessed rating scales. This approach, however, does not yield information

about its effect on the patients’ number of daily motor fluctuations and dyskinesia or

time spent in various conditions after surgery. Patient diaries are capable of differenti-

ating between various motor conditions 6

, and therefore are strongly recommended by

The Core Assessment Program for Surgical Interventional Therapies in Parkinson’s

Disease (CAPSIT-PD) 7

. However, patient self-reporting data after surgery (and espe-

cially STN-DBS) in PD are rare.

We studied the clinical results of all patients with advanced PD (n = 20) who under-

went bilateral STN-DBS between 1999 and 2003, with a postsurgical follow-up period

of 12 months. In addition to clinical rating scales we used patient diaries to assess the

efficacy of STN-DBS on daily motor performance.

39

Chronic stimulation of the subthalamic nucleus increases daily on-time

without dyskinesia in advanced Parkinson’s Disease

Chapter 3

40

Methods

Patients

Between October 1999 and January 2003 20 patients were treated by bilateral STN-

DBS. The patients were recruited from the Movement Disorder Unit of our outpa-

tients’ clinic. All patients (9 men and 11 women, mean age 59 ± 7 years, mean disease

duration 13 ± 5 years) showed at least 30 % improvement of the motor part (III) of the

Unified Parkinson’s Disease Rating Scale (UPDRS) 8

after L-dopa. All patients suffered

from severe intractable motor fluctuations and dyskinesia, despite optimal antiparkin-

sonian pharmacotherapy. The age, disease duration, UPDRS part III score, levodopa

equivalent daily dose (LEDD 9

) and the antiparkinsonian medication of all study

patients are summarised in table 1. Additional in- and exclusion criteria for surgery

were: no depression (Montgomery and Asberg Depression Rating Scale, score < 19),

no dementia (Mattis Dementia Rating Scale, score > 130), abnormalities on cerebral

MRI like severe brain atrophy, extensive white matter lesions or no abnormalities sug-

gestive of atypical parkinsonism, and no recent psychiatric illness or restricted physi-

cal condition for surgery. One patient (male, 59 years) who initially was selected for

STN-DBS, was finally excluded for surgery because of dementia.

All patients gave their informed consent prior to study inclusion.

Surgery and peroperative assessment

Before surgery all antiparkinsonian medication was withdrawn overnight. All

patients, except for the first 2, had surgery in the supine position by the same neuro-

surgeon (MJS). A 3D-volume T1-weighted MRI scan (Siemens Sonata Vision, 1 ½ Tesla)

was performed with the Leksell G frame in place, generating 2 mm-slices, which were

transferred subsequently into a computerised planning system (@Target BrainLAB).

These images were then fused with a preoperative MRI T2-weighted scan and after

depiction of the AC-PC line the STN Talairach coordinates were determined by direct

visualisation of the STN in anatomical reference to well known anatomical landmarks.

The targeting was completed using semi-micro electrode (SME) recording in combina-

tion with macro-stimulation and assessment of the clinical effect. Finally, the SME was

replaced by a quadripolar lead (Medtronic, type 3389, containing 4 electrode contacts

over a length of 7,5 mm) on both sides. Postoperatively the position of the lead was

verified by skull X-ray and T2-weighted MRI, and additionally the MRI images were

fused with the target planning MRI. Additionally the patients’ peroperative clinical

response was reproduced through external STN-stimulation a few days afterwards.

One week later a programmable pulse generator (Medtronic, Kinetra) was implanted

in a subclavicular subcutaneous pocket and connected with the DBS leads by two

extension wires. Finally, dopaminergic therapy and DBS stimulation parameters were

gradually adjusted by the investigators based on the patients’ clinical response.

41



Preoperative and 12 month follow-up evaluations

Clinical assessments were performed at baseline (3 months before planned surgery)

and 12 months after surgery. Antiparkinsonian medication was kept unchanged du-

ring a period of 2 weeks prior to the clinical assessments. Clinical rating scales consis-

ted of the UPDRS part III, including the subscores speech (item 18, range 0-4), tremor

(items 20 + 21, range 0-8), rigidity over all extremities and neck (item 22, range 0-20),

bradykinesia (items 23, 24, 25, 26, 31, range 0-20) and gait (item 29, range 0-4), UPDRS

part VI 8

(Schwab & England Activities of Daily Living (ADL) Scale, range 0-100 %)

and the Clinical Dyskinesia Rating Scale 7

(CDRS, range 0-28). All scores were assessed

in the off-medication condition (after withholding regular antiparkinsonian medica-

tion for at least 12 hours overnight) and in the on-medication condition (1 ½ hour after

regular, postponed, early morning levodopa dosage) on the same morning. All

patients completed a home diary (as recommended by CAPSIT-PD) documenting their

motor status at 30-minute intervals during the week before each clinical assessment.

Before the beginning of the study, all patients were instructed in the identification of 4

motor states; no or worst mobility (“complete off”), moderate mobility (“partial off”),

good mobility without dyskinesia (“complete on”) and mobility with dyskinesia (“on

with dyskinesia”). After implantation of the DBS device all scores were assessed in the

sti-mulator-on condition.

The Wilcoxon Signed Ranks test was applied for post-hoc comparisons of clinical and

diary baseline data vs. 12-month data. Since multiple analyses over time were conduc-

ted, a p-value of 0.005 was considered to indicate statistical significance using the

Bonferroni correction method. A univariate analysis (Spearman’s nonparametric rank

correlation) was performed to correlate clinical and diary data. All analyses were per-

formed using SPSS 10.0 software.

Results

Stimulation parameters

The best clinical results at 12 months were achieved by bilateral monopolar stimulati-

on in 15 patients, while 3 patients had monopolar/bipolar, 1 patient had unilateral

bipolar and 1 patient had bilateral bipolar stimulation. The median frequency of sti-

mulation was 135 Hz, the pulsewidth 60 µsec, and the mean voltage 2.49 ± 0.74 (range:

1.00-3.00) V.

Clinical assessments

At 12 months after STN-DBS the off-medication motor score (UPDRS part III) (31 ± 15)

on part III of the UPDRS significantly improved by 33 % (p = 0.0001), while the on-

medication motor score slightly, but not significant, improved (23 ± 7 vs. 20 ± 9, p =

0.104). In addition, the off-medication motor subscores on tremor (-64 %, p = 0.004),

bradykinesia (-28 %, p = 0.002), and rigidity (-42 %, p = 0.001) all improved significant-

ly. In contrast, speech (+ 8 %, p = 0.366) did not change significantly after surgery,

Chapter 3

42

Pat

ients

Age

(yea

rs)

Dis

ease

du

rati

on

(yea

rs)

UP

DR

S p

art

III

(off

)L

R#

Tre

atm

ent

(LE

DD

)*

Co

mp

osi

tio

n

1

48

12

35

40

3

00

0

D, P

, A

2

48

14

49

42

5

50

D

, R

3

63

22

32

62

1

39

0

D, B

, P

r, S

, A

4

52

18

34

67

1

09

0

D, P

5

62

8

46

50

2

09

0

D, R

6

67

7

35

31

6

00

D

, P

r

7

56

13

55

43

6

70

D

, P

, S

8

69

13

38

57

4

25

D

, P

9

61

13

54

59

1

42

3

D

10

48

6

26

31

1

11

0

D, P

r

11

52

14

60

45

1

15

5

D, P

, A

12

64

14

59

54

5

50

D

, R

, B

i

Ta

ble

1 S

tud

y p

ati

ent

chara

cter

isti

cs

43



Pat

ients

Age

(yea

rs)

Dis

ease

du

rati

on

(yea

rs)

UP

DR

S p

art

III

(off

)L

R#

Tre

atm

ent

(LE

DD

)*

Co

mp

osi

tio

n

13

62

15

74

5

2

16

80

D

, R

, E

14

51

14

66

6

0

13

75

D

, P

r, A

15

68

19

66

4

8

65

0

D, P

16

54

13

30

3

6

25

25

D

, P

, E

17

67

10

28

5

3

15

60

D

, P

, E

, A

18

63

17

45

3

7

98

0

D, R

, S

19

67

17

50

6

4

10

25

D

, E

20

67

17

45

3

1

10

00

D

, R

, E

, B

i

mean

±S

D59 ±

7

13 ±

5

46

± 1

4

48

± 1

1

12

42

± 6

78

# l

evo

do

pa

resp

on

siv

enes

s =

(p

reo

per

ativ

e U

PD

RS

par

t II

I sc

ore

wh

ile

off

med

icat

ion -

pre

oper

ativ

e U

PD

RS

par

t II

I sc

ore

whil

e on-m

edic

atio

n)

/ pre

oper

ativ

e

UP

DR

S p

art

III

sco

re w

hil

e o

ff m

edic

atio

n (

in %

)

*le

vodopa

equiv

alen

t dai

ly d

ose

= l

evodopa

dose

(100 m

g)

x 1

(ad

ded

wit

h 0

.2 x

lev

odopa

dose

if

usi

ng e

nta

capone

wit

h e

ach d

ose

) +

(sl

ow

rel

ease

lev

odopa

x

0.7

5)

+ b

rom

ocr

ipti

ne

x 1

0 +

ropin

irole

x 2

0 +

per

goli

de

x 1

00 +

pra

mip

exole

x 1

00

Ab

bre

viati

ons:

D =

dopam

ine,

P=

per

goli

de,

R =

ropin

irole

, P

r =

pra

mip

exole

, B

= b

rom

ocr

ipti

ne,

S =

sel

egel

ine,

A=

am

anta

din

e, E

= e

nta

capone,

Bi

= b

ipir

i-

den

e

44

Chapter 3

while gait (- 20 %, p = 0.029) improved slightly. These data are illustrated in figure 1.

The severity of off-medication dystonia, as assessed by the CDRS, did not change sig-

nificantly after surgery (1.9 ± 3.1 vs 0.45 ± 1.0, p = 0.394), while the severity of on-me-

dication dyskinesia clearly improved by 57 % (8.8 ± 5.1 vs 3.75 ± 3.7, p = 0.002). In the

off-medication condition, the Schwab & England Activities of Daily Living (ADL)

score improved from 52 ± 22 % to 72 ± 23 % (p = 0.0001) following STN-DBS, while a

synergistic effect of STN-DBS and medication led to a smaller but still significant

improvement in the on-medication ADL score (78 ± 7 % vs. 88 ± 8 %, p = 0.0001) at 12

months after surgery.

Patient diary data

The results of the patients’ diaries are presented in figure 2. In summary, they showed

a 34 % increase in on-time without dyskinesia (“complete on”) (p = 0.002) and a reci-

procal reduction of both complete on-time with dyskinesia (- 19 %, p = 0.0001) and

complete off-time (-10 %, p = 0.002).

If a subscore consisted of more items, each subscore was calculated by summing all items. Values are expressed as

mean values ± SD.

Figure 1 UPDRS part III off-medication subscores before surgery and 12 months after STN-DBS.

-

45

Figure 2

A Patient diary before surgery

B Patient diary 12 months after STN-DBS

Patient self-reporting by diary before surgery (A) and 12 months after STN-DBS (B). Scores were

registrated in 4 conditions (on + dyskinesia, complete on, partial off and complete off).



46

Chapter 3

Reduction in medical treatment

After STN-DBS the LEDD could be reduced by 39 % (1242 ± 678 vs. 751 ± 398, p =

0.001). One patient could stop all antiparkinsonian medication.

Side-effects and complications

No haemorrhage, infection or ischaemic stroke directly related to surgery was noted.

Two patients suffered from transient peroperative respiratory insufficiency due to pul-

monal air emboli. Because of this complication, which interrupted the surgical proce-

dure, 1 patient (the fourth in table 1) only had one electrode positioned. Three patients

suffered from transient confusion, which lasted several days following surgery. Two

patients could not cope with the gradual reduction of their levodopa dose after sur-

gery, despite their excellent motor response, because of persistent anhedonia. They

preferred their preoperative levodopa doses and thereby returned to a severe dyski-

netic state, despite adaptation of their DBS stimulation parameters. In 3 patients the

increase of voltage of the pulse generator induced reversible but severe side-effects

(facial and limb dystonia) which limited the range of stimulation adjustment.

Discussion

Our study confirms the clinical efficacy of chronic bilateral STN-DBS in advanced PD

12 months after surgery. STN-DBS improved off-medication parkinsonian motor fea-

tures significantly and thereby reduced the total motor disability by 33 %. This motor

improvement is in accordance with previous studies on STN-DBS in ad-vanced PD,

although within the lower range of already published results (28-67 %) 9-17

. Surgery also

resulted in a marked reduction of antiparkinsonian medication (-39 %, range in the li-

terature: 33-80 % 9-17

) and, as a consequence, reduced the severity of peak-dose dyski-

nesia dramatically. In addition, STN-DBS increased ADL activities in off- and on-me-

dication conditions. This finding supports the idea of a partially synergistic effect of

antiparkinsonian medication and STN-DBS on daily activities15

. Finally, the patient

diaries following STN-DBS showed a significant increase in daily complete on-time

without dyskinesia, which is in accordance with previous published studies 14;15

.

Several explanations could account for the relatively smaller motor improvement in

our STN-DBS series. First, although our study population characteristics largely corre-

spond to those in previous studies, their preoperative levodopa responsiveness (i.e.:

(UPDRS part III score in off-medication condition – UPDRS part III score in on-me-

dication condition) / UPDRS part III score in off-medication condition) was lower

(mean: 48 %) as compared to earlier published series (range: 57 to “ > 60 “) 9-13;15;17

. Since

the preoperative clinical response to levodopa seems strongly associated with the

(motor) outcome of STN-DBS 18

, this relatively smaller response may account for the

smaller percentage of motor improvement in our study, which equals the data pub-

lished by Pahwa 14

and Ford 19

. Second, the mean voltage of DBS in our study group

was lower than those published in most previous studies. This was probably related to

47

the restricted range of adjustment of DBS voltage in 3 patients, which, in turn, limited

the extent of their best clinical response. Third, since this study reports the results of

our first cohort of PD patients having STN-DBS, this relative smaller effect may be

related to the learning curve for both neurosurgeon and neurologists. This is suppor-

ted by a subgroup analysis of achieved motor improvement in the last 10 included

patients which revealed a mean reduction of 40 % in UPDRS III off-medication score.

Although surgery improved all cardinal parkinsonian features significantly, speech

did not while gait only slightly improved. This is probably due to the non-dopaminer-

gic origin of these “axial” symptoms20

, but the possibility that decreased striatal

dopaminergic transmission contributes to this symptomatology cannot be ruled out 21

.

The patients’ diaries showed a robust increase in daily complete on-time spent with-

out disabling dyskinesia at 12 months after surgery. In contrast to the clinically per-

formed assessments, which only give insight in the severity of motor features, these

diary data serve as an indicator of patients’ “non-hospitalized” functional motor sta-

tus after surgery. The validity of these longitudinal diary data are supported by the

negative correlation (ρ = -0.497, p = 0.018) existing between diary derived data (com-

plete on-time without dyskinesia) and clinically assessed motor scores (UPDRS part III

off-medication score) 12 months after surgery. In addition, a recent study provides

strong support for the overall accuracy and validity of the four category CAPSIT-PD 6

.

Although it is suggested that a three category diary format (by omitting the partial off

status) might improve its validity, it is our experience that well-instructed patients are

capable of defining all 4 diary conditions adequately.

Our series of 20 patients did not show any life-threatening adverse events as a direct

consequence of intracerebral surgery. Two patients in our study cohort suffered from

severe anhedonia and apathy after surgery, as has been described in earlier cases 12;22

.

Preoperatively both patients were on high levodopa doses ( > 2000 mg / day) and suf-

fered from severe chorea. Gradual decrease of their antiparkinsonian medication after

surgery led to a complete on-condition without troublesome dyskinesia in both

patients. Unfortunately, both patients started to complain of sustained intolerable lack

of initiative and anhedonia. These mental symptoms could not be positively influ-

enced by changing the stimulation parameters, which suggests that these mood

changes were not the result of STN stimulation itself, as has been described previous-

ly 22-24

, but resulted from levodopa deprivation. Both patients decided to return to their

preoperative high dose of levodopa, which altered their mental status positively, and

accepted the irrevocable return of severe dyskinesia.

In conclusion, our study confirmes the efficacy of STN-DBS in ameliorating all cardi-

nal motor features in PD, which specifically results in a marked increase of patients’

daily on-time without disabling dyskinesia.



Acknowledgement

The authors wish to thank R.E. Stewart (University Medical Center Groningen) for his

statistical support. This study was funded by a donation from the Stichting

Internationaal Parkinson Fonds (Hoofddorp, the Netherlands).

48

Chapter 3

49

References

1. Benazzouz A, Gross C, Feger J, Boraud T, Bioulac B. Reversal of rigidity and improvement inmotor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur JNeurosci 1993;5:382-9.

2. Limousin P, Pollak P, Benazzouz A, Hoffmann D, Broussolle E, Perret JE et al. Bilateral subthala-mic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995;10:672-4.

3. Deuschl G, Wenzelburger R, Kopper F, Volkmann J. Deep brain stimulation of the subthalamicnucleus for Parkinson’s disease: a therapy approaching evidence-based standards. J Neurol2003;250 (Suppl 1):I43-I46.

4. Krack P, Poepping M, Weinert D, Schrader B, Deuschl G. Thalamic, pallidal, or subthalamic sur-gery for Parkinson’s disease? J Neurol 2000;247 (Suppl 2):II122-II134.

5. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL. Electrical sti-mulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med1998;339:1105-11.

6. Reimer J, Grabowski M, Lindvall O, Hagell P. Use and interpretation of on/off diaries inParkinson’s disease. J Neurol Neurosurg Psychiatry 2004;75:396-400.

7. Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical inter-ventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord 1999;14:572-84.

8. Fahn S, Elton R.L., Members of the UPDRs development committee. Unified Parkinson’s DiseaseRating Scale. In: Fahn S, Marsden CD, Calne D.B., Goldstein M. (eds.). Recent developments inParkinson’s disease. New Jersey: MacMillan 2000: 293-304.

9. Esselink RA, de Bie RM, de Haan RJ, Lenders MW, Nijssen PC, Staal MJ et al. Unilateral pallido-tomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial. Neurology2004;62:201-7.

10. Herzog J, Volkmann J, Krack P, Kopper F, Potter M, Lorenz D et al. Two-year follow-up of subtha-lamic deep brain stimulation in Parkinson’s disease. Mov Disord 2003;18:1332-7.

11. Houeto JL, Damier P, Bejjani PB, Staedler C, Bonnet AM, Arnulf I et al. Subthalamic stimulation inParkinson’s disease: a multidisciplinary approach. Arch Neurol 2000;57:461-5.

12. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C et al. Five-year follow-up ofbilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med2003;349:1925-34.

13. Molinuevo JL, Valldeoriola F, Tolosa E, Rumia J, Valls-Sole J, Roldan H et al. Levodopa withdra-wal after bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease. Arch Neurol2000;57:983-8.

14. Pahwa R, Wilkinson SB, Overman J, Lyons KE. Bilateral subthalamic stimulation in patients withParkinson’s disease: long-term follow up. J Neurosurg 2003;99:71-7.



50

Chapter 3

15. The Deep-Brain Stimulation for Parkinson’s Disease study group. Deep-brain stimulation of thesubthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl JMed 2001;345:956-63.

16. Thobois S, Mertens P, Guenot M, Hermier M, Mollion H, Bouvard M et al. Subthalamic nucleusstimulation in Parkinson’s disease: clinical evaluation of 18 patients. J Neurol 2002;249:529-34.

17. Vingerhoets FJ, Villemure JG, Temperli P, Pollo C, Pralong E, Ghika J. Subthalamic DBS replaceslevodopa in Parkinson’s disease: two-year follow-up. Neurology 2002;58:396-401.

18. Welter ML, Houeto JL, Tezenas du MS, Mesnage V, Bonnet AM, Pillon B et al. Clinical predictivefactors of subthalamic stimulation in Parkinson’s disease. Brain 2002;125:575-83.

19. Ford B, Winfield L, Pullman SL, Frucht SJ, Du Y, Greene P et al. Subthalamic nucleus stimulationin advanced Parkinson’s disease: blinded assessments at one year follow up. J Neurol NeurosurgPsychiatry 2004;75:1255-9.

20. Agid Y. Parkinson’s Disease - Pathophysiology. Lancet 1991;337:1321-4.

21. Steiger MJ, Thompson PD, Marsden CD. Disordered axial movement in Parkinson’s disease. JNeurol Neurosurg Psychiatry 1996;61:645-8.

22. Volkmann J, Allert N, Voges J, Weiss PH, Freund HJ, Sturm V. Safety and efficacy of pallidal orsubthalamic nucleus stimulation in advanced PD. Neurology 2001;56:548-51.

23. Berney A, Vingerhoets F, Perrin A, Guex P, Villemure JG, Burkhard PR et al. Effect on mood of sub-thalamic DBS for Parkinson’s disease: a consecutive series of 24 patients. Neurology 2002;59:1427-9.

24. Okun MS, Green J, Saben R, Gross R, Foote KD, Vitek JL. Mood changes with deep brain stimula-tion of STN and GPi: results of a pilot study. J Neurol Neurosurg Psychiatry 2003;74:1584-6.

Chapter 4

Striatal FDOPA uptake and cognition in advanced non-dementedParkinson’s Disease: a clinical and FDOPA-PET study

van Beilen M1,2

, Portman AT1

, Maguire RP1,2

, Kaasinen V1

, Koning M1

, Pruim J2,3

,

Leenders KL1,2


the Netherlands

2 School for Behavioral and Cognitive Neurosciences (BCN),

University Medical Center, Groningen, the Netherlands

3 PET Center, University Medical Center, Groningen, the Netherlands

Submitted

51

Abstract

Parkinson’s disease (PD) is often accompanied by cognitive impairments in several

cognitive domains. These are thought to result from deficient frontal lobe functioning

secondary to striatal dopamine depletion. PET studies in PD have revealed relation-

ships between striatal FDOPA uptake and cognitive functioning, as well as motor func-

tioning.

This study sought to determine the nature of the relationship between cognition and

striatal dopaminergic functioning in patients with advanced PD.

FDOPA-PET was assessed in 28 patients and successive PET data were correlated with

neuropsychological test scores. In both, putamen and caudate FDOPA uptake was sig-

nificantly correlated with cognition. Putamen FDOPA uptake showed the strongest

relationship to executive functioning (flexibility), while caudate FDOPA uptake

appeared to correlate most strongly with the organizational aspects of executive func-

tioning in memory processes and fluency. The non-executive memory functions were

not correlated with striatal FDOPA uptake.

In conclusion, previously reported associations between striatal FDOPA uptake and

cognition in PD are replicated in a group of advanced PD patients: it appears to be the

executive functions that are related to striatal dopaminergic functioning. The caudate

may be more important in the mental components of executive functioning, while the

putamen may be more important in the motor components of executive functioning.

Introduction

PD is a neurodegenerative disorder of unknown etiology, characterized by progressive

loss of dopaminergic neurons in the nigrostriatal pathway 1

. PD is clinically featured

by its motor symptoms consisting of an insidious (asymmetric) onset of bradykinesia,

rigidity and (rest) tremor 2

.

However, PD is also often accompanied by cognitive impairments 3;4

. Cognitive deficits

are found in several domains including memory and the executive functions.

Executive functions are typically impaired, which itself results in deficient cognitive

switching, impaired concept formation and response-inhibition, and impaired plan-

ning abilities 3

. Impaired fluency performance is another example of impaired execu-

tive functioning in PD 4

since frontally mediated searching strategies are needed for

optimal performance. Deficits in the executive functions can negatively influence other

cognitive domains too. Most importantly, memory profiles show that in PD, the execu-

tive components of memory performance are disturbed, while the non-executive storage

components are relatively intact. PD patients experience problems in the organizatio-

nal strategies needed for the encoding and retrieval of new information, but not in the

storage of information.

Chapter 4

52

In sum, cognitive impairments, as they are found in PD, can be seen as the result of

deficient executive functioning, which results in impaired executive functioning, and

subsequently broader cognitive dysfunctioning.

A possible explanation for the cognitive deficits can be found in the striatal connec-

tions with the frontal lobes 5

. Positron Emission Tomography (PET), using the radio-

tracer 6-L (18

F)- fluorodopa. (FDOPA), provides a means of quantifying the loss of stri-

atal dopaminergic terminal function in vivo in PD. Specific striatal FDOPA uptake

reflects nigrostriatal dopamine storage capacity and enzymatic decarboxylase activity

in surviving neurons 6

. According to the current model of basal ganglia organization,

dopaminergic connections between the caudate nucleus and frontal areas are more

strongly related to cognition and less strongly related to motor function. On the con-

trary, putaminal FDOPA uptake has been related to motor function in both early and

advanced PD patients 7

, but until recently not to cognition, although Marie et al. 8

reported an inverse correlation between putamen [11

C] nomifensine uptake and asso-

ciative learning. Most studies have shown that diminished (posterior) putamen

FDOPA uptake correlates with clinical severity of PD motor symptomatology 6;7

.

This study was performed to determine whether striatal FDOPA uptake is related to

cognitive functioning in a sample of advanced PD patients. While previous FDOPA-

PET studies on cognition in PD patients involved early or heterogeneous (both early

and advanced patients) samples of patients, our study included only moderately to

severely advanced PD patients.

The nature of these relationships between striatal dopamine uptake and cognitive

functioning was studied to find an answer to the following questions: first, are these

deficits mainly related to the dopaminergic function in the caudate, the putamen, or

both? Second, are the cognitive deficits in advanced PD restricted to the executive

functions or do they also include non-executive cognitive processes?

Methods

Patients

28 right-handed PD patients with moderately to severely advanced disease (modified

Hoehn & Yahr Staging in off-medication condition: 2.5 (n = 1), 3 (n = 13), 4 (n = 9), 5 (n

= 5)) participated in the study. There were 15 men and 13 women (age 60 ± 7.4 years,

disease duration 11.8 ± 4.5 years) (see also table 1). All patients had idiopathic PD fol-

lowing the criteria of the UK Parkinson’s Disease Society Brain Bank criteria and

showed sustained levodopa responsiveness. They were recruited from our outpa-

tients’ Movement Disorder Unit between October 1999 and July 2003. All patients suf-

fered from severe pharmacotherapy resistant tremor or intractable motor fluctuations,

despite optimal antiparkinsonian treatment (levodopa and dopamine agonists; n = 28;

amantadine, n = 6; anticholinergics, n = 5) and were suitable candidates for bilateral

Deep Brain Stimulation (DBS) of the thalamus (thalamus-DBS, n = 3) or subthalamic

Striatal FDOPA uptake and cognition in advanced non-demented Parkinson’s Disease:

a clinical and FDOPA-PET study

53

Chapter 4

54

nucleus (STN-DBS, n = 25) respectively. On a 1 (elementary school not finished) to 7

(university degree) Dutch scale for education the patients’ median score was 4 (SD 1.4).

All patients gave their informed consent prior to study inclusion according to the de-

claration of Helsinki.

Procedure

Preoperatively all patients were clinically and neuropsychologically evaluated follo-

wing the Core Assessment Program for Surgical Interventional Therapy in Parkinson’s

Disease (CAPSIT-PD) 9

. Additional in- and exclusion criteria were: a positive levodopa

response (at least 30 % improvement of the motor part (III) of the Unified Parkinson’s

Disease Rating Scale (UPDRS III) 10

, no depression (Montgomery and Asberg

Depression Rating Scale (MADRS), score < 19) or recent psychiatric illness, no demen-

Mean (± SD) Range

Disease duration (years) 11.8 (4.5) 3-20

UPDRS part III score*

45.6 (14.2) 24-74

Hoehn & Yahr Staging *

3.5 (0.8) 2.5-5

Medication (LEDD)**

1179 (732) 450-3250

FDOPA uptake putamen***

0.64 (0.19) 0.29-0.98

-women 0.72 (0.18) 0.32 – 0.98

-men 0.58 (0.19) 0.29 - 0.88

FDOPA uptake caudate***

0.83 (0.29) 0.41-1.41

-women 0.90 (0.27) 0.45 – 1.41

-men 0.78 (0.30) 0.41 – 1.19

* in off-medication condition; ** LEDD = Levodopa Equivalent Daily Dose: levodopa dose (100 mg) x 1 (added with 0.2 x levodopa dose

if using entacapone with each dose) + (slow release levodopa x 0.7) + bromocriptine x 10 + ropinirolex 20 + pergolide x 100 + pramipexole x 100.

*** Reference values FDOPA uptake, UMC Groningen. Healthy volunteers (n = 10, age 56 ± 19 years):1.69 ± 0.29 (putamen), 1.68 ± 0.25 (caudate), PD (n = 18, age 64 ± 6 years, disease duration 9 ± 3 years): 0.79 ± 0.1 (putamen), 1.07 ± 0.19 (caudate)

Table 1 Clinical characteristics and striatal FDOPA uptake values of the study patients

tia (Mattis Dementia Rating Scale, score > 130), and no abnormalities on cerebral MRI

suggestive of atypical parkinsonism.

All clinical, neuropsychological and FDOPA-PET assessments were performed on se-

parate successive days during hospitalisation for 2-4 days within 3-6 months prior to

planned surgery (bilateral thalamus-DBS or STN-DBS). Antiparkinsonian medication

was kept unchanged during a period of at least 2 weeks prior to every assessment. The

UPDRS part III score was assessed in the off-medication condition (after withholding

regular antiparkinsonian drugs for 12 hours overnight) by the same investigator

(ATP). The neuropsychological testing was performed in the medication-on condition

following the recommendations of CAPSIT-PD. All subjects were scanned in the med-

ication-on condition.

Neuropsychological Tests

Neuropsychological tests included measures for memory, executive functioning, flu-

ency, and psychomotor speed. Memory was tested with the memory scale of the

Matthis Dementia Rating Scale (MDRS) and the 15 Words Test (15WT) Learning Score

(sum score of 15 words that were presented 5 times) and Recall score (words remem-

bered after a 20 minute delay). The recognition score of the 15WT was used to further

explore the nature of the possible relationships between memory and striatal FDOPA

uptake. Executive functioning was tested with the Odd Man Out (OMO) test for cogni-

tive switching, the Stroop Color-Word Card divided by the Stroop Color Card (inter-

ference index), and the time needed on the Trailmaking B divided by the time needed

on the Trailmaking A (cognitive switching). Fluency performance was measured with

several versions including two categorical tests (Animals and Professions, 1 minute

each), and three letter Fluency tests.

PET data acquisition and analysis

All PET measurements were performed at the UMCG PET Center on a Siemens ECAT

Exact HR+ (n = 13) or ECAT 951 (n = 15) scanner. Subjects were positioned supine in

a resting state with their eyes closed and ears unplugged. After pretreatment with 2

mg/kg carbidopa to block peripheral dopa-decarboxylase activity, 180 ± 33 MBq of

FDOPA was intravenously injected over 1 minute with an infusion pump. All subjects

were measured following a static or dynamic protocol with identical time range for

data analysis. The static protocol consisted of 1 single scan from 90-120 minutes post-

injection, while the dynamic protocol consisted of 21 time frames with increasing

duration over 120 minutes: then the last 2 frames (2 x 900 sec.) were averaged to cre-

ate a equivalent volume to the static scan.

Linear normalization with SPM99 was used 11

to align the measured volume data to a

rCBF template fixed in Talairach coordinate space 12

. Region of interest (ROI) analysis

was based on a standardized template fixed in Talairach coordinate space. This tem-

plate, consisting of 6 ROIs (putamen, caudate and occipital lobe on both sides) was

used to sample the volume data and compute mean ROI activity concentration.

55



Specific FDOPA uptake was expressed as a striato-occipital ratio (SOR) index follo-

wing the equation: SOR index13

= CROI - CREF / CREF (CROI = average (left and right) ROI activity concentration,

CREF = average occipital activity in the occipital reference region).

Statistical analyses

Since patients were scanned on two different scanners, t-tests (p ≤ 0.05) for all variables

were performed to exclude differences between type of scanner used. No significant

differences were found. All variables were tested for normality with the Shapiro-Wilk

test. Sex, H&Y, Ledd-score, MDRS memory, Stroop III/II and OMO total scores were

not normally distributed, all others were. Often, non-parametric tests are used when

non-normally distributed variables are concerned to decrease the chance of false-po-

sitives. However, non-parametric tests have major disadvantages, as they lose valuable

data information such as the absolute value of (test) scores and they increase the

chance of false negatives. Therefore, all statistical tests were performed parametrical-

ly, and the results of the parametric tests were reported. To ensure that no false posi-

tives were reported, non-parametric tests were performed for those variables that were

not normally distributed to check and justify the parametric results. If, in these cases,

the non-parametric result lost significance compared to the parametric result, this was

indicated in table 2 and 3.

Hypothesis-driven analyses

All cognitive variables were converted to Z-scores using mean values and standard

deviations. Composite cognitive scores (i.e. mean Z-scores) were formed for memory

(MDRS memory scale, 15 WT Learning score, and 15 WT Recall score), executive func-

tioning, and fluency. Since recognition was not used in a composite score, it did not

need to be converted to a standard score and the raw score was used. In this way, the

number of correlations to be studied was limited to 6 and it was not necessary to per-

form a multiple comparisons correction. To justify this approach, each correlation itself

was provided with a 95% confidence interval, so as to indicate its accuracy as an esti-

mate of the correlation in the population. Because the direction of the correlations was

predictable based on previous literature on the subject 8;14-17

, it was justified to perform

one-tailed correlational analyses. One-tailed correlations between mean FDOPA

uptake values (combined left and right putamen; combined left and right caudate) and

the composite scores for memory, executive functioning and fluency were performed.

Further explorative analyses

Two-tailed correlations (Pearson’s r) between sex, UPDRS part III off-medication con-

dition score and illness duration and striatal FDOPA uptake and cognition were

assessed. Again, each correlation itself was provided with a 95% confidence interval,

so as to indicate its accuracy as an estimate of the correlation in the population.

Partial correlations were also used to explore the relationship between memory and

striatal uptake, corrected for the influence of executive functioning to investigate the

relationship of non-executive components of memory with FDOPA uptake.

Chapter 4

56

57

Results

Striatal FDOPA uptake values of the study PD group were lower than the PD norm

group (see table 1). Female subjects showed higher putamen FDOPA uptake com-

pared to males. Significant relationships between the illness variables, sex, psychomo-

tor speed and some of the cognitive variables (memory) and FDOPA uptake were

found (see table 2). Putamen FDOPA uptake was not significantly related to the

UPDRS part III off-medication score.

Hypothesis-driven analyses: all correlations between FDOPA uptake and cognitive

composite scores were significant, except for the correlation between putamen uptake

and the memory score (see table 2 and figure 1). Interestingly, the correlation between

caudate uptake and the memory summary score lost significance when corrected for



Table 2 One-tailed correlation coefficients between sex, disease duration, motor score, and cognition with

striatal FDOPA uptake

Putamen Caudate

R (p) R (p)

Conf. int. 95 %* Conf. int. 95 %*

Sex .38 (.024) .20 (ns)

.01,.66 -.19,.53

Disease duration (years) .37 (.026) .40 (.017)

.00,.65 .03,.67

UPDRS part III score ** .062 (ns) .39 (.012)

-.32,.43 .02,.67

Memory ns .41 (.027)

.04,.68

Executive functions .44 (.010) .37 (.010)

.08,.70 .00,.65

Fluency .32 (.048) .44 (.010)

.09,.70 .08,.70

ns = not significant; * 95 % confidence interval; ** in off-medication condition

58

Chapter 4

the influence of executive functioning. Recognition of learned verbal material was not

related to either putamen or caudate uptake. Non-parametric supported all parame-

tric findings.

Discussion

Putamen and caudate FDOPA uptake in our study group were lower than in our PD

norm group, and also within the lower range of those stated in the literature 13

, proba-

bly because of more advanced disease status. In our study putaminal FDOPA uptake

was not significantly related to the clinically evaluated level of motor dysfunction (as

assessed by the UPDRS part III), although the correlation was in the expected negative

direction. Caudate FDOPA uptake was related to motor dysfunction. These inconsis-

tent results may be caused by the fact that UPDRS III scores were measured in off-

medication condition, while FDOPA-PET was measured in on-medication condition.

However, since this study was aimed at the relationships between cognition and

FDOPA uptake, UPDRS on-medication scores were not measured.

-2 0 2

0

0.2

0.4

0.6

0.8

1

-2 0 2

0

0.2

0.4

0.6

0.8

1

-2 0 2

0

0.2

0.4

0.6

0.8

1

-2 0 2

0

0.5

1

1.5

Exe

-2 0 2

0

0.5

1

1.5

Memory

-2 0 2

0

0.5

1

1.5

Fluency

Figure 1 Scatterplots of Pearson's r, striatal FDOPA uptake and cognitionC

AU

MP

UT

M

PUTM = mean putamen FDOPA uptake

CAUM = mean caudatus FDOPA uptake

59

Hypothesis-driven analyses

Caudate FDOPA uptake was related to cognition. These relationships were expected,

based on a. previous PD literature on caudate dopaminergic function and cognition, b.

findings in other patient groups such as patients with Huntington’s disease18

and cau-

date hemorrhage 19

, and c. findings in healthy subjects 20

. In PD, caudate dopaminergic

fun-ction has been linked to tests measuring executive function 8;15;17

and memory 16

. In

particular the interference effect on the Stroop test has been associated with caudate

dopaminergic function15-17

in addition to measurement of cognitive switching that

included reward for the right response 8

. However, measurements of cognitive swit-

ching that did not include reward (i.e. WCST) have not revealed significant relation-

ships with caudate FDOPA uptake in PD 14;15

. Similarly, memory has not been consis-

tently related to caudate FDOPA uptake 14;15

or may only show this relationship in more

advanced patients 16

. Rinne et al. reported memory to be related to frontal FDOPA

uptake but not to caudate FDOPA uptake 17

. Fluency performance was studied in two

larger FDOPA-PET studies with interesting results: Broussolle et al. concluded that

fluency is independent from striatal FDOPA uptake, and Rinne et al. found fluency to

be related to frontal but not to striatal uptake 14;17

.

Our main finding compared to previous studies is the association found between puta-

men FDOPA-uptake and executive functioning. This is a surprising finding, since pre-

vious reports and neuroanatomical findings suggest that the putamen is involved in

motor functioning but not in cognition. However, other authors have also suggested

an association between FDOPA uptake in the putamen and cognitive processing 21;22

using comparable paradigms (FDG-PET and [123

I]b-CIT SPECT, respectively), in addi-

tion to findings with other paradigms 23;24

.

In our patients, putamen FDOPA uptake was related to executive functioning and flu-

ency, but not to memory. It should be noted that, as addressed in the introduction, the

measures for memory and fluency also concern executive functioning since they reflect

cognitive searching strategies and organization of verbal material. However, different

aspects of executive functioning can be distinguished from each other; our variable

“executive functioning” concerned mostly mental flexibility, while the others concerned

the organization of behavior. Putamen FDOPA uptake was related to the “flexibility”

factor in executive functioning. Monchi et al offer a possible explanation for this fin-

ding with their activation study in which they investigated brain activation patterns

during neuropsychological testing instead of relying on correlational analyses 25

. They

concluded that the putamen was activated during actions that followed a cognitive

switch, i.e. actions according to specific behavioural rules. The mental components of

this cognitive switch were unrelated to putamen activity. Since most neuropsycholo-

gical tests require such a motor response after mental switching, it may be this motor

component of test performance that is related to putamen FDOPA uptake. Indeed, our

tests (e.g. Trail Making Test and OMO Test) and those of Lozza et al 21

required motor

actions after cognitive switching while some of the studies that did not find a relation



60

Chapter 4

between putamen FDOPA uptake and neuropsychological test behaviour did not

include tests that require motor actions after cognitive switching 16;17

However, results

are not consistent, some authors did include such a test but did not find putaminal

FDOPA uptake related to them 8;14;15

. Also, the relationship between putamen and cog-

nition found in the study of Müller 22

et al did involve tests with an action component,

but not specifically an action after switching.

Explorative analyses

The analysis of the nature of cognitive deficits showed interesting results. When

exploring memory functioning in these patients, it appears that it are the executive

components of memory are deficient and related to FDOPA uptake. Other authors

have also reported this memory profile in PD patients3

. Our results confirm this cog-

nitive profile in two ways. First, learning and recall of new verbal material requires

organizational skills in structuring the information and searching for information.

These are the executive stages of memory processes mostly mediated by the frontal

cortex (in interaction with the temporal cortex). The consolidation of learned material

is thought to rely more on temporal lobe function, and can be measured by the recog-

nition score. When newly learned material is not recalled, but is recognized, consoli-

dation is intact. Our results showed that recognition of verbal material (non-executive)

was not related to caudate FDOPA uptake, while learning and recall of information

(executive) was. Secondly, the results are confirmed since the relationships between

verbal learning and recall and caudate FDOPA uptake lost significance when correct-

ed for the influence of executive functioning with partial correlational analyses. The

methodological aspects of the study should be considered in the interpretation of the

study results. The FDOPA uptake in the striatum was lower in our patient study group

as compared to previous studies with de novo patients. However, it should be noted,

that although the mean striatal FDOPA uptake was low, the range of values was suffi-

cient for a correlation analysis. Finally, our analyses were not corrected for multiple

compa-risons. Although most of the correlations would not have remained significant

after a conservative correction for multiple comparisons, the present results, in the

light of previous literature, confirm the a priori hypothesis of negative correlations

between FDOPA uptake and cognition in the striatum. Confidence intervals were pro-

vided to show the chances of false positives for each correlation individually.

Furthermore, scatter plots were provided to provide a detailed view on the data.

In conclusion, three main inferences can be made about the association between stri-

atal FDOPA uptake and cognition, based on these data on non-demented PD patients.

First, putamen FDOPA uptake was more related to mental flexibility (i.e. cognitive

switching), which may represent difficulty performing the actions after cognitive

switching during test performance.

Second, caudate FDOPA uptake was related to executive functioning, fluency perfor-

61

mance and the organizational aspects of memory (i.e. cognitive organization). Third,

neither putamen nor caudate FDOPA uptake was related to the non-executive (sto-

rage) aspect of memory.

Therefore, it appears to be the executive functions that are related to striatal dopami-

nergic functioning. The caudate may be more important in the mental components of

executive functioning, while the putamen may be more important in the motor com-

ponents of executive functioning.

Acknowledgements

This study was sponsored by the Stichting Internationaal Parkinson Fonds

(Hoofddorp, the Netherlands).



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2. Schapira AH. Science, medicine, and the future: Parkinson’s disease. BMJ 1999;318:311-4.

3. Dubois B, Pillon B. Cognitive deficits in Parkinson’s disease. J Neurol 1997;244:2-8.

4. Green J, McDonald WM, Vitek JL, Evatt M, Freeman A, Haber M et al. Cognitive impairments inadvanced PD without dementia. Neurology 2002;59:1320-4.

5. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuitslinking basal ganglia and cortex. Annu Rev Neurosci 1986;9:357-81.

6. Leenders KL, Salmon EP, Tyrrell P, Perani D, Brooks DJ, Sager H et al.The nigrostriatal dopami-nergic system assessed in vivo by positron emission tomography in healthy volunteer subjectsand patients with Parkinson’s disease. Arch Neurol 1990;47:1290-8.

7. Antonini A, Vontobel P, Psylla M, Gunther I, Maguire PR, Missimer J et al. Complementarypositron emission tomographic studies of the striatal dopaminergic system in Parkinson’s disease.Arch Neurol 1995;52:1183-90.

8. Marie RM, Barre L, Dupuy B, Viader F, Defer G, Baron JC. Relationships between striataldopamine denervation and frontal executive tests in Parkinson’s disease. Neurosci Letters1999;260:77-80.


10. Fahn S, Elton R.L., Members of the UPDRs development committee. Unified Parkinson’s DiseaseRating Scale. In: Fahn S, Marsden CD, Calne D.B., Goldstein M., eds. Recent developments inParkinson’s disease. New Jersey: MacMillan 2000: 293-304.

11. Friston KJ. Commentary and Opinion .2. Statistical Parametric Mapping - Ontology and CurrentIssues. Cerebral Blood Flow Metab 1995;15:361-70.

12. Talairach J, Tournoux P. Co-planar stereotactic atlas of the human brain. New York: ThiemeMedical Publishers, 1988.

13. Dhawan V, Ma Y, Pillai V, Spetsieris P, Chaly T, Belakhlef A et al. Comparative analysis of striatalFDOPA uptake in Parkinson’s disease: ratio method versus graphical approach. J Nucl Med2002;43:1324-30.

14. Broussolle E, Dentresangle C, Landais P, Garcia-Larrea L, Pollak P, Croisile B et al. The relation ofputamen and caudate nucleus 18F-Dopa uptake to motor and cognitive performances inParkinson’s disease. J Neurol Sci 1999;166:141-51.

15. Bruck A, Portin R, Lindell A, Laihinen A, Bergman J, Haaparanta M et al. Positron emissiontomography shows that impaired frontal lobe functioning in Parkinson’s disease is related todopaminergic hypofunction in the caudate nucleus. Neurosci Lett 2001;311:81-4.

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16. Holthoff-Detto VA, Kessler J, Herholz K, Bonner H, Pietrzyk U, Wurker M et al. Functional effectsof striatal dysfunction in Parkinson’s disease. Arch Neurol 1997;54:145-50.

17. Rinne JO, Portin R, Ruottinen H, Nurmi E, Bergman J, Haaparanta M et al. Cognitive impairmentand the brain dopaminergic system in Parkinson disease: [18F]fluorodopa positron emissiontomographic study. Arch Neurol 2000;57:470-5.

18. Backman L, Robins-Wahlin TB, Lundin A, Ginovart N, Farde L. Cognitive deficits in Huntington’sdisease are predicted by dopaminergic PET markers and brain volumes. Brain 1997;120:2207-17.

19. Fuh JL, Wang SJ. Caudate Hemorrhage - Clinical-Features, Neuropsychological Assessments andRadiological Findings. Clin Neurol Neurosurg1995;97:296-9.

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21. Lozza C, Baron JC, Eidelberg D, Mentis MJ, Carbon M, Marie RM. Executive processes inParkinson’s disease: FDG-PET and network analysis. Human Brain Mapping 2004;22:236-45.

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64

Chapter 4

Chapter 5

Disease progression continues in patients with advanced Parkinson’s

Disease and effective subthalamic nucleus stimulation

Hilker R1*

, Portman AT 2*

, Voges J 3

, Staal MJ 4

, Burghaus L 1

, van Laar T 2

,

Koulousakis A 3

, Maguire RP 2

, Pruim J 5

, de Jong BM 2

, Herholz K 1

, Sturm V 3

, Heiss

W-D 1,6

, Leenders KL 2

1 Department of Neurology, Medical University of Cologne, Cologne,

Germany


the Netherlands

3 Department of Stereotaxy and Functional Neurosurgery, Medical University

of Cologne, Cologne, Germany


the Netherlands


6 Max-Planck-Institute for Neurological Research Cologne, Cologne, Germany

* contributed equally to this work

J Neurol Neurosurg Psychiatry 2005;76:1217-1221

65

Abstract

Objectives: Glutamate-mediated excitotoxicity of the hyperactive subthalamic nucleus

(STN) has been reported to contribute to nigral degeneration in Parkinson’s disease

(PD). Deep brain stimulation of the STN (STN-DBS) as a highly effective treatment of

severe PD motor complications was considered to inhibit STN hyperactivity and,

therefore, to decrease PD progression.

Methods: In a prospective two-center study design, we determined disease progression

by means of serial 18-Fluorodopa (FDOPA) positron emission tomography (PET) in 30

patients with successful STN-DBS over the first 16 ± 6 months after surgery.

Results: Dependent on the PET data analysis approach, annual progression rates rela-

tive to baseline were 9.5 to 12.4 % in the caudate and 10.7 to 12.9 % in the putamen.

Conclusions: This is the first functional imaging study demonstrating a continuous

decline of dopaminergic function in advanced PD patients under clinically effective

bilateral STN stimulation. The progression rates in patients with STN-DBS are within

the range of previously reported data from longitudinal imaging studies in PD.

Therefore, neuroprotective properties of DBS in the STN target could not be con-

firmed.

Chapter 5

66

Introduction

Deep Brain Stimulation of the subthalamic nucleus (STN-DBS) is a highly effective and

increasingly used treatment for patients with advanced Parkinson’s disease (PD). A

marked off-time reduction in case of severe motor fluctuations and the disappearance

of levodopa-induced dyskinesias after dosage reduction of antiparkinson medication

are the most prominent properties of this intervention 1

. In the hands of experienced

and specialized teams, STN-DBS has been proven to be a safe surgical procedure with

an acceptable rate of side effects and surgical risks 2

.

Several recent papers confirmed a long-term motor benefit of STN-DBS in patients

with advanced PD 3-7

. Such a sustained motor benefit might possibly reflect slowing of

disease progression, since a neuroprotective effect of STN stimulation was hypothe-

sized previously 8

. The rationale to assume protective properties of DBS in this target

are the strong glutamatergic efferents from the STN to the dopaminergic neurons in

the substantia nigra pars compacta (SNc), which get overactive within the abnormal

parkinsonian basal ganglia network 9

. Therefore, glutamatergic STN-mediated excito-

toxicity was considered a relevant etiologic factor for the progressive decline of intact

dopamine neurons in the SNc 10

. It was postulated that the reduction of STN neuronal

hyperactivity by inhibiting high-frequent stimulation might slow or even halt the pro-

gression of neurodegeneration in PD 8,10

. In fact, chemical lesioning of the STN was

shown to prevent the nigrostriatal dopaminergic pathway from degeneration in the 6-

hydroxydopamine rat model 11-13

.

These pathophysiological considerations gave rise to expectations that DBS in the STN

target might offer a novel neuroprotective approach in PD and demanded an objective

investigation of disease progression in STN stimulated PD patients. For this purpose,

serial functional imaging studies with positron emission tomography (PET) or single-

photon-emission-computed tomography (SPECT) were applied to quantify presynap-

tic dopaminergic function in living humans 14-16

. This paper reports the results of the

first prospective study on PD progression after successful STN-DBS measured with 18-

Fluorodopa (FDOPA) PET.

67

Disease progression continues in patients with advanced Parkinson’s Disease

and effective subthalamic nucleus stimulation

Chapter 5

68

Subjects and Methods

Subjects, clinical evaluation and surgical procedure

After giving written informed consent according to the declaration of Helsinki, 30

patients with advanced PD (19 males, 11 females, age 59.8 ± 7.2 years, disease duration

12.6 ± 4.2 years, Hoehn and Yahr stage 17

off-drug 3.6 ± 0.5, disease types: 26 akinetic-

rigid, 4 tremor-dominant) were consecutively recruited during the years 1999-2003

and prospectively followed-up in two centers, the Neurological Departments of

Cologne University, Germany, and of the University Medical Center, Groningen, the

Netherlands. The study was approved by local ethics committees of both medical fa-

culties. PD was diagnosed according to the UK Parkinson’s Disease Society Brain Bank

criteria 18

. STN-DBS was indicated according to the CAPSIT-PD protocol 19

because of

parkinsonian symptoms that were refractory to medication, such as severe levodopa-

associated on-off-fluctuations, peak-dose dyskinesias and severe resting hand tremor.

All study subjects had a clear but short levodopa-response and did not show any aty-

pical clinical signs. In each patient, bilateral STN electrodes (Medtronic model 3389,

Medtronic, Minneapolis, USA) and impulse generators (Itrel

II or Kinetra

, Medtronic

GmbH) were implanted. The surgical procedures were similar in both centers

(Departments of Stereotaxy and Functional Neurosurgery of Cologne and Groningen

Universities) and described in detail previously 20, 21

. Intraoperative target verification

was done by semi micro- (Groningen) and macrostimulation (Cologne) and repeated

neurological monitoring of clinical DBS effects (Groningen, Cologne). The Unified

Parkinson’s Disease Rating Scale (UPDRS) 22

as clinical measures of disease severity

was used before surgery in the drug-off condition 12 hours after cessation of

antiparkinson medication (“practically defined off”) and 1-2 hours after the oral intake

of 150-300 mg soluble levodopa (“best on”). After surgery, clinical testing was per-

formed in the same way as mentioned above under continuous STN stimulation (DBS

on condition), at first 6 months after electrode implantation and second at time of the

follow-up PET scan. The levodopa equivalent daily dose (LEDD) was calculated on the

basis of the following formula 4

: 1 mg of pergolide = 1 mg of lisuride = 1 mg of

pramipexole = 2 mg of carbergoline = 5 mg of ropinirole = 10 mg of bromocriptine = 5

mg of apomorphine = 20 mg of dihydroergocriptine = 100 mg levodopa. In order to

assure a correct electrode placement in the study sample, only PD patients with a

favourable stimulation effect, i.e. more than 30 % improvement of the UPDRS III score

in the DBS on versus off condition obtained 6 months after surgery, were included in

the PET follow-up protocol.

PET data acquisition

In each patient, one baseline scan 4 ± 6 weeks (range: 1-14 weeks) prior to STN elec-

trode implantation and one follow-up scan at least one year after the beginning of

STN-DBS was undertaken on the same PET camera following the same study proto-

col. The mean follow-up interval was 16 ± 6 months (range: 12-36 months). In both

study centers, two 24 detector ring scanners (ECAT EXACT HR + and ECAT EXACT,

69

Siemens-CTI, Knoxville, Tenn, USA) were used23, 24

. Subjects were positioned supine in

a resting state with their eyes closed and ears unplugged. To avoid drug interference,

in Cologne the antiparkinson medication was stopped for a minimum of 12 hours

prior to the PET scanning procedure (drug off condition), and the follow-up scan was

performed in the DBS on and drug off condition (see table 1 for DBS parameters).

After pretreatment with 100 mg Carbidopa to block peripheral dopa-decarboxylase

activity, 150-370 MBq of FDOPA were intravenously injected. Subsequently, all

patients from the Cologne Center (n = 20) were measured with a dynamic series of nine

10 minutes frames over 90 minutes in a three-dimensional mode. In the Groningen

center, the first 3 patients had a static scan protocol which consisted of a single scan

from 90 to 120 minutes post-injection. The following 7 patients had a dynamic scan

protocol with 21 time frames of increasing duration over a period of 120 minutes.

Images were corrected for scatter and attenuation. Individual frames from all dynam-

ic scans were re-aligned with a summed image from 0-90 and 0-120 minutes resp. in

order to reduce possible motion artefacts.

PET data analysis

Data analysis was performed on SUN Sparc 2 workstations (Sun Microsystems, Silicon

Valley, CA, USA). For each subject, both PET scans were analysed at the same time fol-

lowing a standardized protocol by one rater blinded for the presence of baseline or fol-

low-up PET scans. Four regions of interest (ROIs) were placed on the summed axial

FDOPA images, namely the right and left head of the caudate nucleus and the right

and left putamen. Reference regions were defined over the occipital cortex. In

Cologne, both PET scans were exactly co-aligned with standard software (MPI-tool)25

.

Afterwards, the ROI set was placed by inspection of the coaligned summed images

and slightly adapted to the individual basal ganglia anatomy. In Groningen, the PET

volume data were first linearly normalised to the Talairach coordinate space using the

rCBF template of the SPM99 software package (SPM99, The Wellcome Department of

Cognitive Neurology, London, UK). Then, ROI analysis was based on a standard tem-

plate fixed in Talairach stereotactic space.

We used two previously validated methods of striatal FDOPA uptake determination,

the striatal-to-occipital-ratio (SOR) method (patients from both centers) and the influx

constant (Kocc) calculated by the multiple time graphical analysis (MTGA) method

(patients from the Cologne center only)26

. For SOR calculation, the mean ROI activity

concentration was computed in either static scans or the averaged last 2 frames of

dynamic scans. The SOR index was expressed as: SOR = CROI - CREF / CREF (CROI = average

ROI activity concentration, CREF = average occipital activity concentration in the occi-

pital reference region). For MTGA analysis, time activity curves of dynamic PET series



Chapter 5

70

a o

bta

ined

at

leas

t 1

2 h

ou

rs a

fter

ces

sati

on

of

anti

par

kin

son

ian

med

icat

ion (

“pra

ctic

ally

def

ined

off

”)

b

ob

tain

ed a

fter

ora

l in

tak

e o

f 2

00

mg s

olu

ble

lev

od

op

a (“

bes

t o

n”)

c o

bta

ined

at

leas

t 1

2 h

ou

rs a

fter

ces

sati

on

of

anti

par

kin

son

ian

med

icat

ion

un

der

conti

nuous

ST

N s

tim

ula

tion (

DB

S-o

n)

d

ob

tain

ed a

fter

ora

l in

tak

e o

f 2

00

mg

so

lub

le l

evo

do

pa

un

der

co

nti

nu

ou

s S

TN

sti

mu

lati

on

(D

BS

-on

)

*

dif

fere

nce

bet

wee

n b

asel

ine

dru

g-o

ff a

nd d

rug

-on

co

nd

itio

ns:

p <

0.0

01

(p

aire

d t

tes

t)

†

dif

fere

nce

bet

wee

n d

rug-o

ff b

asel

ine

and f

oll

ow

-up

sco

res:

p <

0.0

01

(p

aire

d t

tes

t)

‡

dif

fere

nce

bet

wee

n d

rug-o

n b

asel

ine

and

fo

llo

w-u

p s

core

s: p

< 0

.05

(p

aire

d t

tes

t)

§

dif

fere

nce

bet

wee

n d

rug-o

n f

oll

ow

-up s

core

s: p

< 0

.01 (

pai

red t

tes

t)

Bef

ore

su

rger

y

Aft

er s

urg

ery

ba

seli

ne

FD

OP

A P

ET

6

-mo

nth

s fo

llo

w-u

p

foll

ow

-up

FD

OP

A-P

ET

(12

-36

mo

nth

s)

dru

g-o

ff c

on

dit

ion

4

2.9

(1

1.4

) a

19

.4 (

9.1

) c

†

20

.4 (

8.4

) c

†

UP

DR

S I

II s

core

dru

g-o

n c

on

dit

ion

1

6.5

(7

.6) b

*1

3.8

(6

.9)

d ‡

16

.0 (

7.4

) d ,§

L

ED

D

935 (

384)

611 (

288)

†

67

0 (

32

4)

†

amp

litu

de

(V)

- 3

.2 (

0.9

) 3

.4 (

0.7

)

pu

lse

wid

th (

s)

- 7

2.5

(1

4.3

) 7

2.5

(1

4.2

)

freq

uen

cy (

Hz)

-

13

3.9

(1

0.2

) 1

37

.1 (

14

.5)

DB

S p

aram

eter

s

mo

de

- m

on

op

ola

r (n

= 5

8 e

lect

rod

es)

bip

ola

r (n

= 2

ele

ctro

des

)

mo

no

po

lar

(n =

58

ele

ctro

des

)

bip

ola

r (n

= 2

ele

ctro

des

)

Tab

le 1

Cli

nic

al

ou

tco

me

an

d S

TN

-DB

S p

ara

met

ers

of

the

stu

dy

su

bje

cts

(n =

30

; m

ean

(S

D))

.

71

were plotted with the occipital reference region activity serving as input function

resulting in the striatal FDOPA influx constant Kocc (min –1

) which represents the rate

of striatal FDOPA uptake and storage 27

.

Calculation of disease progression and statistical analysis

Right and left striatal FDOPA Kocc and SOR values were averaged for each subject.

Within each ROI, the annual decline of FDOPA Kocc and SOR over the entire study

period was given by the difference of baseline minus follow-up PET data divided by

the duration of the individual PET follow-up period. For each individual and each

ROI, annual progression rates were then expressed in percent of baseline Kocc and SOR

values. Intra-individual differences between baseline and follow-up Kocc and SOR val-

ues and between UPDRS scores were evaluated with paired Student’s t test. Statistical

significance was accepted at the level of p < 0.05 (SPSS for Windows 10.0, SPSS UK Ltd,

Surrey, England).

Results

At the time of the follow-up PET scan, a significant clinical improvement caused by

STN-DBS was documented by a 52 % decrease of the drug-off/DBS-on UPDRS motor

score compared to the corresponding drug-off baseline value (16.5 ± 7.6 vs. 42.9 ±11.4,

p < 0.001, table 1). The levodopa equivalent daily dose (LEDD) was significantly

reduced by 28 % from 935 ± 384 mg before surgery to 670 ± 324 mg at the follow-up

PET investigation (p < 0.001). An additional dopamine agonist therapy was maintained

in the majority of patients also after surgery (agonist medication in 27/30 patients (90

%) at baseline and in 24/30 patients (80 %) at time of follow-up PET). During the fol-

low-up period, the drug-off/DBS-on UPDRS motor score remained nearly unchanged

(19.4 ± 9.1 at 6 months follow-up versus 20.4 ± 8.4 at PET-follow-up; p = 0.4, paired t

test). In contrast, a significant improvement of the corresponding drug-on value was

found at 6 months versus baseline (13.8 ± 6.9 vs. 16.5 ± 7.6; p < 0.05), which was, how-

ever, lost at the PET follow-up (16.0 ± 7.4, p < 0.01 versus 6 months scores, p = 0.7 ver-

sus baseline). Data on clinical outcome and STN-DBS parameters are summarized in

table 1.

Both PET investigations showed a similar FDOPA uptake reduction pattern with a

more severely affected putamen compared to the caudate nucleus (table 2). The mean

striatal Kocc and SOR values decreased significantly during the follow-up period (table

2 and figure 1). The annual decline of Kocc values was 0.00041 ± 0.00071 min-1

in the cau-

date and 0.00049 ± 0.00074 min-1

in the putamen (table 3). Likewise, SOR values

decreased by 0.10 ± 0.11 per year in the caudate and by 0.08 ± 0.10 per year in the puta-

men. These decline rates were reflected in the following annual progression rates re-

lative to baseline: 9.5 ± 12.4 % in the caudate and 10.7 ± 17.9 % in the putamen (mea-

sured with the Kocc method) as well as 12.1 ± 11.6 % in the caudate and 12.4 ± 14.3 %

in the putamen (measured with the SOR approach). Progression data based on SOR

values were nearly identical in both study centers (table 3). No significant correlations



72

Chapter 5

were found between PET progression rates determined with either method and the

clinical deterioration measured with UPDRS motor scores (data not shown).

Discussion

This prospectively designed two-center FDOPA-PET study is the first which objective-

ly measured disease progression in PD patients with clinically effective bilateral STN

DBS. In a total of 30 patients, a significant decrease of striatal FDOPA uptake was do-

cumented over the 16 month follow-up period which corresponded to progression

rates ranging from 9.5 to 12.9 % loss of baseline radiotracer binding per year depend-

ing on the used PET data analysis approach. Therefore, our data are the first to prove

a continuing decline of dopaminergic function also in PD subjects with effective STN

stimulation.

Our data are in good agreement with disease progression rates which had been repor-

ted in previous studies on medically treated PD patients establishing FDOPA-PET as

a valid tool for PD progression measurement 28-30

. For example, Morrish and colleagues

found an average annual decline of 12.5 % from baseline in the putamen and 4 % from

baseline in the caudate 29

. More recent SPECT and PET studies using the dopamine

transporter ligands [123

I]β-CIT and [18

F]CFT also reported 4 to 12.5 % baseline progres-

sion in the caudate nucleus and 8 to 13.1 % in the putamen 14, 31

. However, most of these

studies investigated PD patients in earlier disease stages compared with our STN sti-

mulated cohort. Therefore, our results are the first to show a comparable rate of

dopaminergic deterioration even in PD patients with a long disease duration and

severe motor complications at the time of baseline PET. In line with the cited previous

studies, we found a high inter-individual variability of disease progression rates in our

STN patients reflected by high standard deviations and 95% confidence intervals of

the data. Differences in PET data acquisition and analysis can be widely disregarded

as causal factors in view of nearly identical results in both study centers. Since in both

centres, the two PET scans in each patient were performed in a completely identical

manner on the same PET camera, methodological differences should not influence the

percentage baseline progression values. Thus, our data are in agreement with a high

inter-individual biological variability in the velocity of dopaminergic degeneration

even in advanced PD patients.

In line with our PET data, two recent long-term follow up studies on STN DBS repor-

ted a slight increase of UPDRS motor scores over 2 and 5 years resp., in particular a

worsening of axial symptoms subscores such as akinesia, postural instability and

freezing of gait 5, 6

. In contrast, Herzog et al. found no relevant deterioration of UPDRS

scores in their two-year-follow up of 20 STN-DBS patients 4

. However, it has to be kept

in mind that clinical data on PD progression are regularly influenced by hang over

effects of medication on the “drug off, stimulation on” motor performance and also of

73

Ba

seli

ne

FD

OP

A-P

ET

F

oll

ow

-up

FD

OP

A-P

ET

Ko

cc[m

in-1

]S

OR

K

occ

[m

in-1

]S

OR

Co

log

ne

0.0

07

6 (

0.0

02

1)

0.8

5 (

0.2

0)

0.0

06

7 (

0.0

02

0)

0.7

1 (

0.2

1)

a

Ca

ud

ate

G

ron

ing

en

- 0

.94

(0

.32

) -

0.6

5 (

0.2

7)

b

To

tal

0.0

07

6 (

0.0

02

1)

0.8

8 (

0.2

4)

0.0

06

7 (

0.0

02

0)

**

0.6

9 (

0.2

3)

**

*

Co

log

ne

0.0

04

2 (

0.0

01

0)

0.6

5 (

0.1

5)

0.0

03

6 (

0.0

01

1)

0.5

5 (

0.1

9)

a

Pu

tam

en

Gro

nin

gen

-

0.6

8 (

0.1

9)

- 0

.49

(0

.20

) b

To

tal

0.0

04

2 (

0.0

01

0)

0.6

6 (

0.1

6)

0.0

03

6 (

0.0

01

1)

*

0.5

2 (

0.1

9)

**

*



Tab

le 2

Str

iata

l F

DO

PA

infl

ux

co

nst

an

ts (

Kocc

) a

nd

SO

R v

alu

es a

t b

ase

lin

e a

nd

fo

llo

w-u

p P

ET

sca

ns

(n =

30

; m

ean

(S

D))

.

dif

fere

nce

bet

wee

n t

ota

l bas

elin

e an

d f

oll

ow

-up v

alues

: * p

< 0

.05,

** p

< 0

.01,

*** p

< 0

.001 (

pai

red t

tes

t)

length

of

the

foll

ow

-up p

erio

d (

mea

n ±

SD

): a

15.6

± 3

.6 m

onth

s (n

= 2

0),

b 2

7.0

± 8

.8 m

onth

s (n

= 1

0)

norm

al r

anges

in h

ealt

hy c

ontr

ols

:

SO

R:

caudat

e 1.6

8 ±

0,2

5,

puta

men

1.6

9 ±

0.2

9 (

n =

7,

age

56 ±

9 y

ears

)

Kocc

: ca

udat

e 0.0

125 ±

0.0

015 m

in-1,

puta

men

0.0

126 ±

0.0

013 m

in-1

(n =

16;

age

54 ±

12 y

ears

)

74

Chapter 5

An

nu

al

red

uct

ion

of

An

nu

al

dis

ease

pro

gre

ssio

n f

rom

ba

seli

ne

[%]

Ko

cc[m

in-1

]S

OR

K

occ

95

% C

I S

OR

95

% C

I

Co

log

ne

0.0

00

71

(0

.00

08

1)

0.1

0 (

0.1

0)

9.5

(1

2.4

) 3

.2.

– 1

4.4

1

2.2

(1

2.6

) 6

.4 –

18

.1

Cau

date

G

ron

ing

en

- 0

.11

(0

.10

) -

- 1

1.8

(1

0.0

) 4

.6 –

18

.9

To

tal

0.0

00

71

(0

.00

08

1)

0.1

1 (

0.1

0)

9.5

(1

2.4

) 3

.2.

– 1

4.4

1

2.1

(1

1.6

) 7

.7 –

16

.4

Co

log

ne

0.0

00

49

(0

.00

07

4)

0.0

8 (

0.0

9)

10

.7 (

17

.9)

2.5

– 1

8.3

1

2.8

(1

5.5

) 5

.5 –

20

.0

Pu

tam

en

Gro

nin

gen

-

0.0

8 (

0.0

8)

- -

11

.8 (

12

.4)

2.9

– 2

0.6

To

tal

0.0

00

49

(0

.00

07

40

.08

(0

.09

) 1

0.7

(1

7.9

) 2

.5 –

18

.3

12

.4 (

14

.3)

7.1

– 1

7.8

K

occ

= F

DO

PA

infl

ux c

onst

ant,

SO

R =

str

iata

l-to

-occ

ipit

al r

atio

, C

I =

co

nfi

den

ce i

nte

rval

Ta

ble

3

An

nu

al

red

uct

ion

of

stri

ata

l K

occ

an

d S

OR

va

lues

an

d d

isea

se p

rogre

ssio

n r

ate

s fr

om

ba

seli

ne

(n =

30

; m

ean

(S

D))

.

75

DBS on the “drug off, stimulation off” condition 32

. Therefore, the most important

value of our study is the objective monitoring of dopaminergic decline by using

FDOPA as a PET biomarker. In our study subjects, we also found a slight and with

respect to the drug-on data significant deterioration of the UPDRS scores over time.

The absent correlation of clinical and PET-based progression rates is line with previ-

ous longitudinal FDOPA-PET studies in medically treated PD patients 33

. The main rea-

son for this might be the effective long-term control of dopamine deficiency signs by

STN stimulation in the “drug-off, stimulation on” condition, but our PET data suggest

that DBS rather masks than prevents clinical PD progression.

We are aware that our study does not directly disprove a neuroprotective effect of

STN-DBS in due to a small sample size and a lacking randomized study design with

progression determination in the DBS and a medically treated control group.

However, this study design was not considered for ethical reasons since the empirical-

ly well proven symptomatic relief of PD symptoms by STN-DBS would have been

withheld to severely handicapped patients for at least one year. Thus, our data mere-

ly prove an ongoing significant loss of dopaminergic function within the first 2 years

of STN stimulation in advanced PD which, however, makes a clinically relevant neu-

roprotective effect of STN stimulation highly unlikely.

The presumption of neuroprotective properties of STN stimulation was essentially

based on its putative blocking effect on glutamatergic STN hyperactivity which is con-

sidered as an important etiological factor for excitotoxicity and cell death within the

substantia nigra 8

. Though the reasons for the lack of protective STN-DBS effects



Figure 1. Significant reduction of the striatal FDOPA uptake from baseline to follow-up PET calculated withthe SOR (n = 30, left panel) and the Kocc method (n = 20, right panel).

remain unclear, our findings can be interpreted as indirect arguments against the neu-

ron inhibiting theory of DBS. Corroborating this view, recent PET studies showed a

local increase of energy metabolism in the midbrain and the STN target area under

effective STN-DBS suggesting rather activating than blocking stimulation effects 20, 34

.

Recent animal studies showed increased glutamate levels in the internal pallidum of

normal rats and elevated firing rates of internal pallidum neurons in parkinsonian

monkeys during chronic STN stimulation 35, 36

. These data demonstrating vascular and

metabolic activation in the DBS target region and its projection sites suggest that STN

stimulation might originate a high-frequent, tonic and regular neuronal activity pat-

tern (so-called neuronal jamming) which replaces an abnormally synchronized and

oscillating basal ganglia firing characteristic for the parkinsonian state 37, 38

. Thus, it is

probable that the glutamatergic transmission as well as the excitotoxic drive from STN

to the substantia nigra is not diminished by chronic STN stimulation alone.

From a clinical point of view, our PET data might help to maintain realistic expecta-

tions from STN stimulation, that is a strong symptomatic relief, but not a slowing of

disease progression or even a cure from the disorder. They also underline the need of

a careful pre-surgical information of DBS candidates with respect to realistic treatment

goals and to the unchanged progressive character of PD after surgery. However, it has

to be kept in mind that our study failed to show a mitigation of disease progression

only in advanced PD patients with STN stimulation. Our data cannot rule out that STN

DBS might have a disease modifying effect in earlier PD stages which might help to

prevent these patients from the development of severe on-off fluctuations and levo-

dopa-induced dyskinesias. Future research on this important question is needed.

In conclusion, this is the first PET study to demonstrate that the decline of dopami-

nergic function proceeds in advanced PD despite clinically effective bilateral STN

stimulation. Therefore, neuroprotective properties of DBS in the STN target could not

be confirmed. Nevertheless, it has to be emphasized that STN-DBS is a very effective

treatment option offering a favourable symptomatic long-term efficacy to advanced

PD patients with treatment fluctuations or an otherwise intractable tremor. Further

research is needed to investigate whether DBS of subcortical targets might still play a

role in a more comprehensive neuroprotective treatment concept.

Acknowledgements

This study was supported by the Stichting Internationaal Parkinson Fonds, Hoofddorp

(the Netherlands).

76

Chapter 5

77

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13. Nakao N, Nakai E, Nakai K, Itakura T. Ablation of the subthalamic nucleus supports the survival of nigral dopaminergic neurons after nigrostriatal lesions induced by the mitochondrial toxin 3-nitropropionic acid. Ann Neurol 1999;45:640-51.

14. Nurmi E, Ruottinen HM, Kaasinen V et al. Progression in Parkinson’s disease: a positron emissiontomography study with a dopamine transporter ligand [18F]CFT. Ann Neurol 2000;47:804-8.

15. Morrish PK, Sawle GV, Brooks DJ. The rate of progression of Parkinson’s disease. A longitudinal [18F]DOPA PET study. Adv Neurol 1996;69:427-31.

16. Leenders KL, Palmer AJ, Quinn N et al. Brain dopamine metabolism in patients with Parkinson’s disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry 1986;49:853-60.



78

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17. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427-42.

18. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-4.


20. Hilker R, Voges J, Weisenbach S et al. Subthalamic nucleus stimulation restores glucose metabo-lism in associative and limbic cortices and in cerebellum: evidence from a FDG-PET study in advanced Parkinson’s disease. J Cereb Blood Flow Metab 2004;24:7-16.

21. Voges J, Volkmann J, Allert N et al. Bilateral high-frequency stimulation in the subthalamic nu-cleus for the treatment of Parkinson’s disease: correlation of therapeutic effect with anatomicalelectrode position. J Neurosurg 2002;96:269-79.

22. Fahn S, Elton RL. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, editors. Recent development in Parkinson’s disease. Florham Park, NJ: Mac-Millan Health Care Information; 1987:153-63.

23. Wienhard K, Dahlbom M, Eriksson L, et al. The ECAT EXACT HR: performance of a new highresolution positron scanner. J Comput Assist Tomogr 1994;18:110-8.

24. Wienhard K, Eriksson L, Grootoonk S, Casey M, Pietrzyk U, Heiss WD. Performance evaluation of the positron scanner ECAT EXACT. J Comput Assist Tomogr 1992;16:804-13.

25. Pietrzyk U, Herholz K, Fink G et al. An interactive technique for three-dimensional image regi-stration: validation for PET, SPECT, MRI and CT brain studies. J Nucl Med 1994;35:2011-8.

26. Dhawan V, Ma Y, Pillai V et al. Comparative analysis of striatal FDOPA uptake in Parkinson’s di-sease: ratio method versus graphical approach. J Nucl Med 2002;43:1324-30.

27. Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 1985;5:584-90.

28. Morrish PK, Rakshi JS, Bailey DL, Sawle GV, Brooks DJ. Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F]dopa PET. J Neurol NeurosurgPsychiatry 1998;64:314-9.

29. Morrish PK, Sawle GV, Brooks DJ. An [18F]dopa-PET and clinical study of the rate of progression in Parkinson’s disease. Brain 1996;119:585-91.

30. Vingerhoets FJ, Snow BJ, Lee CS, Schulzer M, Mak E, Calne DB. Longitudinal fluorodopa positronemission tomographic studies of the evolution of idiopathic parkinsonism. Ann Neurol 1994;36:759-64.

31. Marek K, Innis R, van Dyck C, et al. [123I]beta-CIT SPECT imaging assessment of the rate of Parkinson’s disease progression. Neurology 2001:57:2089-94.

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33. Brooks DJ. Monitoring neuroprotection and restorative therapies in Parkinson’s disease with PET. J Neural Transm Suppl 2000:125-37.

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34. Hilker R, Voges J, Burghaus L et al. Deep Brain Stimulation of the STN activates the electrode target area in patients with advanced Parkinson’s disease. Mov Disord 2004;19:S300.

35. Windels F, Bruet N, Poupard A et al. Effects of high frequency stimulation of subthalamic nucle-us on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat.Eur J Neurosci 2000;12:4141-6.

36. Hashimoto T, Elder CM, DeLong MR, Vitek JL. Responses of pallidal neurons to electrical stimu-lation of the subthalamic nucleus in experimental primates. Mov Disord 2001;15:S31

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38. Miller WC, DeLong MR. Parkinsonian symptomatology. An anatomical and physiological analy-sis. Ann N Y Acad Sci 1988;515:287-302.



80

Hoofdstuk 5

Chapter 6

Presurgical FDOPA-PET and motor outcome of subthalamic nucleus

stimulation in Parkinson’s Disease

Portman AT1

, van Laar T1

, Staal MJ2

, Maguire RP1

, Pruim J3

, Leenders KL 1


the Netherlands


the Netherlands


Submitted

81

Abstract

Objective: to predict the efficacy of STN-DBS on motor disability by quantification of

the presurgical presynaptic striatal dopaminergic function in a selected population of

levodopa responsive PD patients.

Methods: motor improvement after STN-DBS was analysed in a series of 19 patients

with advanced PD at 12 and 24 months after surgery, and motor scores were related to

presurgical putamen FDOPA-PET data.

Results: motor scores after STN-DBS were negatively correlated to presurgical FDOPA-

PET data.

Conclusion: FDOPA-PET is not a meaningful predictor of surgical outcome of STN-

DBS. Our study data might support the hypothesis that the efficacy of STN-DBS on

motor symptoms in PD is modulated at the poststriatal level and downstream within

the basal ganglia circuitry.

Chapter 6

82

Introduction

Idiopathic Parkinson’s disease (PD) is a progressive, neurodegenerative disease, which

is clinically characterised by an asymmetric onset of bradykinesia, rigidity and resting

tremor 1

. Current drug therapy in PD is symptomatic and primarily aimed at resto-

ring dopaminergic function in the striatum, and levodopa remains the most effective

treatment 2

. However, its long-term use is associated with the inevitable development

of motor fluctuations and dyskinesia despite optimisation of pharmacological treat-

ment 3

.

A selected population of PD patients with severe motor complications are suitable can-

didates for surgical intervention, especially Deep Brain Stimulation (DBS) of the sub-

thalamic nucleus (STN)4

. Several longitudinal studies have shown a convincing im-

provement in almost all cardinal motor features of PD by chronic bilateral STN-DBS5-8

.

It is assumed that patients’ preoperative dopamine responsiveness predicts the clinical

efficacy of STN-DBS. However, not all PD patients benefit equally from surgery, and

thus far only few studies have attempted to assess additional clinical predictive factors

of successful STN-DBS 9-12

. In this study we related the efficacy of STN-DBS on motor

disability to the presurgical presynaptic striatal dopaminergic function, by means of

18-Fluorodopa Positron Emission Tomography (FDOPA-PET) and levodopa respon-

siveness, in a selected population of PD patients.

83

Presurgical FDOPA-PET and motor outcome of subthalamic nucleus stimulation in Parkinson’s Disease

Chapter 6

84

Methods

Patients

During a 4-year period 20 PD patients, 10 women and 10 men, were selected by one of

the investigators at our outpatients’ Movement Disorder Unit and initially included in

the study. All patients suffered from severe motor fluctuations and dyskinesia and

were therefore selected for chronic bilateral STN-DBS. 1 female patient (age 52 years,

disease duration 18 years) was retrospectively excluded from the study because she

only had 1 DBS electrode positioned (due to surgical complications), although she

completed the clinical follow up. Their mean age (n = 19) was 61 ± 8 years, and all

patients showed preserved levodopa responsiveness with a substantial improvement

(mean 23 ± 9, range 8-40) on the Unified Parkinson’s Disease Rating Scale (UPDRS) part

III score 13

. All patients were treated with levodopa (and a peripheral decarboxylase

inhibitor) and dopamine agonists. For additional patient characteristics see table 1.

Additional inclusion criteria for surgery, according to the CAPSIT-PD protocol 14

, were:

no depression (Montgomery and Asberg Depression Rating Scale, score < 19) nor

dementia (Mattis Dementia Rating Scale, score > 130), no abnormalities on cerebral

MRI, and no recent psychiatric illness nor restricted physical condition for surgery.

This study was approved by the hospital ethics committee and all patients gave their

informed consent prior to study inclusion.

Clinical evaluation

Patients were evaluated clinically at baseline (3 - 6 months before planned surgery), 12

months (n = 19) and 24 months (n = 8) after STN-DBS. Antiparkinsonian medication

was kept unchanged during a period of 2 weeks prior to all assessments. The patients’

motor status was obtained using the UPDRS part III in off- (after withdrawal of all

parkinsonian medication overnight) and on- (1 ½ hour after regular, postponed, early

morning levodopa dosage) medication condition. Postoperatively the UPDRS part III

was assessed in the on-stimulation condition.

Surgery

Before surgery all antiparkinsonian medication was withdrawn overnight. All patients

had surgery in the supine position by the same neurosurgeon (MJS). A 3D-volume T1

weighted MRI scan (Siemens Sonata Vision, 1 ½ Tesla) was performed with the Leksell

G frame in place, generating 2 mm-slices, which were transferred subsequently into a

computerised planning system (@TargetBrainLAB). These images were then fused

with a preoperative MRI T2-weighted scan and after depiction of the AC-PC line the

STN Talairach coordinates were determined by direct visualisation of the STN in

anatomical reference to well known anatomical landmarks. The targeting was com-

pleted using semi-micro electrode (SME) recording in combination with macro-stimu-

lation and assessment of the clinical effect. Finally, the SME was replaced by a

quadripolar lead (Medtronic, Minneapolis, MN; type 3389, containing 4 electrode con-

tacts over a length of 7,5 mm) on both sides. Postoperatively the position of the lead

85

was verified by skull X-ray and T2-weighted MRI, and additionally the MRI images

were fused with the target planning MRI. After surgery the patients’ peroperative cli-

nical response was reproduced through external STN-stimulation. One week later the

programmable pulse generator (Kinetra, Medtronic) was implanted in a subclavicular

subcutaneous pocket and connected with the DBS leads by two extension wires.

Finally, dopaminergic therapy and DBS stimulation parameters were gradually adjus-

ted by the investigators based on the patients’ best clinical response.

PET data acquisition and analysis

All PET measurements were performed at the UMC PET Center on a Siemens ECAT

951 (n = 8; 6 men, 2 women) or Exact HR + (n = 11; 3 men, 8 women) scanner in a 2 D-

mode. In each patient a single FDOPA-PET scan was undertaken 4 ± 3 months (range:

1 - 10) prior to STN electrode implantation. Subjects were positioned supine in a res-

ting state with their eyes closed and ears unplugged. After pre-treatment with 2 mg/kg

carbidopa orally to block peripheral dopamine decarboxylase activity, 185 ± 31 MBq

FDOPA was injected intravenously over 1 minute with an infusion pump. All subjects

were measured following a static or dynamic scanning protocol with identical time

range for data analysis. The static protocol consisted of 1 single scan from 90-120 min-

utes post-injection. The dynamic protocol consisted of 21 time frames with increasing

duration over a period of 120 minutes; then the last 2 frames (2 x 900 sec) were ave-

raged to create a volume equivalent to the static protocol. Linear normalisation with

SPM99 15

(Fil, London) was used to align the measured volume data to a rCBF template

fixed in Talairach co-ordinate space 16

. Region of interest (ROI) analysis was based a

standardised template fixed in Talairach coordinate space. This template, consisting of

6 regions of interest (ROI) (putamen, caudate, and occipital lobe on both sides) was

used to sample the volume data and compute mean ROI activity concentration.

Specific FDOPA uptake was expressed as a striato-occipital ratio (SOR)-index follo-

wing the equation: SOR-index 17

= (CROI – CREF ) / CREF (CROI = average (left and right) ROI activity con-

centration, CREF = average occipital activity in the occipital reference region).

Clinical and statistical data analysis

The surgical efficacy of STN-DBS, e.g. the postoperative clinical response to stimula-

tion, was calculated as: improvement from stimulation = preoperative UPDRS part III

score (off-medication) – postoperative UPDRS part III score (off-medication / on-sti-

mulation) 9

. The presurgical motor response to levodopa was calculated as: improve-

ment from levodopa = preoperative UPDRS part III score (off-medication) - preope-

rative UPDRS part III score (on-medication). Spearman’s nonparametric rank correla-

tion (ρ) was used to determine predictors of clinical outcome after surgery (SPSS for

Windows 10.0, SPSS UK Ltd, Surrey, England) and a p-value of < 0.05 was considered

to indicate statistical significance.


Chapter 6

86

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88

Chapter 6

Results

All study patients completed clinical follow-up at 12 months, and additionally 8

patients were also assessed 24 months after surgery. They all underwent uncomplica-

ted surgery, while 2 patients suffered from transient confusion direct postoperatively.

The best clinical results 12 and 24 months after STN-DBS were achieved by bilateral

monopolar (n = 15), bipolar (1) or monopolar / bipolar (n = 3) stimulation. The median

frequency of stimulation was 135 Hz, the pulse width 60 µsec, and the mean voltage

2.72 ± 0.74 V (12 months) and 2.54 ± 0.52 V (24 months). STN-DBS resulted in a consi-

derable decrease in motor disability 12 and 24 months after surgery (mean reduction

in UPDRS part III off-medication score: 20 ± 9 (n = 11, range: 2 – 35) and 23 ± 8 (n = 8,

14 - 35). The mean putamen FDOPA-uptake was 0.58 ± 0.21 (range: 0.27 - 0.98).

Negative correlations were found between presurgical putamen FDOPA uptake and

the surgical outcome at 12 (n = 19, ρ = -0.485, p = 0.049) (see figure 1) and 24 months

after surgery (n = 8, ρ = -0.712, p = 0.048). No significant correlations were found

between the surgical outcome and presurgical motor response to levodopa at 12 (ρ =

0.062, p = 0.8) and 24 (ρ = 0.38, p = 0.35) months after STN-DBS, nor between presurgi-

cal putamen FDOPA uptake and presurgical levodopa responsiveness (ρ = -0.38 and p

= 0.88 respectively).

Discussion

This is the first study aimed at providing a non clinical predictor of the motor efficacy

of STN-DBS in advanced PD by means of assessment of the presurgical nigrostriatal

dopaminergic status in individual patients. Thus far only one indirect measure of stri-

atal dopamine integrity (levodopa responsiveness) has been used as an important cli-

nical predictor of surgical efficacy, and reports thus far showed an excellent outcome

of STN-DBS in levodopa-responsive forms of PD 10;12

. However, additional clinical

patient characteristics have been less predictive or study results seem conflicting, and

further individual data on “non-responders” are mostly lacking 9-12

.

Our study confirms the long term efficacy of STN-DBS in levodopa responsive PD, and

the postsurgical reduction in motor disability equals those stated previously 7;8

. The

mean putamen FDOPA uptake in our study population was 34 % of healthy controls,

and individual uptake ratios were in the range of values of PD patients with an

advanced nigrostriatal dopaminergic deficit 17

.

The presurgical nigrostriatal integrity in our patient population, as assessed by puta-

men FDOPA-PET, was negatively correlated to the achieved surgical efficacy of STN-

DBS at clinical follow-up. This finding is somewhat counterintuitive. However, it can

be argued that the more severely lesioned nigrostriatal dopaminergic system leaves

more “room” for clinical improvement if by way of STN-DBS alternative neuronal net-

works can be activated or inhibited, in order to circumvent the deleterious influence of

the nigrostriatal dopaminergic lesion.

89

Since a low putaminal FDOPA uptake reflects a high presynaptic enzymatic nigrostri-

atal deficit, our data might reflect the hypothesis that the efficacy of STN-DBS on

motor symptoms in PD is mainly achieved at the poststriatal level. In addition, it is

suggested that STN-DBS may work only or mainly downstream within the basal gan-

glia simply by altering or blocking the transmission of pathological information to the

thalamocortical and brainstem motor area 18

. This hypothesis is further supported by

recent studies demonstrating that the main mechanism of action of STN-DBS seems

not related to an increased dopamine release by modulation of dopaminergic activi-

ty19;20

. In addition, we recently finished a study on PD disease progression after STN-

DBS using serial FDOPA-PET, and demonstrated a continuing and ongoing decline of

dopaminergic function in PD after successful surgery (personal communication).

Although in our study a negative correlation was found between preoperative FDOPA

uptake and surgical outcome, this association is too weak to predict meaningfully pre-

operatively the outcome of STN surgery. In addition, accurate placement of DBS elec-

trodes and adjustment of DBS stimulation parameters optimise clinical improvement

and remain important critical factors to obtain maximum benefit of stereotactic sur-

gery 21

.

Case numbers correspond to patient numbers used in table 1. Broken lines indicate mean regression prediction line and 95% confidence interval.

Mean putamen FDOPA-PET control values (UMC, Groningen):- healthy volunteers (56 ± 19 years, n = 10): 1.69 ± 0.29- PD patients (64 ± 6 years, disease duration 9 ± 3 years, n = 18): 0.79 ± 0.10

Figure 1. Mean putamen FDOPA uptake and motor improvement 12 months after STN-DBS.


90

Chapter 6

In conclusion, FDOPA-PET is not a meaningful predictor of surgical outcome of STN-

DBS, and our data might support the hypothesis that the efficacy of STN-DBS on

motor symptoms in PD is modulated at a level downstream within the basal ganglia

circuitry.

Acknowledgement

The authors wish to thank R.E. Stewart (Groningen University Medical Center) for his

statistical support. This study was funded by a donation from the Stichting

Internationaal Parkinson Fonds (Hoofddorp, the Netherlands).

91

References

1. Lang AE, Lozano AM. Parkinson's disease. First of two parts. N Engl J Med 1998;339:1044-53.

2. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for Parkinson's di-sease: an evidence based assessment. Lancet 2002;359:1589-98.

3. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management ofParkinson's disease (2001): treatment guidelines. Neurology 2001;56:S1-S88.

4. Goetz CG, Hinson VK. Therapies for movement disorders. Arch Neurol 2002;59:699-702.

5. Deuschl G, Wenzelburger R, Kopper F, Volkmann J. Deep brain stimulation of the subthalamicnucleus for Parkinson's disease: a therapy approaching evidence-based standards. J Neurol2003;250 (Suppl 1):I43-I46.

6. Esselink RA, de Bie RM, de Haan RJ, Lenders MW, Nijssen PC, Staal MJ et al. Unilateral pallido-tomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial. Neurology2004;62:201-7.

7. Herzog J, Volkmann J, Krack P, Kopper F, Potter M, Lorenz D et al. Two-year follow-up of subtha-lamic deep brain stimulation in Parkinson's disease. Mov Disord 2003;18:1332-7.

8. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C et al. Five-year follow-up ofbilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med2003;349:1925-34.

9. Charles PD, Van Blercom N, Krack P, Lee SL, Xie J, Besson G et al. Predictors of effective bilateralsubthalamic nucleus stimulation for PD. Neurology 2002;59:932-4.

10. Jaggi JL, Umemura A, Hurtig HI, Siderowf AD, Colcher A, Stern MB et al. Bilateral stimulation ofthe subthalamic nucleus in Parkinson's disease: Surgical efficacy and prediction of outcome.Stereot Funct Neurosurgery 2004;82:104-14.

11. Pinter MM, Alesch F, Murg M, Helscher RJ, Binder H. Apomorphine test: a predictor for motorresponsiveness to deep brain stimulation of the subthalamic nucleus. J Neurology 1999;246:907-13.

12. Welter ML, Houeto JL, Tezenas du MS, Mesnage V, Bonnet AM, Pillon B et al. Clinical predictivefactors of subthalamic stimulation in Parkinson's disease. Brain 2002;125:575-83.

13. Fahn S, Elton R.L., Members of the UPDRs development committee. Unified Parkinson's DiseaseRating Scale. In: Fahn S, Marsden CD, Calne D.B., Goldstein M. (eds.). Recent developments inParkinson's disease. New Jersey: MacMillan 2000: 293-304.

14. Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical inter-ventional therapies in Parkinson's disease (CAPSIT-PD). Mov Disord 1999;14:572-84.

15. Friston KJ. Commentary and Opinion .2. Statistical Parametric Mapping - Ontology and CurrentIssues. Cereb Blood Flow and Metab 1995;15:361-70.


16. Talairach J, Tournoux P. Co-planar stereotactic atlas of the human brain. New York: ThiemeMedical Publishers, 1988.

17. Dhawan V, Ma Y, Pillai V, Spetsieris P, Chaly T, Belakhlef A et al. Comparative analysis of striatalFDOPA uptake in Parkinson's disease: ratio method versus graphical approach. J Nucl Med2002;43:1324-30.

18. Abosch A, Kapur S, Lang AE, Hussey D, Sime E, Miyasaki J et al. Stimulation of the subthalamicnucleus in Parkinson's disease does not produce striatal dopamine relaease. Neurosurgery2003;53:1095-102.

19. Hilker R, Voges J, Ghaemi M, Lehrke R, Rudolf J, Koulousakis A et al. Deep brain stimulation ofthe subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonianhumans. Mov Disord 2003;18:41-8.

20. Thobois S, Fraix V, Savasta M, Costes N, Pollak P, Mertens P et al. Chronic subthalamic nucleusstimulation and striatal D2 dopamine receptors in Parkinson's disease - A [C-11]-raclopride PETstudy. J Neurology 2003;250:1219-23.

21. Moro E, Esselink RJ, Xie J, Hommel M, Benabid AL, Pollak P. The impact on Parkinson's diseaseof electrical parameter settings in STN stimulation. Neurology 2002;59:706-13.

92

Chapter 6

Chapter 7

Summary and conclusions

93

Summary

Parkinson’s Disease (PD) is characterised by the progressive death of selected hetero-

geneous populations of neurons, including dopaminergic neurons in the mesen-

cephalon. The etiology of PD is unknown but likely results from complex environmen-

tal and genetic interactions. Clinically, the typical PD motor features (bradykinesia,

rigidity, rest tremor and eventually postural instability) often are accompanied by cog-

nitive symptomatology.

Current treatment in PD is symptomatic and basically focussed on motor symptom

control. However, since PD progresses over time nowadays a major therapeutic aim is

the halting of the underlying and ongoing disease process. Chronic bilateral Deep

Brain Stimulation (DBS) of the subthalamic nucleus (STN) has shown to improve

motor features sufficiently in a selected population of PD patients. Since glutamate-

mediated excitotoxicity of the hyperactive STN is suggested to contribute to nigrostri-

atal degeneration in PD, the clinical introduction of STN-DBS also provided an oppor-

tunity to functionally inhibit STN activity and therefore decrease disease progression.

Positron Emission Tomography (PET), using the tracer FDOPA, has provided an objec-

tive means of assessing the functional integrity of the presynaptic nigrostriatal

dopaminergic projections in vivo. Besides discriminating PD from normal popula-

tions, FDOPA-PET has shown to be an objective monitor of disease progression in PD.

The primary aim of this thesis was to prospectively determine disease progression in

a population of PD patients after STN-DBS by means of repetitive FDOPA-PET. In

addition, the evaluation of the clinical efficacy of STN-DBS on motor features in

advanced PD was studied. In another study we assessed the nature of the relationship

between striatal dopamine activity and cognitive impairments in PD using FDOPA-

PET and neuropsychological data. Finally, we sought to determine the predictive value

of the patients’ presurgical nigrostriatal status on motor efficacy of STN-DBS in PD

using FDOPA-PET.

In Chapter 1 we described the motor and non-motor features of PD and discussed the

differential diagnosis of parkinsonism. The current knowledge on etiology, patho-

physiology and basal ganglia function in PD was reviewed, and drug and surgical

treatment options (especially the efficacy of STN-DBS) were evaluated. In addition, the

concept that overactivity of the STN might contribute to PD progression is discussed,

and a glutamate-mediated excitotoxic hypothesis in PD was presented. Based on these

considerations we suggested that the clinical introduction of STN-DBS in PD repre-

sents a promising option to attenuate dopaminergic cell decline in PD. Chapter 2

showed the employed study design (and study population) in the UMC Groningen,

which was basically derived from the CAPSIT-PD protocol. The aim of the study in

Chapter 3 was to prospectively assess the efficacy of STN-DBS in a population of

advanced PD patients using clinical assessments and patient self reporting by means

Chapter 7

94

of daily diaries. We showed that STN-DBS reduced motor disability and severity of

motor complications significantly, and substantially improved daily “on-time” spent

without dyskinesia. These findings clearly demonstrated the efficacy of STN-DBS on

motor features in advanced PD, and in addition to clinical assessments, we recom-

mended the use of patient diaries in the evaluation of the functional motor status after

STN-DBS in PD. Chapter 4 presented data on the nature of the relationships between

striatal dopamine activity and cognitive function in PD, using presurgical FDOPA-PET

and neuropsychological data. In a population of non-demented PD patients, who

already had been selected for stereotactic surgery, putamen FDOPA uptake showed

the strongest relationship to executive functioning (flexibility) , while caudate FDOPA

uptake correlated most with the organisational aspects of executive functioning in

memory processes and fluency. We concluded that the putamen, besides being part of

the basal ganglia motor loop, also seemed involved in motor actions after cognitive

switching in PD. We tested the aforesaid STN-mediated excitotoxic hypothesis in vivo

in Chapter 5. In a prospective two-center study design we determined disease progres-

sion after successful STN-DBS in 30 patients using serial FDOPA-PET. We concluded

that the PD progression rates in patients after STN-DBS are within the range of previ-

ously reported data on non-operated PD patients, and, therefore, neuroprotective

properties of STN-DBS could not be confirmed. In Chapter 6 we sought to assess if the

nigrostriatal dopaminergic integrity predicted surgical outcome on motor disability of

STN-DBS in advanced PD. Using presurgical FDOPA-PET and clinical data, we

demonstrated that presurgical putaminal FDOPA-uptake was negatively correlated to

clinical improvement. However, we concluded that the nigrostriatal dopaminergic

integrity does not meaningfully predict surgical outcome of STN-DBS.

Conclusions of the thesis

• STN-DBS markedly ameliorates motor disability in a selected population of

advanced PD patients

• Cognitive (dys) functioning in PD is both related to caudate and putamen

dopaminergic integrity

• STN-DBS does not provide “neuroprotection”

• The nigrostriatal dopaminergic status does not meaningfully predict motor

improvement after STN-DBS in PD.

95

Summary and conclusions

Chapter 7

96

Chapter 8

Samenvatting en conclusies

97

Samenvatting

De ziekte van Parkinson (ZvP) is één van de meest vóórkomende hersenziekten. Het

wordt gekenmerkt door progressieve celdood van verschillende populaties zenuw-

cellen, waaronder dopamineproducerende neuronen in de middenhersenen. De ty-

pische motorische manifestaties van de ZvP (langzaamheid in intiatie en uitvoering

van bewegingen, spierstijfheid, trillen van ledematen en eventueel balansstoornissen),

worden vaak vergezeld door mentale ziekteverschijnselen. De oorzaak van de ZvP is

vooralsnog onbekend, maar is zeer waarschijnlijk het gevolg van complexe interacties

tussen omgevings- en genetische factoren. De huidige (mediamenteuze en chirurgi-

sche) behandelingen van de ZvP zijn symptomatisch en met name gericht op vermin-

dering van de motorische klachten. Gezien het feit dat deze behandelingen géén

invloed uitoefenen op de onderliggende ziekteprogressie, is men op zoek naar een

therapie die deze ziekteprogressie verlangzaamt of zelfs stopt.

Chronische dubbelzijdige “Deep Brain Stimulation” (DBS) van de subthalamische

kern (STN) is een relatief nieuwe, stereotactisch uitgevoerde hersenoperatie die bij de

ZvP kan worden toegepast. STN-DBS werkt waarschijnlijk via remming van de “over-

activiteit” van de STN bij de ZvP en leidt tot een sterke verbetering van motorische

klachten. Echter, deze overactiviteit van de STN (via “glutamaat-gemedieerde excito-

toxiciteit”) zou mogelijk óók kunnen bijdragen aan de versnelde celdood van

dopaminecellen bij de ZvP. Toepassing van STN-DBS zou dan, naast het verlichten van

ziektesymptomen, ook ziekteprogressie kunnen vertragen. Positron Emmissie

Tomografie (PET) is een nucleair geneeskundige onderzoekstechniek, waarbij m.b.v.

de tracer FDOPA een betrouwbare maat kan worden verkregen van het nigrostriatale

dopaminerge systeem. FDOPA-PET onderzoek is tevens in staat om ziekteprogressie

bij de ZvP te objectiveren en te kwantificeren.

Het doel van de studies in dit proefschrift was allereerst, om, via herhaald FDOPA-

PET onderzoek, na te gaan of de ziekteprogressie van de ZvP door STN-DBS wordt

beïnvloedt. Tevens werd de klinische effectiviteit van STN-DBS op motorische symp-

tomen van de ZvP onderzocht, en werd de relatie tussen mentale ziektesymptomen en

striataal dopaminegebrek bij de ZvP nader geëvalueerd. Tenslotte onderzochten we of

de presynaptische nigrostriatale dopaminestatus een voorspellende waarde bezet ten

aanzien van de klinische effectiviteit van STN-DBS bij de ZvP.

In Hoofdstuk 1 beschreven we de motorische en niet-motorische kenmerken van de

ZvP, alsmede de diffentiaaldiagnose van parkinsonisme. De huidige kennis omtrent

etiologie en pathofysiologie bij de ZvP werd besproken, en huidige therapeutische

opties, en dan met name STN-DBS, werden geëvalueerd. Aansluitend werd de

mogelijke relatie tussen STN-overactiviteit en ziekteprogressie bij de ZvP bedis-

cussieerd, en de glutamaat-gemedieerde excitotoxische hypothese geïntroduceerd. We

concludeerden dat de klinische toepassing van STN-DBS bij de ZvP tevens de

Chapter 8

98

mogelijkheid biedt tot onderzoek naar de potentiële neuroprotectieve eigenschappen

van deze chirurgische ingreep. In Hoofdstuk 2 werden de gehanteerde inclusiecriteria

en onderzoeksprotocollen van alle beschreven studies in het UMCG beschreven. In

Hoofdstuk 3 onderzochten we het effect van STN-DBS op motorische symptomen van

de ZvP via klinische onderzoeken en patiëntendagboeken. We toonden aan dat STN-

DBS deze symptomen fors verbeterde: dit resulteerde dan ook in een sterke toename

van het aantal uren over de dag waarin de patiënten met goede beweeglijkheid maar

zònder overbeweeglijkheid functioneerden. Deze data bevestigden de effectiviteit van

STN-DBS bij de ZvP, en in aanvulling op de klinische onderzoeken raadden we het

gebruik van patiëntendagboeken in de evaluatie van het operatie-effect ten zeerste

aan.

Hoofdstuk 4 beschreef de relatie tussen striataal dopaminedeficiëntie en mentale func-

ties in een populatie parkinsonpatiënten, welke om klinische redenen reeds was gese-

lecteerd voor een stereotactische hersenoperatie. Uit neuropsychologische onder-

zoeken en FDOPA-PET data bleek, dat zowel putamen als caudatus FDOPA-uptake

was gerelateerd aan cognitieve maten. Waar de putamen FDOPA-opname met name

was gerelateerd aan executieve functies, d.w.z. cognitieve flexibiliteit in de vorm van

cognitief switchen en responsinhibitie, bleek de caudatus FDOPA-opname samen te

hangen met de organisatorische aspecten van executive functies (verbale geheugen en

“fluency”). We concludeerden, dat het putamen (dat deel uitmaakt van de “motor

loop” in de basale ganglia) mogelijk betrokken is bij motorische acties na een cogni-

tieve “switch”.

Aansluitend testten we in Hoofdstuk 5 de “glutamaat-gemedieerde excitotoxische

hypothese”, door overactiviteit van de STN, bij de ZvP. In een prospectieve two cen-

ter-studie bepaalden we, met behulp van repetitief FDOPA-PET onderzoek, de

dopaminerge ziekteprogressie na succesvolle STN-DBS bij 30 Parkinsonpatiënten. Op

basis van de resultaten concludeerden we dat hun ziekteprogressie niet verschilt van

die van niet-geopereerde patiënten, en een “neuroprotectief” effect van STN-DBS op

de dopaminerge celpopulatie kon dan ook niet worden bevestigd.

Tenslotte, in Hoofstuk 6 bepaalden we of de integriteit van het presynaptische nigro-

striatale systeem het operatieresultaat van STN-DBS bij de ZvP kon voorspellen. Door

middel van preoperatief FDOPA-PET onderzoek toonden we aan dat het operatie-

effect bij patiënten met de ZvP negatief was gecorreleerd aan hun preoperatieve

dopaminerge status. We concludeerden echter dat de preoperatieve nigrostriatale

dopaminerge status geen betrouwbare voorspellende waarde bezit voor het ope-

ratieresultaat van STN-DBS bij de ZvP.

99

Samenvatting en conclusies

Chapter 8

100

Conclusies van het proefschrift

• STN-DBS verbetert de motorische verschijnselen van de ZvP in een

geselecteerde patiëntenpopulatie aanzienlijk

• Het cognitieve (dys) functioneren van Parkinsonpatiënten is afhankelijk van

de dopaminerge integriteit van zowel de caudatus als het putamen

• STN-DBS geeft géén “protectie” van het nigrostriatale dopaminerge systeem

• De nigrostriatale dopaminerge status bezit geen betrouwbare voorspellende

waarde voor het operatie-effect van STN-DBS bij de ZvP

Appendices

Appendix 1 Unified Parkinson’s Disease Rating Scale part III

(Motor Examination)

Appendix 2 Modified Hoehn and Yahr Staging

Appendix 3 Schwab and England Activities of Daily Living Scale

Appendix 4 Clinical Dyskinesia Rating Scale

101

Appendices

102

Appendix 1

Unified Parkinson’s Disease Rating Scale part III (Motor Examination)

18. Speech

0 = normal

1 = slight loss of expression, diction and / or volume

2 = monotone, slurred but understandable; moderately impaired

3 = marked impaired, difficult to understand

4 = unintelligible

19. Facial Expression

0 = normal

1 = minimal hypomimia, could be normal “poker face”

2 = slight but definitely abnormal dimunition of facial expression

3 = moderate hypomimia; lips parted some of the time

4 = masked or fixed facies with severe or complete loss of facial expres-

sion; lips parted ¼ inch or more

20. Tremor at rest

0 = absent

1 = slight; present with action

2 = mild in amplitude and persistent. Or moderate in amplitude, but

only intermittently present

3 = moderate in amplitude and present most of the time

4 = marked in amplitude; interferes with feeding

21. Action or Postural Tremor of hands

0 = absent

1 = slight; present with action

2 = mild in amplitude and persistent. Or moderate in amplitude, but

only intermittently present

3 = moderate in amplitude and present most of the time

4 = marked in amplitude; interferes with feeding

22. Rigidity

0 = absent

1 = slight or detectable only when activated by mirror or other

movements

2 = mild to moderate

3 = marked, but full range of motion easily achieved

4 = severe, range of motion achieved with difficulty

103

Appendices

23. Finger Taps

0 = normal

1 = mild slowing and / or reduction in amplitude

2 = moderately impaired. Definite and early fatiguing. May have occa-

sional arrests in movement

3 = severely impaired. Frequent hesitation in initiating movements or

arrests in ongoing movement

4= can barely perform the task

24. Hand Movements

0 = normal







25. Rapid Alternating Movements of Hands

0 = normal







26. Leg Agility

0 = normal







27. Arising from chair

0 = normale

2 = low; or may need more than one attempt

3 = pushes self up from arms of seat

4 = unable to arise without help

Appendices

104

28. Posture

0 = normal erect

1 = not quite erect, slightly stooped posture; could be normal for elder

person

2 = moderately stooped posture, definitely abnormal; can be slightly

leaning to one side

4 = marked flexion with extreme abnormality of posture

29. Gait

0 = normal

1 = walks slowly, may shuffle with short steps, but no festination or

propulsion

2 = walks with difficulty, but requires little or no assistance; may have

some festination, short steps or propulsion

3 = severe disturbance of gait, requiring assistance

4 = cannot walk at all, even with assistance

30. Postural stability

0 = normal

1 = retropulsion, but covers unaided

2 = absence of postural response; would fall if not caught by examiner

3 = very unstable, tends to lose balance spontaneously

4 = unable to stand without assistance

31. Body bradykinesia and Hypokinesia

0 = none

1 = minimal slowness, giving movement a deliberate character; could be

normal for some persons. Possibly reduced amplitude

2 = mild degree of slowness and poverty of movement which is definite-

ly abnormal. Alternatively, some reduced amplitude

3 = moderate slowness, poverty or small amplitude of movement

4 = marked slowness, poverty or small amplitude of movement

105

Appendix 2

Modified Hoehn and Yahr Staging

Stage 0 No sign of disease

Stage 1 Unilateral disease

Stage 1.5 Unilateral plus axial involvement

Stage 2 Bilateral disease, without impairment of balance

Stage 2.5 Mild bilateral disease, with recovery on pull test

Stage 3 Mild to moderate bilateral disease; some postural instability;

physically independent

Stage 4 Severe disability; still able to walk or stand unassisted

Stage 5 Wheelchair bound or bedridden unless aided

Appendices

Appendices

106

Appendix 3

Schwab and England Activities of Daily Living Scale

100 % Completely independent. Able to do all chores without slowness,

difficulty or impairment. Essentially normal. Unaware of any difficulty.

90 % Completely independent. Able to do all chores with some degree of slowness,

difficulty and impairment. Might take twice as long. Beginning to be aware of

difficulty.

80 % Completely independent in most chores. Takes twice as long. Conscious of

difficulty and slowness.

70 % Not completely independent. More difficulty with some chores. Three to four times

as long in some. Must spend a large part of the days with chores.

60 % Some dependency. Can do most chores, but exceedingly slowly and with much

effort. Errors; some impossible.

50 % More dependent. Help with half of chores, slower etc. Difficulty with everything.

40 % Very dependent. Can assist with all chores, but few alone.

30 % With effort, now and then does a few chores alone or begins alone. Much help

needed.

20 % Nothing alone. Can be a slight help with some chores. Severe invalid.

10 % Totally dependent, helpless. Complete invalid.

0 % Vegetative functions such as swallowing, bladder and bowel functions are not

functioning. Bed-ridden.

(It is O.K. to select a number in between the definitions.)

107

Appendix 4

Clinical Dyskinesia Rating Scale

For hyperkinesia (defined on):

0 = non observed

1 = mild, absent at rest, present with voluntary muscle activation,

or co-activation

2 = moderate, present at rest, at rest and motion

3 = severe, present at rest and interferes with function

4 = extreme

In: Face, including grimaces, jaws, lips and tongue

Neck, involving complete head nods and rotations

Trunk, including shoulders, trunk and hips

Upper limbs, including upper arms, arms and hand (left / right)

Lower limbs, including overshooting of the legs when walking and rotations ( left / right)

For dystonia (defined off)

0 = non observed

1 = mild, observable at rest

2 = moderate, observable

3= severe, interferes with function

4 = extreme, including painful

In: Face (including tongue)

Neck, involving tension and twisting of the neck, ante- and retrocolles

Trunk, including shoulders and trunk, which includes e.g. trunchal twisting, hip rotation and

shoulder elevation

Upper limb, including upper arms, arms and hands (left / right)

Lower limbs, including rotation of the leg, thigh, calves cramping and foot elevation etc.

(left / right)

Rate highest severity observed separately for each of the 7 body parts ( max. 28).

Appendices

108

Appendices

Dankwoord

Tussen dokter en doctor lagen 7 “vette” jaren van opleiding en onderzoek, die uitein-

delijk hebben geleid tot dit proefschrift. Natuurlijk zou dit niet mogelijk zijn geweest,

zonder de meer dan prettige medewerking en ondersteuning die ik heb gekregen van

tal van personen. Dit dankwoord is dan ook speciaal voor jullie!

Allereerst veel dank aan mijn 2 promotoren, Nico Leenders en Michiel Staal.

Beste Nico. Jouw kennis op medisch, maar ook niet-medisch, gebied hebben me enorm

gestimuleerd om dit langlopende project, waarin we ooit met letterlijk niets begonnen,

tot een vruchtbaar einde te brengen. Altijd maakte je tijd vrij voor mijn talrijke “ritue-

le”, zowel zinnige als onzinnige, vragen en mededelingen, en met veel enthousiasme

was je betrokken bij mijn werkzaamheden. Bovendien was je de stimulator voor veel

sociale activiteiten die jouw “onderzoeksgroep” de afgelopen jaren heeft ondernomen,

en dat siert je enorm. Ik weet dan ook zeker dat mijn verandering van werkplek ons

goede persoonlijk contact in de toekomst niet in de weg zal staan. Tot slot: jouw dage-

lijkse vraag “is het proefschrift al af? ” kan eindelijk met een volmondig “ja” door mij

worden beantwoord. Lees!

Beste Michiel. Toen je me tijdens mijn eerste neurochirurgiestage betrok bij het toen-

malige pallidotomie-onderzoek, konden we beide (toch?) niet vermoeden dat dit de

eerste stap zou zijn tot het stereotaxie-onderzoek dat deel uitmaakt van dit proef-

schrift. Jouw specifieke kennis op het gebied van Deep Brain Stimulation en met name

jouw persoonlijke zorg voor je patiënten zijn zeer leerzaam voor mij geweest. En, niet

het onbelangrijkst: altijd heb ik onze samenwerking op alle fronten als zeer prettig

ervaren.

Mijn co-promotor Teus van Laar: ik heb zelden een energiekere dokter meegemaakt!

Jouw kennis over met name de medicamenteuze en operatieve behandeling van

Parkinsonpatiënten is bijzonder groot. Meer bijzonder nog is de zeldzame kwaliteit die

je bezit om jouw kennis goed te kunnen overdragen, in dit geval aan mij. Mijn dank is

groot!

Prof. dr. J.H.A. de Keyser, prof. dr. J.J.A. Mooij en prof. dr. R.A.C. de Roos dank ik voor

hun bereidheid om mijn proefschrift te beoordelen.

En dan Paul Maguire. Beste Paul, wereldburger, jouw kennis van PET methodologie

was absoluut noodzakelijk voor de uitvoering van alle onderzoeken. Bovendien von-

den we vaak nog tijd om obscure 80’s-songteksten met elkaar uit te wisselen, en ook

daarin bleek je nog goed. Thanks!

109

Lammy Veenma bedank ik voor al haar tijdrovende werk in alle PET-studies. Beste

Lammy, je bleek onmisbaar.

Louis Journee en Cor Kliphuis: bedankt voor jullie “stereotactische” inzet in alle voor-

afgaande jaren, het was altijd een plezier om met jullie te werken.

Rudiger Hilker dank ik voor zijn medewerking aan ons gezamenlijke onderzoek: de 1-

1 tussen Duitsland en Nederland in 2004 was achteraf dan ook een terechte uitslag!

Alle medewerkers van het PET-centrum bedank ik voor hun medewerking aan de

veelal tijdrovende onderzoeken. In het bijzonder de wetenschappelijke input van Jan

Pruim, alsmede de flexibiliteit van het secretariaat (Arja Hoekman en Erna van der

Wijk) bleken onontbeerlijk.

Ook de vakgroep Neuropsychologie verdient een pluim. Marthe Koning dank ik voor

haar inbreng in met name de opzet van de vele verrichtte protocollaire neuropsycho-

logische onderzoeken. Betere medewerking dan van Grace Grommers-Dam, Riemie

Reijntjes en Femmie Heeres in uitvoering en planning van genoemde onderzoeken

kon ik niet wensen.

Veel dank ben ik tevens verschuldigd aan Roy Stewart: beste Roy, voor jou was “De

Brug” nooit te ver om mij statistisch te ondersteunen!

Doctor van Beilen, beste Marije. Dank voor je energieke bijdrage aan ons gezamenlijke

artikel. Ik moet nu toegeven: vrouwen met gevoel voor humor, ze bestaan echt.

Renée Staal mag ik zeker niet vergeten. Beste Renée, je bent dè secretariële spil geweest

in al mijn drukke werkzaamheden vanaf het “nulpunt” tot nu. Dit belette je nooit om

ook nog eens aandacht te schenken aan mijn “sociale activiteiten”, waarvoor ik je niet

genoeg mijn waardering kan laten blijken. Bedankt!

Alle neurologen en neurochirurgen van het UMCG ben ik veel dank verschuldigd

voor de mogelijkheid die mij werd geboden om ook tijdens klinische stages mijn

onderzoeksactiviteiten te continueren.

De inzet van alle verpleegkundigen van de afdelingen Neurologie was onmisbaar in

de noodzakelijke zorg voor alle klinische patiënten: jullie belangstelling voor mijn

onderzoekswerkzaamheden heb ik altijd zeer op prijs gesteld. Hulde.

Alle medewerkers van de polikliniek Neurologie dank ik voor hun niet te onderschat-

ten bijdrage aan de zorg voor mij en mijn patiënten. De rust is vanaf nu wedergekeerd!

De collega-onderzoekers die de laatste jaren de GNIP-kamer met mij hebben gedeeld

dank ik voor hun samenwerking, uithoudingsvermogen en gezelschap in alle vooraf-

gaande tropenjaren. Het was de moeite waard! Een speciaal woord richt ik met name

tot Silvia Eshuis. Beste Sil, wij startten vanaf het begin zonder kamer en zonder ideeën,

en zie wat er van ons is geworden…. Een Friezin en een Groninger in 1 kamer: het kon

dus wel.

Jan-Willem Elting en Marc Langedijk, leden van de voormalige “bende van 4”: met

name dank voor jullie persoonlijke interesse en vriendschap in alle UMCG-jaren!

Bijna tot slot, de keuze voor Geert Sulter en Peter Vos tot mijn paranimfen was een

“inkoppertje”. Beste Geert, we hebben een prachtige opleidings- en onderzoekstijd

gehad, waarin we, met name buiten het ziekenhuisterrein, veel tijd hebben besteed aan

Dankwoord

110

onze wederzijdse niet-medische hobby’s. Ondanks je verhuizing naar het Dokkumse

ben ik blij dat we nog steeds deze contacten onderhouden, binnenkort zelfs ook vanaf

het sponsorterras, en eerlijk gezegd had ik niet anders verwacht! Beste Peter, vanaf

onze ontmoeting op Vlieland in 1982 zijn we elkaar nooit meer uit het oog verloren,

zowel privé als op “werkgebied”. Ik zal nooit vergeten dat jouw introductie van mij

in Arnhem de basis bleek voor mijn latere specialisatie tot neuroloog. Jouw visie, als

niet-medicus, op mijn werkzaamheden is altijd verhelderend (geweest), en ik ben blij

dat we menige pauze hebben kunnen “delen” in de daarvoor beschikbare, steeds

schaarser wordende, ruimtes. Geert en Peter: bedankt!

Mijn lieve ouders, pa en ma: zonder jullie onvoorwaardelijke steun, zeker in de begin-

jaren van mijn studie, was ik nooit de eerste dokter in de familie geworden. Ik ben blij

dat jullie in goede gezondheid mijn promotie kunnen bijwonen.

Lieve Stéphanie, lieve Mara: inmiddels zijn we een gezin! Jullie zijn het mooiste dat mij

ooit is overkomen.

111

Dankwoord

Dankwoord

112

113

Curriculum Vitae

Axel Portman is geboren en getogen in Groningen, alwaar hij ook zijn studie Genees-

kunde voltooide. Zijn co-schappen volgde hij in Enschede. Na een jaar als dienstplich-

tig militair arts gewerkt te hebben in Seedorf (Duitsland), werkte hij als assistent neu-

rologie in Arnhem. In 1997 startte hij met de opleiding tot neuroloog in het

Academisch Ziekenhuis te Groningen, en in 1998 begon hij aan zijn onderzoekswerk-

zaamheden die beschreven staan in dit proefschrift. Tevens was hij werkzaam op de

polikliniek Bewegingsstoornissen. Vanaf 1 april 2005 is hij als neuroloog verbonden

aan het Refajaziekenhuis te Stadskanaal.

Curriculum Vitae

114

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