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The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer's disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The clinical syndromes of Progressive Supranuclear Palsy (PSP) may be mediated by abnormal temporal dynamics of brain networks, due to the impact of atrophy, synapse loss and neurotransmitter deficits. We tested the hypothesis that alterations in signal complexity in neural networks influence short-latency state transitions. Ninety-four participants with PSP and 64 healthy controls were recruited from two independent cohorts. All participants underwent clinical and neuropsychological testing and resting-state functional MRI. Network dynamics were assessed using hidden Markov models and neural signal complexity measured in terms of multiscale entropy. In both cohorts, PSP increased the proportion of time in networks associated with higher cognitive functions. This effect correlated with clinical severity as measured by the PSP-rating-scale, and with reduced neural signal complexity. Regional atrophy influenced abnormal brain-state occupancy, but abnormal network topology and dynamics were not restricted to areas of atrophy. Our findings show that the pathology of PSP causes clinically relevant changes in neural temporal dynamics, leading to a greater proportion of time in inefficient brain-states., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Blood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin-O-acyl transferase-null (GOAT -/- ) mice that lack acyl-ghrelin (AG) but have high levels of UAG were rescued by acyl-ghrelin. Acyl-ghrelin-mediated neurogenesis in vitro was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice. To determine relevance in humans, we analyzed circulating AG:UAG in Parkinson disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. Notably, plasma AG:UAG was only reduced in PDD. Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT + cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

Importance: Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied., Objective: To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD., Design, Setting, Participants: This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019., Main Outcomes and Measures: Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures., Results: A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05)., Conclusions and Relevance: These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

Objectives: MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP., Methods: Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21)., Results: The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm., Conclusions: We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.

Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinson's disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohen's kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The "hummingbird" and "morning glory" signs were highly specific for PSP, and "the middle cerebellar peduncle sign" and "hot cross bun" for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy., (Copyright © 2012 Movement Disorder Society.)

Progressive supranuclear palsy (PSP) is a tauopathy that generally results in a hypokinetic disorder. Treatment is largely symptomatic, with some small studies indicating a benefit with dopaminergic therapy. Myoclonus is a hyperkinetic disorder that can be seen as part of later stage Parkinson's disease and in multiple system atrophy, but is rarely seen in PSP. Here we report a case of myoclonus precipitated by amantadine in a patient with PSP.

The objective of this study was to compare subjective health status and its correlates in progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). One hundred eighty-eight patients with PSP and 286 patients with MSA completed EQ-5D and Hospital Depression and Anxiety Scale. The impact on mobility, usual activities, and self-care was similarly high in both groups after similar duration. Fifty-six percent of PSP and 43% of MSA had probable depression, and 37% of both groups had probable anxiety. Patients with PSP had significantly higher depression scores, but groups did not differ in anxiety scores. Patients with MSA had significantly greater pain/discomfort than patients with PSP. The most important association with subjective health status was with depressive symptoms, which accounted for 38% and 29% of EQ-5D variance in patients with PSP and MSA, followed by disease severity and anxiety scores. We conclude that depressive symptoms were common in both disorders, but more severe in PSP. Anxiety symptoms affected 37% of patients in both groups and contributed to impaired subjective health status. Pain was more problematic in MSA than PSP., ((c) 2010 Movement Disorder Society.)

Previous studies suggested that olfaction is normal in progressive supranuclear palsy (PSP). We applied the University of Pennsylvania Smell Identification Test (UPSIT) to 36 patients with PSP who scored more than 18 on the Mini Mental State Examination (MMSE), 140 patients with nondemented Parkinson's disease (PD) and 126 controls. Mean UPSIT scores in PSP were lower than in controls (P < 0.001) but higher than in PD (P < 0.001) after adjusting for age, gender, and smoking history. For patients with PSP, UPSIT scores correlated with MMSE (r = 0.44, P = 0.006) but not disease duration (P = 0.6), motor subscale of the Unified Parkinson's Disease Rating Scale (P = 0.2), or Frontal Assessment Battery (P = 0.5). The brains of six of the patients with PSP were examined postmortem and all revealed neurofibrillary tangles and tau accumulation in the rhinencephalon, although only three had hyposmia. Further prospective studies including patients with early PSP and PSP-P with postmortem confirmation might help clarify if smell tests could be useful when the differential diagnosis lies between PD and PSP., ((c) 2010 Movement Disorder Society.)

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterised clinically by motor and cognitive symptoms. Cholinergic dysfunction is thought to be responsible for much of the cognitive symptomatology. To date, however, cholinergic replacement therapies have been ineffective. We used receptor specific radioligand autoradiography to measure M1, M2, and M4 receptor density, and the functional status of the principal cortical subtype, M1, in the frontal cortex in post-mortem brain tissue of PSP patients (n=14). Results were compared to normal controls (n=17) and patients with dementia with Lewy bodies (DLB, n=12) and Alzheimer's disease (AD, n=15). In PSP there were no changes in M1, M2, or M4 muscarinic receptor densities or M1 coupling. DLB cases showed a non-significant increase in M1 receptors. In AD there was a reduction in M1 receptors and coupling in most frontal cortical areas which reached significance, compared to DLB, for M1 receptors in the cingulate (p<0.05). We conclude from this first systematic study of cortical muscarinic receptors in PSP that functioning cortical muscarinic receptors are preserved. A further, larger trial of cholinergic therapy, such as an M1 agonist, may be warranted.

Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative disorder. In contrast to Parkinson's disease (PD) and dementia with Lewy bodies (DLB), replacement therapy with dopaminergic and cholinergic agents in PSP has been disappointing. The neurochemical basis for this is unclear. Our objective was to measure dopaminergic and cholinergic receptors in the basal ganglia of PSP and control brains. We measured, autoradiographically, dopaminergic (dopamine transporter, 125I PE2I and dopamine D2 receptors, 125I epidepride) and cholinergic (nicotinic alpha4beta2 receptors, 125I 5IA85380 and muscarinic M1 receptors, 3H pirenzepine) parameters in the striatum and pallidum of pathologically confirmed PSP cases (n=15) and controls (n=32). In PSP, there was a marked loss of dopamine transporter and nicotinic alpha4beta2 binding in the striatum and pallidum, consistent with loss of nigrostriatal neurones. Striatal D2 receptors were increased in the caudate and muscarinic M1 receptors were unchanged compared with controls. These results do not account for the poor response to dopaminergic and cholinergic replacement therapies in PSP, and suggest relative preservation of postsynaptic striatal projection neurones bearing D2/M1 receptors., (Copyright (c) 2007 Movement Disorder Society.)

Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder involving motor and cognitive dysfunction. Currently, there is no effective treatment either for symptomatic relief or disease modification. This relates, in part, to a lack of knowledge of the underlying neurochemical abnormalities, including cholinergic receptor status in the basal ganglia., Aim: To measure muscarinic M2 and M4 receptors in the basal ganglia in PSP., Methods: The muscarinic M2 (presynaptic) and M4 (postsynaptic) receptors in the striatum, pallidum and adjacent insular cortex were autoradiographically measured in pathologically confirmed cases of PSP (n = 18), and compared with cases of Lewy body dementias (LBDs; n = 45), Alzheimer's disease (AD; n = 39) and controls (n = 50)., Results: In cases of PSP, there was a reduction in M2 and M4 receptors in the posterior caudate and putamen compared to controls, but no significant changes in the pallidum. Cases with AD showed lower M2 receptors in the posterior striatum. Groups with LBD and AD showed higher M2 binding in the insular cortex compared with controls., Conclusions: The results suggest loss of posterior striatal cholinergic interneurones in PSP, and reduction in medium spiny projection neurones bearing M4 receptors. These results should be taken in the context of more widespread pathology in PSP, but may have implications for future trials of cholinergic treatments.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease with motor, cognitive, and behavioral symptomatology. Cholinergic dysfunction is thought to underpin several key symptoms. There is known pathologic involvement of the corticobasal ganglia-thalamocortical loops in PSP, but little attention has been focused on potential thalamic dysfunction. Using autoradiography, we measured muscarinic M2 and M4 receptors in specific thalamic nuclei involved in the limbic and motor loops in patients with PSP (n = 11) and compared results from brain tissue of subjects with Lewy body dementias (including dementia with Lewy bodies and Parkinson disease with dementia, n = 31), Alzheimer disease (n = 22) and normal elderly control subjects (n = 27). In the thalamus M2 receptors were more abundant than M4 receptors and were most densely concentrated in the anteroprincipal (AP) and mediodorsal (MD) nuclei, which connect to limbic cortices. M2 receptor binding was reduced in the AP nucleus in PSP compared with control subjects and those with Lewy body dementias. M4 receptors were markedly reduced in the MD nucleus in those with PSP compared with control subjects. M4 receptors were also reduced in the subthalamic nucleus in patients with PSP. M4 receptor binding was reduced in the MD nucleus in the Lewy body dementia and Alzheimer disease groups compared with control subjects. There were no significant changes in the ventrolateral nucleus (motor). Cholinergic dysfunction within the AP and MD nuclei of the thalamus may contribute to behavioral and cognitive disturbances associated with PSP.

Frontal lobe dysfunction is a prominent feature of many neurological disorders. Early diagnosis may be enhanced by establishing a profile of cognitive, behavioral, and emotional change. Traditional psychometric assessment focuses on cognitive dysfunction and fails to identify behavioral changes, particularly those associated with orbitofrontal dysfunction. We examined progressive supranuclear palsy (PSP), a prototypical subcortical dementia with frontal features, using commonly available neuropsychological measures and a modification of the Katz Adjustment Scale-Relatives (KAS-R), an instrument first developed to assess dysexecutive changes in head-injured patients. Executive tests identified deficits in reasoning, planning, set shifting, verbal fluency, information processing speed, and response initiation. On the KAS-R, changes in apathy, social withdrawal, and independence were observed, with little change in belligerence, social irresponsibility, uncooperativeness, obstreperousness, anxiety, and depression. The results show the potential utility of this instrument in characterizing behavioral and emotional changes associated with frontal lobe dysfunction in neurodegenerative disease., (Copyright (c) 2005 Movement Disorder Society.)

There is a stern therapeutic challenge for progressive supranuclear palsy (PSP) that has not yet been met. The lack of randomized, controlled trials and negative outcomes from the vast majority of studies make it impossible to set therapeutic standards, or to give clear recommendations. We review progress to date in this area and briefly consider future potential therapeutic strategies., (Copyright 2005 Movement Disorder Society.)

Progressive 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 in motor function, quality of life and cognitive impairment. The five cortico-basal ganglia loops, linking functionally related 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 sufficient acetylcholine, and functional muscarinic and nicotinic receptors. Whilst there is evidence from autopsy and in vivo studies of loss of cholinergic neurons in PSP, the receptor status is unknown. This may be critical to understanding the basis for the poor therapeutic response to cholinomimetics. Symptomatic treatment using cholinergic drugs may thus be improved by more specific targeting of cholinergic receptors or nuclei. There is also evidence that cholinergic agents may have disease-modifying effects. This article reviews the key clinical features of PSP, along with normal basal ganglia anatomy and cholinergic transmission. Cholinergic deficits based on clinical and neurochemical parameters are then discussed, before concluding with suggested future directions for cholinergic treatments.

Objective: To describe clinical features and identify prognostic predictors in progressive supranuclear palsy (PSP)., Methods: Record-based diagnosis according to National Institute of Neurological Disorders and Stroke-Society for Progressive Supranuclear Palsy criteria was performed in 187 cases of PSP. Clinical information was abstracted from patient records. Sixty-two patients (33%) were examined by the investigators. Forty-nine of 62 patients (79%) underwent standardized clinical assessment. Predictors of survival were examined after a mean of 6.4 years., Results: The most common symptoms at disease onset related to mobility (69%). Of patients undergoing standardized clinical assessment, diplopia occurred in 61%, photophobia in 43%, and eyelid apraxia in 43%. Seventy-five cases (40%) died during follow-up. Older age at onset and classification as probable PSP were associated with poorer survival. Onset of falls (hazard ratio 3.28, 95% CI 1.17 to 9.13), speech problems (hazard ratio 4.74, 95% CI 1.10 to 20.4), or diplopia (hazard ratio 4.23, 95% CI 1.23 to 14.6) within 1 year and swallowing problems within 2 years (hazard ratio 3.91, 95% CI 1.39 to 11.0) were associated with a worse prognosis., Conclusions: Mobility problems are the commonest early feature in PSP and visual symptoms are often functionally disabling. Early falls, speech and swallowing problems, diplopia, and early insertion of a percutaneous gastrostomy predict reduced survival.

This review provides an update on progressive supranuclear palsy (PSP, or Steele-Richardson-Olszewski disease), an adult-onset neurodegenerative disorder characterised by early postural instability, which leads to falls, and a vertical supranuclear-gaze palsy. Recent epidemiological studies have shown that the disorder is more common than previously recognised, that it is commonly misdiagnosed, and that it may present to a wide range of hospital specialists. The diagnosis of PSP hinges on clinical acumen. Attempts to identify a suitable biomarker in the CSF or a specific and sensitive imaging or neurophysiological technique have so far failed to have a significant effect on the diagnostic process. Better understanding of the molecular pathology of PSP has highlighted the importance of tau-protein accumulation and tau-genotype susceptibility in its pathogenesis. No drug treatment significantly and consistently benefits patients, and novel therapies are urgently required.

We performed a study to estimate the point prevalence of progressive supranuclear palsy (PSP) in the UK at national, regional and community levels. A 'Russian doll' design was used in which the population denominator for each of the three studies was successively smaller, whilst the method of case ascertainment became increasingly more rigorous. The NINDS-SPSP (National Institute of Neurological Disorders and the Society for Progressive Supranuclear Palsy) diagnostic criteria for PSP were applied throughout the study for case definition. The national study identified cases using passive referral mechanisms [e.g. the British Neurological Surveillance Unit (BNSU), PSP (Europe) Association patient register]. We identified 577 cases of PSP, giving a national prevalence estimate of 1.0 per 100 000 [95% confidence interval (CI) 0.9-1.1]. The North of England regional study used active 'multiple source' case ascertainment from a collaborative network of neurologists and non-neurologists. We identified 80 cases of PSP in this study, giving a crude and age-adjusted prevalence of 3.1 (95% CI 2.4-3.8) and 2.4 (1.9-3.0) per 100 000, respectively. Of these 80 cases, 51 patients (65%) were referred initially to non-neurologists and 10 patients (13%) had not seen a neurologist at any stage of their illness. The proportion of female cases was significantly greater in the regional than in the national study (61% versus 44%; P < 0.02). Cases referred to non-neurologists were significantly older than those referred to neurologists in the regional study (median age 73 versus 69.5 years; P < 0.01). Patients in the community study were identified via diagnostic and therapeutic registers from a representative sample of general practices in Newcastle upon Tyne. We identified 17 cases of PSP, yielding crude and age-adjusted prevalences of 6.5 (95% CI 3.4-9.7) and 5.0 (95% CI 2.5-7.5) per 100 000, respectively. Seven of the 17 cases (41%) had not previously been diagnosed as PSP. This study suggests that PSP is more common than previously considered, is commonly misdiagnosed and that the majority of cases are not initially referred to neurologists. The study also confirms the importance of active and detailed case ascertainment in ensuring reliable prevalence estimates.

The clinical differentiation of Parkinson's disease from the striatonigral degeneration (SND) type of multiple system atrophy (MSA) and Steele-Richardson-Olszewski syndrome (SRO) may be difficult. This is reflected by a 20-25% misdiagnosis rate in clinicopathological series of cases labelled as 'Parkinson's disease' in life. The caudate and putamen contain a high density of opioidergic neurons and receptors which have a close anatomical and physiological relationship with the dopaminergic system. We used [11C]diprenorphine with PET to investigate striatal opioid receptor binding in groups of patients with clinically defined Parkinson's disease (n = 8), SND (n = 7) and SRO (n = 6), compared with normal controls (n = 8). There was no significant difference between mean ligand binding in the putamen and caudate of Parkinson's disease cases when compared with normals. Mean putamen, but not caudate, opioid receptor binding was significantly reduced in the SND group, when compared with normals. By contrast, in the SRO group, both mean caudate and putamen opioid receptor binding was significantly reduced when compared with both normal and Parkinson's disease groups. When considering the individual patients, none of the eight Parkinson's disease cases (0%), none of the seven SND cases (0%), but four of the six SRO cases (67%) had caudate opioid receptor binding that was > 2.5 SDs below the normal mean. Corresponding figures for putamen opioid receptor binding were: none of the Parkinson's disease cases (0%); three of the SND cases (43%); and all of the SRO cases (100%). We conclude that there are differences in the pattern of opioid receptor binding in the striatum of Parkinson's disease, SND and SRO patients, as determined by [11C]diprenorphine PET. The different binding patterns may help to differentiate these akinetic-rigid syndromes in life.

Clinicopathological series indicate that the clinical diagnosis of Parkinson's disease is correct in only 80% of cases. Multiple system atrophy (MSA) and Steele-Richardson-Olszewski syndrome (SRO) comprise most of the misdiagnoses. By means of 18F-dopa PET the pattern of nigrostriatal dopaminergic dysfunction in 28 patients with clinically probable Parkinson's disease, 25 with MSA, and 10 patients with SRO, was assessed and compared with the pattern in 27 normal subjects. Discriminant function analysis was used to assess the ability of 18F-dopa PET to categorize individual parkinsonian patients on the basis of their caudate and putamen tracer uptake. Discriminant function analysis assigned all control subjects a normal category. One Parkinsonian patient out of 63 was classified as "normal" on the basis of PET findings, although this patient had significantly reduced putamen 18F-dopa uptake. Discriminant function analysis was less effective at distinguishing different categories of akinetic-rigid syndrome on the basis of their striatal 18F-dopa uptake, as judged against clinical criteria. Patients clinically labelled as having typical or atypical Parkinsonian syndromes were assigned the same category on PET criteria 64% and 69% of the time, respectively. When all three categories of Parkinson's disease, MSA, and SRO were considered together, clinical and 18F-dopa PET findings correlated in 64% of patients assigned a diagnosis of Parkinson's disease and 70% of those given a diagnosis of SRO; MSA was less readily discriminated, patients with MSA being assigned to MSA, Parkinson's disease, and SRO groups with equal frequency. The correlation between clinical and discriminant function analysis assignment improved when separate comparisons were made between Parkinson's disease and MSA, or Parkinson's disease and SRO groups. In these analyses, clinical and PET categorisation of MSA and Parkinson's disease agreed in 60% of cases, and of SRO and Parkinson's disease in 90% of cases. In summary, (18)F-dopa PET successfully discriminates normal subjects from parkinsonian patients, and patients with Parkinson's disease from patients with SRO, but is less reliable in distinguishing Parkinson's disease from MSA. The concomitant assessment of striatal neuronal function with additional PET tracers may be necessary to reliably differentiate typical and atypical parkinsonian syndromes.