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
Brain Vol. 128 No. 2 # Guarantors of Brain 2005; all rights reserved
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
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.
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
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
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
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.
242 N. M. Warren et al.
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
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
Cholinergic systems in PSP 243
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
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.
244 N. M. Warren et al.
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
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.
Cholinergic systems in PSP 245
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
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.
References
Akaike A, Tamura Y, Yokota T, Shimohama S, Kimura J. Nicotine-induced
protection of cultured cortical neurons against N-methyl-D-aspartate
receptor-mediated glutamate cytotoxicity. Brain Res 1994; 644: 181–7.
Albers DS, Augood SJ. New insights into progressive supranuclear palsy.
Trends Neurosci 2001; 24: 347–53.
Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally
segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci
1986; 9: 357–81.
Asahina M, Suhara T, Shinotoh H, Inoue O, Suzuki K, Hattori T. Brain
muscarinic receptors in progressive supranuclear palsy and Parkinson’s
246 N. M. Warren et al.
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
disease: a positron emission tomographic study. J Neurol Neurosurg
Psychiatry 1998; 65: 155–63.
Atack JR, Litvan I, Thal LJ, May C, Rapoport SI, Chase TN. Cerebrospinal
fluid acetylcholinesterase in progressive supranuclear palsy: reduced
activity relative to normal subjects and lack of inhibition by oral physos-
tigmine. J Neurol Neurosurg Psychiatry 1991; 54: 832–5.
Bedard MA, Pillon B, Dubois B, Duchesne N, Masson H, Agid Y. Acute and
long-term administration of anticholinergics in Parkinson’s disease:
specific effects on the subcortico-frontal syndrome. Brain Cogn 1999;
40: 289–313.
Bernard V, Normand E, Bloch B. Phenotypical characterization of the rat
striatal neurons expressing muscarinic receptor genes. J Neurosci 1992; 12:
3591–600.
Birdi S, Rajput AH, Fenton M, Donat JR, Rozdilsky B, Robinson C, et al.
Progressive supranuclear palsy diagnosis and confounding features: report
on 16 autopsied cases. Mov Disord 2002; 17: 1255–64.
Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, et al.
Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive
function and behavioral symptoms in Alzheimer disease. Arch Neurol
1997a; 54: 465–73.
Bodick NC, Offen WW, Shannon HE, Satterwhite J, Lucas R, van Lier R, et al.
The selective muscarinic agonist xanomeline improves both the cognitive
deficits and behavioral symptoms of Alzheimer disease. Alzheimer Dis
Assoc Disord 1997b; 11 Suppl 4: S16–22.
Bosboom JL, Stoffers D, Wolters E. Cognitive dysfunction and dementia in
Parkinson’s disease. J Neural Transm 2004; 111: 1303–15.
Brandel JP, Hirsch EC, Hersh LB, Javoy-Agid F. Compartmental ordering of
cholinergic innervation in the mediodorsal nucleus of the thalamus in
human brain. Brain Res 1990; 515: 117–25.
Brandel JP, Hirsch EC, Malessa S, Duyckaerts C, Cervera P,
Agid Y. Differential vulnerability of cholinergic projections to the
mediodorsal nucleus of the thalamus in senile dementia of Alzheimer
type and progressive supranuclear palsy. Neuroscience 1991; 41:
25–31.
Brenneis C, Seppi K, Schocke M, Benke T, Wenning GK, Poewe W.
Voxel based morphometry reveals a distinct pattern of frontal atrophy
in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2004;
75: 246–9.
Burn D, Warren N. Towards future therapies in progressive supranuclear
palsy. Mov Disord 2005. In press.
Calabresi P, Centonze D, Gubellini P, Pisani A, Bernardi G. Acetylcholine-
mediated modulation of striatal function. Trends Neurosci 2000; 23: 120–6.
Carpenter MB, Harbison JW, Peter P. Accessory oculomotor nuclei in the
monkey: projections and effects of discrete lesions. J Comp Neurol 1970;
140: 131–54.
Cavada C, Company T, Hernandez-Gonzalez A, Reinoso-Suarez F. Acetyl-
cholinesterase histochemistry in the macaque thalamus reveals territories
selectively connected to frontal, parietal and temporal association cortices.
J Chem Neuroanat 1995; 8: 245–57.
Charpantier E, Barneoud P, Moser P, Besnard F, Sgard F. Nicotinic acetyl-
choline subunit mRNA expression in dopaminergic neurons of the
rat substantia nigra and ventral tegmental area. Neuroreport 1998; 9:
3097–101.
Chen XQ, Fawcett JR, Rahman YE, Ala TA, Frey IW. Delivery of nerve
growth factor to the brain via the olfactory pathway. J Alzheimers Dis 1998;
1: 35–44.
Clarke CE, Lowry M. Systematic review of proton magnetic resonance spec-
troscopy of the striatum in parkinsonian syndromes. Eur J Neurol 2001; 8:
573–7.
Cordato NJ, Pantelis C, Halliday GM, Velakoulis D, Wood SJ, Stuart GW,
et al. Frontal atrophy correlates with behavioural changes in progressive
supranuclear palsy. Brain 2002; 125: 789–800.
Court J, Clementi F. Distribution of nicotinic subtypes in human brain.
Alzheimer Dis Assoc Disord 1995; 9 Suppl 2: 6–14.
Court JA, Piggott MA, Lloyd S, Cookson N, Ballard CG, McKeith IG, et al.
Nicotine binding in human striatum: elevation in schizophrenia and reduc-
tions in dementia with Lewy bodies, Parkinson’s disease and Alzheimer’s
disease and in relation to neuroleptic medication. Neuroscience 2000; 98:
79–87.
Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol
1993; 50: 873–80.
Davie CA, Barker GJ, Machado C, Miller DH, Lees AJ. Proton magnetic
resonance spectroscopy in Steele–Richardson–Olszewski syndrome.
Mov Disord 1997; 12: 767–71.
Ebersbach G, Stock M, Muller J, Wenning G, Wissel J, Poewe W. Worsening
of motor performance in patients with Parkinson’s disease following trans-
dermal nicotine administration. Mov Disord 1999; 14: 1011–3.
Eidelberg D, Dhawan V. Can imaging distinguish PSP from other neuro-
degenerative disorders? Neurology 2002; 58: 997–8.
Fabbrini G, Barbanti P, Bonifati V, Colosimo C, Gasparini M, Vanacore N,
et al. Donepezil in the treatment of progressive supranuclear palsy. Acta
Neurol Scand 2001; 103: 123–5.
Federico F, Simone IL, Lucivero V, De Mari M, Giannini P, Iliceto G, et al.
Proton magnetic resonance spectroscopy in Parkinson’s disease and pro-
gressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1997a; 62:
239–42.
Federico F, Simone IL, Lucivero V, Iliceto G, De Mari M, Giannini P, et al.
Proton magnetic resonance spectroscopy in Parkinson’s disease and atyp-
ical parkinsonian disorders. Mov Disord 1997b; 12: 903–9.
Fisher A, Brandeis R, Karton I, Pittel Z, Gurwitz D, Haring R, et al. ( + -)-cis-
2-methyl-spiro(1,3-oxathiolane-5,30)quinuclidine, an M1 selective choli-
nergic agonist, attenuates cognitive dysfunctions in an animal model of
Alzheimer’s disease. J Pharmacol Exp Ther 1991; 257: 392–403.
Foster NL, Aldrich MS, Bluemlein L, White RF, Berent S. Failure of cho-
linergic agonist RS-86 to improve cognition and movement in PSP despite
effects on sleep. Neurology 1989; 39: 257–61.
Frattali CM, Sonies BC, Chi-Fishman G, Litvan I. Effects of physostigmine
on swallowing and oral motor functions in patients with progressive supra-
nuclear palsy: A pilot study. Dysphagia 1999; 14: 165–8.
Genis I, Fisher A, Michaelson DM. Site-specific dephosphorylation of tau of
apolipoprotein E-deficient and control mice by M1 muscarinic agonist
treatment. J Neurochem 1999; 72: 206–13.
Goedert M. Tau protein and the neurofibrillary pathology of Alzheimer’s
disease. Trends Neurosci 1993; 16: 460–5.
Goedert M. Tau protein and neurodegeneration. Semin Cell Dev Biol 2004;
15: 45–9.
Grafman J, Litvan I, Stark M. Neuropsychological features of progressive
supranuclear palsy. Brain Cogn 1995; 28: 311–20.
Graveland GA, DiFiglia M. The frequency and distribution of medium-sized
neurons with indented nuclei in the primate and rodent neostriatum. Brain
Res 1985; 327: 307–11.
Ince E, Ciliax BJ, Levey AI. Differential expression of D1 and D2 dopamine
and m4 muscarinic acetylcholine receptor proteins in identified striatoni-
gral neurons. Synapse 1997; 27: 357–66.
Ishikawa A, Miyatake T. Effects of smoking in patients with early-onset
Parkinson’s disease. J Neurol Sci 1993; 117: 28–32.
Iyo M, Namba H, Fukushi K, Shinotoh H, Nagatsuka S, Suhara T, et al.
Measurement of acetylcholinesterase by positron emission tomography
in the brains of healthy controls and patients with Alzheimer’s disease.
Lancet 1997; 349: 1805–9.
Jellinger K. The pedunculopontine nucleus in Parkinson’s disease, progress-
ive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg
Psychiatry 1988; 51: 540–3.
Juncos JL, Hirsch EC, Malessa S, Duyckaerts C, Hersh LB, Agid Y. Mesen-
cephalic cholinergic nuclei in progressive supranuclear palsy. Neurology
1991; 41: 25–30.
Kasashima S, Oda Y. Cholinergic neuronal loss in the basal forebrain and
mesopontine tegmentum of progressive supranuclear palsy and cortico-
basal degeneration. Acta Neuropathol 2003; 105: 117–24.
Kelton MC, Kahn HJ, Conrath CL, Newhouse PA. The effects of nicotine on
Parkinson’s disease. Brain Cogn 2000; 43: 274–82.
Kertzman C, Robinson DL, Litvan I. Effects of physostigmine on spatial
attention in patients with progressive supranuclear palsy. Arch Neurol
1990; 47: 1346–50.
Cholinergic systems in PSP 247
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
Koliatsos VE, Clatterbuck RE, Nauta HJ, Knusel B, Burton LE,
Hefti FF, et al. Human nerve growth factor prevents degeneration of
basal forebrain cholinergic neurons in primates. Ann Neurol 1991; 30:
831–40.
Lachowicz JE, Duffy RA, Ruperto V, Kozlowski J, Zhou G, Clader J, et al.
Facilitation of acetylcholine release and improvement in cognition by a
selective M2 muscarinic antagonist, SCH 72788. Life Sci 2001; 68:
2585–92.
Landwehrmeyer B, Palacios J. Alterations of neurotransmitter receptors and
neurotransmitter transporters in progressive supranuclear palsy. J Neural
Transm Suppl 1994; 42: 229–46.
Lemay S, Blanchet P, Chouinard S, Masson H, Soland V, Bedard MA. Poor
tolerability of a transdermal nicotine treatment in Parkinson’s disease. Clin
Neuropharmacol 2003; 26: 227–9.
Lemay S, Chouinard S, Blanchet P, Masson H, Soland V, Beuter A, et al. Lack
of efficacy of a nicotine transdermal treatment on motor and cognitive
deficits in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychi-
atry 2004; 28: 31–9.
Levin ED, Rezvani AH. Nicotinic treatment for cognitive dysfunction. Curr
Drug Targets CNS Neurol Disord 2002; 1: 423–31.
Litvan I, Hutton M. Clinical and genetic aspects of progressive supranuclear
palsy. J Geriatr Psychiatry Neurol 1998; 11: 107–14.
Litvan I, Gomez C, Atack JR, Gillespie M, Kask AM, Mouradian MM, et al.
Physostigmine treatment of progressive supranuclear palsy. Ann Neurol
1989; 26: 404–7.
Litvan I, Berrettini WH, Atack JR, Chase TN. CSF galanin and neuropeptide
Y immunoreactivity in progressive supranuclear palsy. Acta Neurol Scand
1992; 86: 204–6.
Litvan I, Blesa R, Clark K, Nichelli P, Atack JR, Mouradian MM, et al.
Pharmacological evaluation of the cholinergic system in progressive supra-
nuclear palsy. Ann Neurol 1994; 36: 55–61.
Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC,
et al. Clinical research criteria for the diagnosis of progressive
supranuclear palsy (Steele–Richardson–Olszewski syndrome): report
of the NINDS-SPSP international workshop. Neurology 1996a; 47:
1–9.
Litvan I, Mega MS, Cummings JL, Fairbanks L. Neuropsychiatric aspects of
progressive supranuclear palsy. Neurology 1996b; 47: 1184–9.
Litvan I, Phipps M, Pharr V, Hallett M, Grafman J, Salazar A. Randomized
placebo-controlled trial of donepezil in patients with progressive supra-
nuclear palsy. Neurology 2001; 57: 467–73.
Londos E, Passant U, Risberg J, Gustafson L, Brun A. Contributions of other
brain pathologies in dementia with lewy bodies. Dement Geriatr Cogn
Disord 2002; 13: 130–48.
Maelicke A. Allosteric modulation of nicotinic receptors as a treatment
strategy for Alzheimer’s disease. Dement Geriatr Cogn Disord 2000; 11
(Suppl 1): 11–8.
Maelicke A, Samochocki M, Jostock R, Fehrenbacher A, Ludwig J,
Albuquerque EX, et al. Allosteric sensitization of nicotinic receptors by
galantamine, a new treatment strategy for Alzheimer’s disease. Biol
Psychiatry 2001; 49: 279–88.
Malessa S, Hirsch EC, Cervera P, Javoy-Agid F, Duyckaerts C, Hauw JJ, et al.
Progressive supranuclear palsy: loss of choline-acetyltransferase-like
immunoreactive neurons in the pontine reticular formation. Neurology
1991; 41: 1593–7.
Mufson EJ, Ma SY, Cochran EJ, Bennett DA, Beckett LA, Jaffar S, et al. Loss
of nucleus basalis neurons containing trkA immunoreactivity in individuals
with mild cognitive impairment and early Alzheimer’s disease. J Comp
Neurol 2000; 427: 19–30.
Nandi D, Aziz TZ, Giladi N, Winter J, Stein JF. Reversal of akinesia in
experimental parkinsonism by GABA antagonist microinjections in the
pedunculopontine nucleus. Brain 2002a; 125: 2418–30.
Nandi D, Liu X, Winter JL, Aziz TZ, Stein JF. Deep brain stimulation of the
pedunculopontine region in the normal non-human primate. J Clin Neu-
rosci 2002b; 9: 170–4.
Nandi D, Stein JF, Aziz TZ. Exploration of the role of the upper brainstem in
motor control. Stereotact Funct Neurosurg 2002c; 78: 158–67.
Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features
and natural history of progressive supranuclear palsy: A clinical cohort
study. Neurology 2003; 25: 910–6.
Nordberg A, Hellstrom-Lindahl E, Lee M, Johnson M, Mousavi M, Hall R,
et al. Chronic nicotine treatment reduces beta-amyloidosis in the brain of a
mouse model of Alzheimer’s disease (APPsw). J Neurochem 2002; 81:
655–8.
Oorschot DE. Total number of neurons in the neostriatal, pallidal, subthala-
mic, and substantia nigral nuclei of the rat basal ganglia: a stereological
study using the cavalieri and optical disector methods. J Comp Neurol
1996; 366: 580–99.
Pahapill PA, Lozano AM. The pedunculopontine nucleus and Parkinson’s
disease. Brain 2000; 123: 1767–83.
Parain K, Hapdey C, Rousselet E, Marchand V, Dumery B, Hirsch EC.
Cigarette smoke and nicotine protect dopaminergic neurons against the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin. Brain
Res 2003; 984: 224–32.
Pascual J, Figols J, Grijalba B, Gonzalez AM, del Olmo E, Berciano J, et al.
Changes in aminergic receptors in a PSP postmortem brain: correlation
with pathological findings. J Neural Transm Suppl 1994; 42: 247–60.
Perry EK. Nerve growth factor and the basal forebrain cholinergic system: a
link in the etiopathology of neurodegenerative dementias? Alzheimer Dis
Assoc Disord 1990; 4: 1–13.
Perry EK, Smith CJ, Court JA, Perry RH. Cholinergic nicotinic and muscari-
nic receptors in dementia of Alzheimer, Parkinson and Lewy body types.
J Neural Transm Park Dis Dement Sect 1990; 2: 149–58.
Pfaffenbach DD, Layton DD Jr, Kearns TP. Ocular manifestations in pro-
gressive supranuclear palsy. Am J Ophthalmol 1972; 74: 1179–84.
Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, et al.
Acetylcholine receptors containing the beta2 subunit are involved in the
reinforcing properties of nicotine. Nature 1998; 391: 173–7.
Pimlott SL, Piggott M, Owens J, Greally E, Court JA, Jaros E, et al. Nicotinic
acetylcholine receptor distribution in Alzheimer’s disease, dementia with
Lewy bodies, Parkinson’s disease, and vascular dementia: in vitro binding
study using 5-[(125)i]-a-85380. Neuropsychopharmacology 2004; 29:
108–16.
Pisani A, Bonsi P, Centonze D, Gubellini P, Bernardi G, Calabresi P.
Targeting striatal cholinergic interneurons in Parkinson’s disease:
focus on metabotropic glutamate receptors. Neuropharmacology 2003;
45: 45–56.
Quik M, Bordia T, Forno L, McIntosh JM. Loss of alpha-conotoxinMII- and
A85380-sensitive nicotinic receptors in Parkinson’s disease striatum.
J Neurochem 2004; 88: 668–79.
Rinne JO, Myllykyla T, Lonnberg P, Marjamaki P. A postmortem study of
brain nicotinic receptors in Parkinson’s and Alzheimer’s disease. Brain Res
1991; 547: 167–70.
Rosenberg MB, Friedmann T, Robertson RC, Tuszynski M, Wolff JA,
Breakefield XO, et al. Grafting genetically modified cells to the damaged
brain: restorative effects of NGF expression. Science 1988; 242: 1575–8.
Ruberg M, Javoy-Agid F, Hirsch E, Scatton B, LHeureux R, Hauw JJ, et al.
Dopaminergic and cholinergic lesions in progressive supranuclear palsy.
Ann Neurol 1985; 18: 523–9.
Sadot E, Gurwitz D, Barg J, Behar L, Ginzburg I, Fisher A. Activation of m1
muscarinic acetylcholine receptor regulates tau phosphorylation in trans-
fected PC12 cells. J Neurochem 1996; 66: 877–80.
Schrag A, Good CD, Miszkiel K, Morris HR, Mathias CJ, Lees AJ, et al.
Differentiation of atypical parkinsonian syndromes with routine MRI.
Neurology 2000; 54: 697–702.
Seppi K, Schocke MF, Esterhammer R, Kremser C, Brenneis C, Mueller J,
et al. Diffusion-weighted imaging discriminates progressive supranuclear
palsy from PD, but not from the parkinson variant of multiple system
atrophy. Neurology 2003; 60: 922–7.
Shinotoh H, Namba H, Yamaguchi M, Fukushi K, Nagatsuka S, Iyo M, et al.
Positron emission tomographic measurement of acetylcholinesterase
activity reveals differential loss of ascending cholinergic systems in
Parkinson’s disease and progressive supranuclear palsy. Ann Neurol
1999; 46: 62–9.
248 N. M. Warren et al.
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
Shinotoh H, Namba H, Fukushi K, Nagatsuka S, Tanaka N, Aotsuka A, et al.
Progressive loss of cortical acetylcholinesterase activity in association with
cognitive decline in Alzheimer’s disease: a positron emission tomography
study. Ann Neurol 2000; 48: 194–200.
Shinotoh H, Namba H, Yamaguch M. In vivo mapping of brain cholinergic
function in Parkinson’s disease and progressive supranuclear palsy.
Parkinson’s disease. Adv Neurol 2001; 86: 249–55.
Soliveri P, Monza D, Paridi D, Carella F, Genitrini S, Testa D, et al. Neu-
ropsychological follow up in patients with Parkinson’s disease, striatoni-
gral degeneration-type multisystem atrophy, and progressive supranuclear
palsy. J Neurol Neurosurg Psychiatry 2000; 69: 313–8.
Sovago J, Dupuis DS, Gulyas B, Hall H. An overview on functional receptor
autoradiography using [35S]GTPgammaS. Brain Res Brain Res Rev 2001;
38: 149–64.
Steele JC. Progressive supranuclear palsy. Brain 1972; 95: 693–704.
Suzuki M, Desmond TJ, Albin RL, Frey KA. Cholinergic vesicular
transporters in progressive supranuclear palsy. Neurology 2002; 58:
1013–8.
Tagliavini F, Pilleri G, Gemignani F, Lechi A. Neuronal loss in the basal
nucleus of Meynert in progressive supranuclear palsy. Acta Neuropathol
(Berl) 1983; 61: 157–60.
Tagliavini F, Pilleri G, Bouras C, Constantinidis J. The basal nucleus of
Meynert in patients with progressive supranuclear palsy. Neurosci Lett
1984; 44: 37–42.
Taylor P, Brown J. Acetylcholine. In: Siegel GJ, editor. Basic neurochemistry.
Molecular, cellular and medical aspects. Philadelphia (PA): Lippincott,
Williams and Wilkins; 1999. p. 213–43.
Tedeschi G, Litvan I, Bonavita S, Bertolino A, Lundbom N, Patronas NJ, et al.
Proton magnetic resonance spectroscopic imaging in progressive supra-
nuclear palsy, Parkinson’s disease and corticobasal degeneration. Brain
1997; 120: 1541–52.
Thal LJ, Forrest M, Loft H, Mengel H. Lu 25-109, a muscarinic agonist, fails
to improve cognition in Alzheimer’s disease. Lu25-109 Study Group.
Neurology 2000; 54: 421–6.
Utsuki T, Shoaib M, Holloway HW, Ingram DK, Wallace WC, Haroutunian
V, et al. Nicotine lowers the secretion of the Alzheimer’s amyloid beta-
protein precursor that contains amyloid beta-peptide in rat. J Alzheimers
Dis 2002; 4: 405–15.
Veroff AE, Bodick NC, Offen WW, Sramek JJ, Cutler NR. Efficacy of
xanomeline in Alzheimer disease: cognitive improvement measured
using the Computerized Neuropsychological Test Battery (CNTB).
Alzheimer Dis Assoc Disord 1998; 12: 304–12.
Vieregge A, Sieberer M, Jacobs H, Hagenah JM, Vieregge P. Transdermal
nicotine in PD: a randomized, double-blind, placebo-controlled study.
Neurology 2001; 57: 1032–5.
Villares J, Strada O, Faucheux B, Javoy-Agid F, Agid Y, Hirsch EC. Loss
of striatal high affinity NGF binding sites in progressive supranuclear
palsy but not in Parkinson’s disease. Neurosci Lett 1994; 182:
59–62.
Wakabayashi K, Takahashi H. Pathological heterogeneity in progressive
supranuclear palsy and corticobasal degeneration. Neuropathology 2004;
24: 79–86.
Weiner DM, Levey AI, Brann MR. Expression of muscarinic acetylcholine
and dopamine receptor mRNAs in rat basal ganglia. Proc Natl Acad Sci
USA 1990; 87: 7050–4.
Whitehouse PJ, Kellar KJ. Nicotinic and muscarinic cholinergic receptors in
Alzheimer’s disease and related disorders. J Neural Transm Suppl 1987;
24: 175–82.
Whitehouse PJ, Martino AM, Marcus KA, Zweig RM, Singer HS, Price DL,
et al. Reductions in acetylcholine and nicotine binding in several degen-
erative diseases. Arch Neurol 1988; 45: 722–4.
Williams DR, Paviour DC, Watt HC, Lees AJ. Characteristics of two distinct
clinical phenotypes observed in pathologically proven progressive supra-
nuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Mov Disord
2004; 19: S328–9.
Wu K, Meyers CA, Bennett JA, King MA, Meyer EM, Hughes JA.
Polyethylenimine-mediated NGF gene delivery protects transected septal
cholinergic neurons. Brain Res 2004; 1008: 284–7.
Zhou FM, Wilson CJ, Dani JA. Cholinergic interneuron characteristics
and nicotinic properties in the striatum. J Neurobiol 2002; 53:
590–605.
Zhou FM, Wilson C, Dani JA. Muscarinic and nicotinic cholinergic mechan-
isms in the mesostriatal dopamine systems. Neuroscientist 2003; 9: 23–36.
Zweig RM, Whitehouse PJ, Casanova MF, Walker LC, Jankel WR, Price DL.
Loss of pedunculopontine neurons in progressive supranuclear palsy. Ann
Neurol 1987; 22: 18–25.
Cholinergic systems in PSP 249
Dow
nloaded from https://academ
ic.oup.com/brain/article/128/2/239/402606 by guest on 25 July 2022
Top Related