Cholinergic systems in progressive supranuclear palsy

doi:10.1093/brain/awh391 Brain (2005), 128, 239–249

Cholinergic systems in progressive supranuclearpalsy

N. M. Warren, M. A. Piggott, E. K. Perry and D. J. Burn

Correspondence to: Dr Naomi M. Warren, Clinical

Research Fellow in Neurology, Wolfson Research Centre,

Institute for Ageing and Health, Newcastle General Hospital,

Westgate Road, Newcastle upon Tyne NE4 6BE, UK

E-mail: [email protected]

Institute for Ageing and Health, University of Newcastle

upon Tyne, UK

SummaryProgressive supranuclear palsy (PSP) is a progressive

neurodegenerative disease characterized by akinetic-rigid features, falls, a supranuclear gaze palsy and

subcortical dementia. Pathologically, there is abnormal

accumulation of tau protein. Cholinergic deficits are

thought to underlie the postural instability and cognitive

impairment of PSP, but trials of cholinergic agonists and

cholinesterase inhibitors have failed to show improvement

inmotor function, quality of life and cognitive impairment.

The five cortico-basal ganglia loops, linking functionallyrelated areas of the brain, are damaged in PSP, leading to

specific clinical deficits. Cholinergic dysfunction is related

to loss of cholinergic interneurons in the striatum,

compounded by reduced inputs into the circuits from

other cholinergic nuclei, such as the pedunculopontine

nucleus and nucleus basalis of Meynert. Normal

cholinergic transmission requires the presence of intact

cholinergic neurons capable of releasing sufficientacetylcholine, and functional muscarinic and nicotinic

receptors. Whilst there is evidence from autopsy and invivo studies of loss of cholinergic neurons in PSP, the recep-tor status isunknown.Thismaybecritical tounderstanding

the basis for the poor therapeutic response to cholinomi-

metics. Symptomatic treatment using cholinergic drugs

may thus be improved by more specific targeting of choli-

nergic receptors or nuclei. There is also evidence that cho-linergic agents may have disease-modifying effects. This

article reviews the key clinical features of PSP, along

with normal basal ganglia anatomy and cholinergic trans-

mission. Cholinergic deficits based on clinical and neuro-

chemical parameters are then discussed, before concluding

with suggested futuredirections forcholinergic treatments.

Keywords: basal ganglia; cholinergic; progressive supranuclear palsy

Abbreviations: ACh = acetylcholine; AChE = acetylcholinesterase; ChAT = choline acetyltransferase;

ChEIs = cholinesterase inhibitors; DLB = dementia with Lewy bodies; GABA = g-aminobutyric acid; LTN = laterodorsal

tegmental; nbM = nucleus basalis of Meynert; PPN = pedunculopontine nucleus; PSP = progressive supranuclear palsy

Received October 20, 2004. Revised November 29, 2004. Accepted November 30, 2004. Advance Access publication

January 13, 2005

IntroductionProgressive supranuclear palsy (PSP) is a progressive neuro-

degenerative disease characterized by parkinsonism, falls,

a supranuclear gaze palsy and subcortical dementia. It is

often misdiagnosed as Parkinson’s disease in the early stages.

Unlike Parkinson’s disease, however, the akinetic-rigid

features of PSP invariably fail to respond to dopaminergic

therapy. Cholinergic deficits are thought to be responsible for

the postural instability and cognitive impairment associated

with PSP, but to date, cholinergic replacement therapies have

been ineffective. The neurochemical basis for this therapeutic

refractoriness is uncertain.

In this review we will first summarize the key clinical

features of PSP and relevant basal ganglia anatomy, and

outline normal cholinergic transmission. Cholinergic abnor-

malities in PSP will then be reviewed from clinical and

neurochemical perspectives. Finally, future research direc-

tions will be considered for this system in the context of PSP.

Clinical features of PSP

Classic ‘Richardson’s syndrome’ (Williams et al., 2004) is

diagnosed sensitively and specifically by the National

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Institute of Neurological Disorders and the Society for Pro-

gressive Supranuclear Palsy criteria, which require the pres-

ence of falls within the first year of symptoms and a vertical

supranuclear eye movement disorder (Litvan et al., 1996a).

Mobility difficulties and falls occur due to a combination of

bradykinesia, postural instability, retrocollis and supranuclear

gaze palsy (Birdi et al., 2002; Nath et al., 2003). Most

patients exhibit parkinsonism with symmetrical bradykinesia

and rigidity, especially of the axial muscles, although tremor

is less common (Birdi et al., 2002; Nath et al., 2003). With

time, many patients develop slowing of the vertical saccades,

progressing to a restriction of vertical gaze. Bulbar symptoms

appear early in the disease course, producing a growling

dysarthrophonia and dysphagia. The latter is frequently

severe enough to require percutaneous endoscopic gastro-

stomy feeding.

Cognitive problems and neuropsychiatric symptoms may

be early features, manifesting as change in personality, for-

getfulness, irritability, anhedonia and depressed mood (Nath

et al., 2003). Depression and anxiety occur in approximately

18% of PSP patients (Litvan et al., 1996b). Apathy affects

over 90%, although it is often under-recognized and may be

mistaken for depression (Litvan et al., 1996b). The prototypic

‘dysexecutive dementia’ present in most PSP patients is evid-

enced by difficulties with verbal fluency, working memory,

concept formation, planning and execution (Grafman et al.,

1995; Soliveri et al., 2000). These features are thought to

arise from deafferentation of the prefrontal cortex from the

basal ganglia. PSP patients also exhibit severe slowness in

response time, but neuropsychiatric features associated with

other degenerative dementias, such as visual hallucinations

and fluctuating cognition, characteristic of dementia with

Lewy bodies (DLB), and profound short-term memory

loss, typical of Alzheimer’s disease, are rare.

Despite this striking and unmistakable phenotype, there is

clinical heterogeneity. Pathologically proven cases, recently

described as ‘PSP-parkinsonism’ (Williams et al., 2004),

have a more prolonged disease course, and are less likely

to present with falls and gaze paresis. Furthermore, up to half

may demonstrate a degree of levodopa responsiveness.

Accurate clinical diagnosis of PSP-parkinsonism is, unsur-

prisingly, difficult.

PathologyGiven the clinical heterogeneity of PSP, pathological dia-

gnosis remains the gold standard. Neuronal degeneration

and gliosis is found in several subcortical and brainstem

nuclei in PSP, particularly the basal ganglia. The most

distinctive pathological features are neurofibrillary tangles,

neuropil threads and tufted astrocytes, which are found

predominantly within the substantia nigra, globus pallidus,

subthalamic nucleus, midbrain, pontine reticular formations

and, to a lesser extent, the thalamus (Albers and Augood,

2001). The pedunculopontine nucleus (PPN) is also severely

affected, showing approximately 60% neuronal loss, with

neurofibrillary tangles in the remaining neurons (Zweig

et al., 1987; Jellinger, 1988). Although classically a subcor-

tical disease, neurofibrillary tangles and tufted astrocytes

have been documented in the frontal cortex, particularly

the motor cortex (Wakabayashi and Takahashi, 2004). The

pathological inclusions of PSP comprise insoluble aggregates

of four-repeat tau phosphoprotein. Tau is important in main-

taining neuronal morphology, and mobilizing and stabilizing

microtubules involved in axonal transport within the cytos-

keleton (Litvan and Hutton, 1998). Tau is also found in the

cell body and dendrites. In PSP, tau becomes hyperphos-

phorylated, but how cell death occurs and whether it is a

direct consequence of the tau protein is not known.

Basal ganglia circuitsFive parallel, closed frontal-subcortical circuits link segreg-

ated areas of the frontal cortex with the striatum and other

basal ganglia, and thalamic nuclei (Alexander et al., 1986).

The motor and oculomotor circuits originate in the supple-

mentary motor area and frontal eye fields, respectively. The

other three loops are involved in functionally distinct neuro-

behavioural features. Disruption of projections from the dor-

solateral prefrontal cortex, orbitofrontal cortex and anterior

cingulate/mediofrontal cortex correlate with executive dys-

function, social behavioural abnormalities and poor motiva-

tion, respectively (Cummings, 1993). In PSP, widespread

basal ganglia pathology is associated with dysfunction within

each of these circuits.

Open circuits connect areas functionally related to the

basal ganglia to relevant structures. Cholinergic inputs modu-

late transmission within these circuits (Fig. 1).

The PPN is a rather diffuse nucleus located in the rostral

brainstem tegmentum. It is divided into the pars compacta,

containing >90% cholinergic cells, and the pars dissipata,

Fig. 1 Overview of frontal-subcortical circuits withcholinergic inputs. GPi/e = globus pallidus interna/externa;STN = subthalamic nucleus; SN = substantia nigra;nbM = nucleus basalis of Meynert.

240 N. M. Warren et al.

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containing glutamatergic, cholinergic, dopaminergic and

adrenergic neurons (Pahapill and Lozano, 2000). The PPN

has widespread connections with the basal ganglia, the lower

brainstem and spinal cord.

Striatal organizationThe interaction between dopamine and acetylcholine (ACh)

is vital in maintaining striatal function, the key area of neural

trafficking within the basal ganglia. Medium spiny projection

neurons comprise 90–95% of the striatal neuronal population

and are inhibitory via the transmitter g-aminobutyric acid

(GABA) (Graveland and DiFiglia, 1985; Oorschot, 1996).

Projection neurons of the direct pathway predominantly

express dopaminergic D1 and muscarinic M4 receptors,

whilst D2 and M1 receptors are preferentially located on

projection neurons of the indirect pathway (Weiner et al.,

1990; Bernard et al., 1992; Ince et al., 1997).

The other 5–10% of intrinsic striatal neurons comprise

three populations of interneuron, rapidly and burst-firing

GABAergic interneurons and larger cholinergic interneurons

(1–2%) (Zhou et al., 2003). The cholinergic interneurons,

although small in number, have many axon collaterals,

enabling them to influence synaptic transmission over a large

area. They are tonically active, and stimulation by a neur-

otransmitter causes the firing of the interneurons to ‘pause’

(Zhou et al., 2002; Pisani et al., 2003). Nigrostriatal,

corticostriatal and thalamostriatal afferents all influence

interneuronal discharge. The regulation of release of ACh

from the interneurons is also, in part, via negative feedback

through M2 receptors. ACh from interneurons mediates

inhibitory effects at both glutamatergic and GABAergic

nerve terminals through an action on presynaptic M2 choli-

nergic receptors (Calabresi et al., 2000) (Fig. 2).

Cholinergic neurotransmissionCholinergic receptors are divided into muscarinic and nico-

tinic subtypes. The majority of research in PSP has focused

on the muscarinic cholinergic system, although it is likely that

nicotinic receptors will also be affected.

Muscarinic receptorsMuscarinic receptors are divided into five subgroups, termed

M1 to M5. In the brain, M1 receptors are the predominant

receptor in the cortex and hippocampus, M2 receptors in the

cerebellum and brainstem, while M4 receptors are highly

concentrated in the striatum, although there is much overlap

(Taylor and Brown, 1999). M3 and M5 receptors are found

largely in the peripheral nervous system.

ACh is formed in the presynaptic nerve terminal by the

conversion of choline and acetyl coenzyme A to ACh and

coenzyme A, catalysed by the enzyme choline acetyltransfer-

ase (ChAT). Depolarization of the nerve terminal leads to the

entry into the cell of extracellular calcium ions, which in turn

leads to ACh release over 200 ms (Taylor and Brown, 1999).

In the striatum, ACh binds to postsynaptic M1 or M4 recep-

tors, or presynaptic M2 receptors. Muscarinic receptors are

transmembrane spanning and agonist binding initiates a com-

plex cascade of events via a G protein-coupled secondary

messenger system. The G protein comprises three subunits:

a, b and g. In the inactive state the a subunit is bound to

Fig. 2 Simplified figure demonstrating presynaptic inhibitory effects of ACh via muscarinic receptor (M) activation at bothglutamatergic and GABAergic nerve terminals (based on the figure by Calabresi et al., 2000).

Cholinergic systems in PSP 241

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guanine diphosphate (GDP), and the receptor is in a low

affinity state (uncoupled from the G protein). Following ago-

nist binding, a conformational change occurs in the receptor

that activates coupling to the G protein and the receptor

transforms to a high affinity state (coupled). Coupling causes

the a subunit to release its GDP to preferentially bind guanine

triphosphate (GTP). The GTP-bound subunit interacts with an

effector (usually an enzyme) to activate the secondary mes-

senger and the interaction is terminated by GTPase within the

a subunit (Fig. 3).

The agonist is released from the receptor, returning it to the

low affinity state. Agonist binding to the M1 receptor, and

consequent coupling, stimulates phospholipase C, which

mobilizes intracellular calcium and has an overall excitatory

effect on the nerve cell. M4 binding, and its coupling to the

G protein, causes inhibition of adenylyl cyclase and calcium

channels, producing an overall inhibitory effect on the cell. In

the striatum and cortex M2 receptors are located on presy-

naptic nerve terminals. Like M4, the M2 receptors produce an

inhibitory response and once activated prevent neurotrans-

mitter release. Following release of ACh from the receptor, it

is rapidly degraded by acetylcholinesterase to prevent desens-

itization, and then transported into the presynaptic terminal as

choline for further transmitter synthesis.

In summary, M2 receptors are markers for presynaptic

neurons, ChAT and ACh levels are a measure of intraneur-

onal ACh formation and release from the terminals, and M1

and M4 receptors are postsynaptic markers.

Nicotinic receptorsNicotinic acetylcholine receptors are ligand-gated ion chan-

nels and are morphologically and pharmacologically distinct

from muscarinic receptors. The responses they produce are

fast, short-lived and excitatory. They are composed of a and

b subunits, the most common type found in the central nerv-

ous system being a4b2. Binding of acetylcholine to the

receptor causes a rapid influx of cations that leads to

depolarization. Nicotinic receptors are widely expressed

throughout the brain, with the a4b2 receptors particularly

concentrated in the striatum and substantia nigra (Court

and Clementi, 1995; Charpantier et al., 1998; Picciotto

et al., 1998). Activation of presynaptic nicotinic receptors

enhances the release of several neurotransmitters, including

dopamine (Zhou et al., 2003).

The cholinergic neurochemistry of PSPDespite the development of more selective labelling

techniques for cholinergic receptors, little research has

been directed towards PSP. Post mortem studies using immu-

nocytochemistry and autoradiography provide most of our

knowledge (Figure 4).

StriatumChAT was reduced by approximately 50% in the caudate,

40% in the putamen, 45% in the nucleus accumbens and 70%

in the substantia innominata in nine PSP patients compared

with controls (Ruberg et al., 1985). These findings were later

supported by an autoradiographic study, which demonstrated

a marked reduction in striatal ACh vesicular transporter

expression and ChAT activity in 11 PSP patients (Suzuki

et al., 2002). Nerve growth factor receptors are localized

on nucleus basalis of Meynert (nbM) and intrinsic striatal

cholinergic neurons (Villares et al., 1994). Striatal receptors

were reduced by 30% in three patients with PSP compared

with controls and patients with Parkinson’s disease (Villares

et al., 1994). These results suggest loss of striatal cholinergic

interneurons. The total number of striatal muscarinic recep-

tors measured by [3H]quinuclidynyl benzilate was similar

between controls and PSP patients in one study (Ruberg

et al., 1985). However, two further studies using [3H]N-

methyl-scopolamine, which also binds to all muscarinic

receptors, found an 18–30% reduction in the striatum

(Landwehrmeyer and Palacios, 1994; Pascual et al., 1994).

Studies using more specific ligands to distinguish between

subtypes of muscarinic receptor are needed, but to date, these

limited results suggest relative preservation of medium spiny

neurons.

Brainstem cholinergic nucleiUsing immunohistochemistry to measure ChAT activity,

many small nuclei in the brainstem can be quantitatively

measured in post mortem tissue. The PPN and laterodorsal

tegmental (LTN) nuclei are the main cholinergic nuclei in the

mesopontine tegmentum. Severely decreased ChAT levels

Pi

GDP

GDP

GTP

GTP

GTP

αβγ

α

α

βγ

βγ

agonistA

C

B

effector(enzyme)

activated 2nd

messenger

Fig. 3 Guanine–nucleotide exchange cycle. (A) Low-affinity stateof the receptor (uncoupled from G-protein. (B) High-affinity stateof the receptor (G-protein-coupled). The a subunit releases itsbound GDP and binds GTP. (C) The a subunit of the G-proteindissociates from the complex and interacts with downstreamsignalling effector, which activates the secondary messenger.Reprinted from Brain Res Brain Res Rev; 38; Sovago J, Dupuis DS,Gulyas B and Hall H. An overview on functional receptorautoradiography using [35s] GTP gamma S. pp 149–64; 2001.


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have been demonstrated in the LTN (41%), with a less

marked reduction in the PPN (19%) (Kasashima et al.,

2003). Low frequency electrical stimulation of the PPN

induces positive motor effects in normal non-human primates

(Nandi et al., 2002b), and drug-induced PPN stimulation in

parkinsonian non-human primates improves akinesia (Nandi

et al., 2002a), suggesting that degeneration of these nuclei

may contribute to akinesia and gait initiation abnormalities

(Pahapill and Lozano, 2000).

Compared with controls, ChAT in PSP is also reduced in

the Edinger–Westphal nucleus (69%), the medial longitudinal

fasiculus (97%), the superior colliculus (93%) and the inter-

stitial nucleus of Cajal (78%) (Juncos et al., 1991). Involve-

ment of the latter nucleus is thought to result in axial dystonia

and gait impairment (Carpenter et al., 1970), whilst the other

nuclei mediate eye movements and coordination (Steele,

1972) and pupillary abnormalities (Pfaffenbach et al.,

1972). Cholinergic neurons in cranial nerve nuclei III and

IV appear to be spared, consistent with the ‘supranuclear’

gaze paresis. Decreased ChAT has also been found in the

lower pontine reticular formation (Malessa et al., 1991).

Basal forebrain cholinergic nucleiThe nbM, or basal nucleus, lies within the substantia inno-

minata and is one of the main cholinergic nuclei in the brain,

with widespread projections to the cerebral cortex and hip-

pocampus. Degeneration within this nucleus has attracted

attention in relation to cognitive impairment in Alzheimer’s

disease (Mufson et al., 2000), DLB (Londos et al., 2002) and

Parkinson’s disease (Bosboom et al., 2004). Marked neuronal

loss of 12–55% (Tagliavini et al., 1983, 1984) and reduced

ChAT-positive neurons within the nbM are characteristic of

PSP (Kasashima and Oda, 2003).

ThalamusThe mediodorsal nucleus of the thalamus is innervated by

many brain regions including the LTN and the substantia

innominata, and projects to the prefrontal and premotor cor-

tices (Brandel et al., 1990). ChAT staining in controls reveals

areas of densely staining patches surrounded by less dense

matrix (Brandel et al., 1990). In five PSP patients, ChAT

labelling within the mediodorsal nucleus was reduced by

75% in the matrix and 60% in the patches (Brandel et al.,

1991). In rats the medial matrix connects to the orbitofrontal

cortex, and the densely staining patches to the dorsolateral

prefrontal cortex (Cavada et al., 1995).

Cerebral cortexChAT activity was originally reported to be reduced in the

frontal cortex in PSP by 21%, together with markedly reduced

activity within the substantia innominata (by 70% compared

with controls) (Ruberg et al., 1985). A later study reported a

modest (20%) but non-significant reduction in ChAT activity

in the frontal and temporoparietal cortex in three PSP patients

(Whitehouse et al., 1988) These results suggest damage to

the innominatocortical cholinergic projections in PSP. Two

studies of total muscarinic receptor binding showed similar

values between controls and PSP patients in the frontal cortex

(Ruberg et al., 1985; Pascual et al., 1994), consistent with the

PET study later mentioned.

No study has differentiated between muscarinic receptor

subtypes or assessed the function of the secondary messenger

system.

Nicotinic receptorsDespite the involvement of nicotinic systems in Alzheimer’s

disease, DLB and Parkinson’s disease, there have been few

reports of nicotinic receptor status in PSP. In the only pub-

lished studies, nicotinic receptors, assessed using [3H]nicot-

ine, were reduced in the frontoparietal, temporoparietal and

occipitoparietal cortices in three PSP patients compared with

controls, but the numbers were too small for statistical ana-

lysis (Whitehouse and Kellar, 1987; Whitehouse et al., 1988).

In contrast, cortical and striatal nicotinic receptors are sig-

nificantly reduced in Alzheimer’s disease, DLB and Parkin-

son’s disease (Perry et al., 1990; Rinne et al., 1991; Court

et al., 2000; Pimlott et al., 2004; Quik et al., 2004).

Future neurochemical research in PSP needs to be directed

towards more specific cholinergic receptor subset measure-

ment, with clinicopathological correlation. The interaction of

other neurotransmitters with the cholinergic and dopaminer-

gic systems also needs to be defined.

Clinical studies of cholinergic abnormalitiesin PSPThe majority of research in PSP has focused on transmitter

abnormalities within the dopaminergic system, with relat-

ively little focus on the cholinergic system. Some cholinergic

nuclei, such as those in the brainstem governing eye move-

ments, are so small that neurotransmitter abnormalities within

them cannot easily be identified, making quantation difficult.

There is some evidence, however, from in vivo and in vitro

studies that cholinergic deficits occur in PSP, although little is

known about how these abnormalities contribute to the clin-

ical features.

CSF studiesCSF acetylcholinesterase (AChE) activity is reduced in PSP

by one-third compared with control subjects (Atack et al.,

1991). The neuropeptide galanin is co-localized with acetyl-

choline on neurons of the basal forebrain, and, in contrast to

the AChE, no significant reduction in this peptide has been

found in the CSF of PSP patients compared with controls

(Litvan et al., 1992).

Imaging in PSPWith the development of sophisticated imaging techniques

the detection of more subtle and/or specific abnormalities in


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PSP has become possible. However, few imaging studies

have examined the cholinergic system in PSP (Eidelberg

and Dhawan, 2002).

Structural imagingRoutine MRI can reveal a distinct pattern of atrophy in PSP,

particularly in the midbrain, putamen, globus pallidus and

cerebellar peduncles (Schrag et al., 2000). Frontal cortical

atrophy has also been demonstrated in several studies (Schrag

et al., 2000; Cordato et al., 2002; Brenneis et al., 2004). Using

diffusion-weighted imaging to measure water diffusivity

across fibre tracts, an increase in apparent diffusion coeffi-

cient was found in the lentiform nucleus in PSP, suggestive of

neuronal loss and gliosis (Seppi et al., 2003). The sensitivity

of these investigations, particularly in early PSP, needs to be

established further.

Magnetic resonance spectroscopyMagnetic resonance spectroscopy (MRS) allows in vivo

measurement of the concentration of brain metabolites.

MRS studies have shown a reduction in the N-acetylaspartate

(Naa)/creatine and Naa/choline ratios in PSP patients com-

pared with controls in brainstem, frontal cortex and lentiform

nucleus, suggestive of neuronal loss in these sites (Davie

et al., 1997; Federico et al., 1997a, b; Tedeschi et al., 1997).

Inconsistency of MRS in evaluating akinetic-rigid syndromes

in general means that this technique is currently of limited

diagnostic value (Clarke and Lowry, 2001).

Functional imagingUsing PET and N-methyl-4-[11C]piperidyl acetate to measure

AChE activity in the cerebral cortex, no statistically signi-

ficant reduction was demonstrated in PSP patients compared

with controls (Shinotoh et al., 1999, 2001). This was in con-

trast to a significant reduction (�17%) in Parkinson’s disease

and Alzheimer’s disease patients (Iyo et al., 1997; Shinotoh

et al., 2000). There was, however, a marked reduction in

enzyme activity in the thalamus in PSP, which receives cho-

linergic afferents from the brainstem nuclei including the

PPN. PET and 11C-labelled N-methyl-4-piperidyl benzilate

has been used to measure total muscarinic ACh receptors

(Asahina et al., 1998). PSP patients had no significant

changes in binding in any cerebral cortical region. The ligand

used does not, however, differentiate between muscarinic

receptor subtypes.

Cholinergic treatment in PSPThere is pathology in several cholinergic structures in PSP,

and cholinergic blockade using scopolamine induces gait

disturbance in PSP patients and deterioration in memory in

PSP at lower doses than in controls and Parkinson’s disease

patients (Litvan et al., 1994; Bedard et al., 1999). It is there-

fore not surprising that cholinomimetic drugs have been

explored for their therapeutic potential in PSP.

In a double-blind, placebo-controlled crossover design,

physostigmine, a central and short-acting cholinesterase

inhibitor (0.5–2.0 mg, six times daily for 10 days), did not

benefit extra-ocular, parkinsonian or pseudobulbar features

Fig. 4 Diagramatic representation of location of damage to cholinergic neurons in PSP. MD = mediodorsal nuclei thalamus;+ = mildly affected; ++ = moderately affected; +++ = severely affected.


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in eight PSP patients (Litvan et al., 1989). Some improve-

ments were, however, noted in memory and visuospatial

attention in seven patients (Kertzman et al., 1990). Physos-

tigmine also had no effect upon swallowing or oral motor

function in a 10 day, crossover, placebo-controlled, double-

blind trial (Frattali et al., 1999). The failure of CSF AChE

levels to increase following administration of physostigmine

suggests that the doses used in these studies may have been

insufficient or too short-acting to have any significant central

effect (Atack et al., 1991).

Recently, attention has focused on longer acting cholines-

terase inhibitors (ChEIs), in view of their beneficial effects in

Alzheimer’s disease and DLB. Assessment of cognitive func-

tion, motor skills and activities of daily living (ADL) in six

PSP patients at baseline and after 3 months of treatment with

donepezil 10 mg/day revealed no change from baseline in any

of the parameters measured (Fabbrini et al., 2001). The same

dose of donepezil was used in 21 patients in a double-blind,

placebo-controlled, randomized, crossover trial, with each

arm lasting 6 weeks (Litvan et al., 2001). The dose had to

be reduced in three patients due to worsening of motor func-

tion. There was a modest improvement in one of the memory

tests but a significant worsening in motor and ADL scores.

Based on these studies, ChEIs cannot currently be recom-

mended for treatment of PSP.

For ChEIs to produce a therapeutic effect there needs to be

sufficient synthesis and release of ACh from the presynaptic

terminal. Severe cholinergic neuronal loss in PSP may, in

part, account for the lack of response. To overcome this,

direct stimulation of postsynaptic receptors has been

attempted. The non-selective M1 and M2 muscarinic agonist,

RS-86, was given to 10 PSP patients in a 9 week, double-

blind, placebo-controlled, crossover trial. No beneficial

effects were noted upon motor function, eye movements or

cognitive performance, despite electroencephalographic

evidence of enhanced central cholinergic activity upon

sleep architecture (Foster et al., 1989). To our knowledge,

no other cholinergic agonists have been assessed in PSP.

Future directions for cholinergic treatmentsAutopsy and some in vivo studies have demonstrated a loss of

cholinergic function within the striatum, thalamus and brain-

stem nuclei in PSP (Striatum-Ruberg et al., 1985; Suzuki et al.,

2002; Villares et al., 1994; Thalamus-Brandel et al., 1990;

Brainstem nuclei-Juncos et al., 1991; Malessa et al., 1991;

Kasashima et al., 2003). The former is presumed to reflect

loss of cholinergic interneurons. The limited information

available on the status of muscarinic receptors has indicated

normal binding within the striatum and cortex. Attempts to

apply effective neurotransmitter replacement therapies have

been unsuccessful. This may be due in part to our lack of

detailed understanding of the neurochemistry of the basal

ganglia and associated areas, but may also be influenced

by the small numbers of patients available to take part in

therapeutic trials.

Cholinergic replacement therapiesThe failure of cholinergic replacement therapies in PSP raises

specific questions regarding the underlying neurochemical

abnormalities. First, are the remaining striatal and brainstem

cholinergic neurons unable to produce enough ACh for AChE

inhibitors to act on? Secondly, are the postsynaptic receptors

or a subpopulation of receptors reduced, or is the subsequent

activation of the secondary messenger defective? Thirdly,

despite documented evidence of cholinergic abnormalities

in PSP, is the symptomatology, particularly the cognitive

impairment and gait instability, the result of different neuro-

transmitter abnormalities within the basal ganglia circuitry?

Fourthly, is replacement of neurotransmitters insufficient to

restore the normal physiological function within the basal

ganglia? And finally, rather than a ‘blanket’ approach from

oral cholinergic replacement therapy, do we need to focus on

delivery to specific target nuclei? A better knowledge of the

underlying neurochemical abnormalities in PSP may help to

answer some of these questions.

Extrapolating the results from Alzheimer’s disease trials,

development of selective M1 agonists or M2 antagonists may

improve cognitive function in PSP. M1 agonists were origin-

ally found to improve cognitive function in rats (Fisher et al.,

1991), and M1 receptors are abundant in the hippocampus

and cortex. Clinical trials in Alzheimer’s disease patients

have demonstrated improvement in behaviour and cognition

when treated with xanomeline, a selective M1/M4 agonist,

although its use was limited by dose-dependent adverse

events, particularly gastrointestinal problems (Bodick et al.,

1997a, b; Veroff et al., 1998). When activated, M2 receptors

inhibit ACh release, which may have contributed to the fail-

ure of RS-86, the M1/M2 agonist. Trials of an M2 antagonist

(SCH 72788) in rats increased ACh release in the striatum,

providing a further potential method for cholinergic enhance-

ment (Lachowicz et al., 2001). However, a study of Lu25-

109, a selective M1 partial agonist and M2 antagonist, failed

to improve cognition in a double-blind, placebo-controlled

trial of 496 Alzheimer’s disease patients (Thal et al., 2000).

Overall, these results provide some hope for the use of drugs

acting directly on the muscarinic receptors, although efficacy

may be limited by side-effects.

Direct stimulation of nicotinic receptors could enhance

neurotransmitter release, for example from nigrostriatal dopa-

minergic neurons and cortical afferents. Unfortunately, pro-

longed stimulation with agonists, rather than the pulsed

physiological stimulation, paradoxically appears to cause

nicotinic receptor antagonism, perhaps through desensitiza-

tion (Zhou et al., 2003). However, allosteric modulation of

nicotinic receptors, such as that which occurs with galant-

amine, may heighten receptor sensitivity by increasing the

probability of channel opening following agonist binding

(Maelicke, 2000; Maelicke et al., 2001). The status of the

nicotinic receptors in PSP is unknown, but one would predict

them to be reduced in the striatum and possibly cortex due to

the selective vulnerability of striatal and cortical afferents.


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Nicotine replacement therapy in Parkinson’s disease has pro-

duced variable results. Beneficial effects on motor and cog-

nition in Parkinson’s disease patients were reported from

small-scale studies of nicotine given by either smoking or

transdermal patch (Ishikawa and Miyatake, 1993; Kelton

et al., 2000). However, other studies have reported no bene-

ficial effects, with a large proportion of patients withdrawing

due to side-effects (Vieregge et al., 2001; Lemay et al., 2003,

2004), or even a worsening of motor symptoms (Ebersbach

et al., 1999). In animal models of Parkinson’s disease nicotine

appears to protect the dopaminergic neurons against damage

from MPTP (Parain et al., 2003). Animal models of Alzhei-

mer’s disease with lesions in the cholinergic basal forebrain

show an improvement in cognition when treated with select-

ive nicotine receptors agonists. Furthermore, nicotine appears

to reduce production of b-amyloid in Alzheimer’s disease

models,suggestingapossibleneuroprotectiveeffect (Nordberg

et al., 2002; Utsuki et al., 2002). Treatment with nicotine

patches improves attentional function in normal non-smoking

adults and patients with Alzheimer’s disease (Levin and

Rezvani, 2002), and may protect against glutamate-induced

cytotoxicity (Akaike et al., 1994). As PSP shares some fea-

tures of the nigrostriatal degeneration common to Parkinson’s

disease and the cholinergic forebrain deficits of Alzheimer’s

disease, these studies suggest that the use of nicotine in PSP

warrants further investigation. Therapeutic efficacy may,

however, be limited by side-effects, lack of receptor speci-

ficity or by desensitization of nicotinic receptors.

Cholinergic dysfunction has been demonstrated within the

PPN in PSP, but due to its very small size within the densely

packed upper brainstem its exact functional role and its

interaction with the basal ganglia circuitry is difficult to

establish accurately. It has been suggested, mostly based on

experiments in rats and non-human primates, that as dysfunc-

tion within the PPN leads to akinesia and gait abnormalities,

stimulation of this structure may improve these symptoms

(Pahapill and Lozano, 2000). However, deep brain stimula-

tion of the PPN in normal monkeys leads to impairment of

postural control at high frequencies and tremor at low fre-

quencies (Nandi et al., 2002b). Excessive GABAergic inhibi-

tion from the globus pallidus intera and substantia nigra is

thought to contribute to dysfunction of the PPN. In an MPTP-

treated monkey model of parkinsonism, infusion of a

GABAergic antagonist directly into the PPN alleviated

akinesia (Nandi et al., 2002a, c). If these findings can be repro-

duced in humans it offers hope that either pharmacological or

surgical excitation of the predominantly cholinergic PPN may

relieve some of the most disabling symptoms of PSP.

Disease modification therapiesPotential areas for disease modification include the use of

antioxidants and genetic manipulation of tau protein produc-

tion (Burn and Warren, 2005). Interestingly, some properties

of the cholinergic system suggest it may also be a

useful target for disease modifying therapies. The potential

neuroprotective effects of nicotinic receptor stimulation have

already been discussed. Hyperphosphorylated tau protein

deposition is common to both PSP and Alzheimer’s disease,

and is a major constituent of neurofibrillary tangles, which

can disrupt the neuronal cytoskeleton and thereby lead to

further degeneration (Goedert, 1993, 2004). Tau phosphor-

ylation is controlled by cell surface cholinergic receptors, as

evidenced by M1 receptor agonists producing dephosphory-

lation of tau in rats (Sadot et al., 1996). Furthermore, in apoE-

deficient rats with hyperphosphorylated tau, excess phosphor-

ylation can be reduced using the M1 agonist AF150(S), with

an inverse relationship between the levels of phosphorylation

and working memory (Genis et al., 1999). This suggests that

abnormal tau protein deposition may be a direct result of

cholinergic hypofunction, and that dephosphorylation is pos-

sible with M1 receptor agonists.

Finally, nerve growth factor (NGF) receptors are located

on the basal forebrain and striatal cholinergic neurons and

have been shown to be vital in the function of these cells

(Perry, 1990). As mentioned previously, these receptors are

reduced in the PSP striatum (Villares et al., 1994). NGF, if

delivered to specific target areas of the brain, could protect

cholinergic neurons from degeneration. NGF does not cross

the blood–brain barrier but may be delivered either intraven-

tricularly, by viral vector or gene therapy, or via the olfactory

pathway (Chen et al., 1998). A surgical lesion in the fornix,

leading to retrograde degeneration of the cholinergic septal

neurons, produces an animal Alzheimer’s disease model.

Fibroblasts, genetically modified to secrete NGF and

implanted into this rodent Alzheimer’s disease model, can

prevent the degeneration of cholinergic neurons (Rosenberg

et al., 1988). In non-human primates, recombinant human

NGF prevents cholinergic neuronal degeneration (Koliatsos

et al., 1991). Similar results are found when using polyethyl-

enimine as a vehicle for in vivo gene delivery in rats (Wu

et al., 2004).

If an effective and safe vehicle for trophic factor delivery

in humans can be found, degeneration of the cholinergic

neurons in PSP may be halted, although it is unclear whether

re-growth of affected neurons is possible.

AcknowledgementsN.M.W. is funded by the PSP (Europe) Association.

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Cholinergic systems in progressive supranuclear palsy

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