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Parkinson's DiseasePortman, Axel Tiddo
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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
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.
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
.
General introduction and aims of the thesis
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
.
General introduction and aims of the thesis
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
General introduction and aims of the thesis
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
General introduction and aims of the thesis
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
General introduction and aims of the thesis
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
General introduction and aims of the thesis
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
General introduction and aims of the thesis
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
General introduction and aims of the thesis
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
General introduction and aims of the thesis
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
General introduction and aims of the thesis
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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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 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
Chronic stimulation of the subthalamic nucleus increases daily on-time
without dyskinesia in advanced Parkinson’s Disease
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
Chronic stimulation of the subthalamic nucleus increases daily on-time
without dyskinesia in advanced Parkinson’s Disease
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).
Chronic stimulation of the subthalamic nucleus increases daily on-time
without dyskinesia in advanced Parkinson’s Disease
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.
Chronic stimulation of the subthalamic nucleus increases daily on-time
without dyskinesia in advanced Parkinson’s Disease
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.
Chronic stimulation of the subthalamic nucleus increases daily on-time
without dyskinesia in advanced Parkinson’s Disease
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
1 Department of Neurology, University Medical Center, Groningen,
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
Striatal FDOPA uptake and cognition in advanced non-demented Parkinson’s Disease:
a clinical and FDOPA-PET study
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
Striatal FDOPA uptake and cognition in advanced non-demented Parkinson’s Disease:
a clinical and FDOPA-PET study
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
Striatal FDOPA uptake and cognition in advanced non-demented Parkinson’s Disease:
a clinical and FDOPA-PET study
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).
Striatal FDOPA uptake and cognition in advanced non-demented Parkinson’s Disease:
a clinical and FDOPA-PET study
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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.
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Striatal FDOPA uptake and cognition in advanced non-demented Parkinson’s Disease:
a clinical and FDOPA-PET study
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
2 Department of Neurology, University Medical Center, Groningen,
the Netherlands
3 Department of Stereotaxy and Functional Neurosurgery, Medical University
of Cologne, Cologne, Germany
4 Department of Neurosurgery, University Medical Center, Groningen,
the Netherlands
5 PET Center, University Medical Center, Groningen, 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
Disease progression continues in patients with advanced Parkinson’s Disease
and effective subthalamic nucleus stimulation
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
Disease progression continues in patients with advanced Parkinson’s Disease
and effective subthalamic nucleus stimulation
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)
**
*
Disease progression continues in patients with advanced Parkinson’s Disease
and effective subthalamic nucleus stimulation
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
Disease progression continues in patients with advanced Parkinson’s Disease
and effective subthalamic nucleus stimulation
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
References
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2. Benabid AL, Koudsie A, Benazzouz A et al. Deep brain stimulation for Parkinson’s disease. Adv Neurol 2001;86:405-12.
3. Ashkan K, Wallace B, Bell BA, Benabid AL. Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease 1993-2003: where are we 10 years on? Br J Neurosurg 2004;18:19-34.
4. Herzog J, Volkmann J, Krack P et al. Two-year follow-up of subthalamic deep brain stimulation in Parkinson’s disease. Mov Disord 2003;18:1332-7.
5. Krack P, Batir A, Van Blercom N et al. Five-year follow-up of bilateral stimulation of the subtha-lamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003;349:1925-34.
6. Kleiner-Fisman G, Fisman DN, Sime E, Saint-Cyr JA, Lozano AM, Lang AE. Long-term follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson’s disease. J Neurosurg 2003;99:489-95.
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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.
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Hoofdstuk 5
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.
19. 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.
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.
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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.
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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.
79
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.
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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.
Disease progression continues in patients with advanced Parkinson’s Disease
and effective subthalamic nucleus stimulation
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
1 Department of Neurology, University Medical Center, Groningen,
the Netherlands
2 Department of Neurosurgery, University Medical Center, Groningen,
the Netherlands
3 PET Center, University Medical Center, Groningen, 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.
Presurgical FDOPA-PET and motor outcome of subthalamic nucleus stimulation in Parkinson’s Disease
Chapter 6
86
Pat
ient
Sex
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*
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ura
tion *
U
PD
RS
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#M
edic
atio
n &
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rs
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35
14
30
00
2
F
48
14
49
31
550
3
F
62
8
46
23
2090
4
F
67
7
35
11
600
5
F
56
13
55
24
670
6
F
69
13
38
22
425
7
F
61
13
54
32
1423
8
M
48
6
2
6
8
11
10
9
F
64
14
59
32
550
10
M
5
1
1
4
6
6
4
0
1
37
5
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ble
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ara
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87
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16
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17
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7
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Presurgical FDOPA-PET and motor outcome of subthalamic nucleus stimulation in Parkinson’s Disease
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.
Presurgical FDOPA-PET and motor outcome of subthalamic nucleus stimulation in Parkinson’s Disease
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
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16. Talairach J, Tournoux P. Co-planar stereotactic atlas of the human brain. New York: ThiemeMedical Publishers, 1988.
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92
Chapter 6
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
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
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
25. Rapid Alternating Movements of Hands
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
26. Leg Agility
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
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
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
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.
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