Search

BACKGROUND: The Movement Disorder Society diagnostic criteria for progressive supranuclear palsy introduced the diagnostic certainty level "suggestive of progressive supranuclear palsy" for clinical conditions with subtle signs, suggestive of the disease. This category aims at the early identification of patients, in whom the diagnosis may be confirmed as the disease evolves. OBJECTIVE: To assess the diagnostic performance of the defined clinical conditions suggestive of progressive supranuclear palsy in an autopsy-confirmed cohort. METHODS: Diagnostic performance of the criteria was analyzed based on retrospective clinical data of 204 autopsy-confirmed patients with progressive supranuclear palsy and 216 patients with other neurological diseases. RESULTS: The conditions suggestive of progressive supranuclear palsy strongly increased the sensitivity compared to the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria. Within the first year after symptom onset, 40% of patients with definite progressive supranuclear palsy fulfilled criteria for suggestive of progressive supranuclear palsy. Two-thirds of patients suggestive of progressive supranuclear palsy evolved into probable progressive supranuclear palsy after an average of 3.6 years. Application of the criteria for suggestive of progressive supranuclear palsy reduced the average time to diagnosis from 3.8 to 2.2 years. CONCLUSIONS: Clinical conditions suggestive of progressive supranuclear palsy allow earlier identification of patients likely to evolve into clinically possible or probable progressive supranuclear and to have underlying progressive supranuclear palsy pathology. Further work needs to establish the specificity and positive predictive value of this category in real-life clinical settings, and to develop specific biomarkers that enhance their diagnostic accuracy in early disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied common genetic variation in only autopsy-confirmed cases (N = 731) and controls (N = 2,898).The most strongly disease-associated markers were rs16859966 on chromosome 3 (P = 8.6 × 10−7, odds ratio (OR) = 1.58, [95% confidence interval (CI) = 1.32-1.89]), rs7013955 on chromosome 8 (P = 3.7 × 10−6, OR = 1.8 [1.40-2.31]), and rs116607983 on chromosome 4 (P = 4.0 × 10−6, OR = 2.93 [1.86-4.63]), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms with P-values below 5 × 10−5. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4).Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4 positive neurons were significantly reduced in patients with olivopontocerebellar atrophy.These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.

[See related article at [www.cmaj.ca/lookup/doi/10.1503/cmaj.191089][2]][2] KEY POINTS Parkinson disease is chronic and progressive in nature, decreasing the quality of life for both patients with the disease and their caregivers and placing an onerous economic burden on society.[1][2] The first

BACKGROUND: The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them. METHODS: We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations. RESULTS: Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1. CONCLUSIONS: The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

Summary Background The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP). Methods In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets. Findings Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10−10, hazard ratio 1·42 [95% CI 1·22–1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00–1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10−10, 1·37 [1·25–1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant. Interpretation Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies. Funding PSP Association, CBD Solutions, Medical Research Council (UK).

Introduction Resting limb tremor (RLT) is a well known feature in parkinsonism. There is very little information on resting head tremor (RHT) in parkinsonism, and none in pathologically confirmed cases. The association between RLT and RHT remains uncertain. Methods A Caucasian male developed upper limb tremor and voice changes at age 70. He was first assessed at our clinic at age 72. At age 73 he developed resting head tremor (RHT) which prevented him from falling asleep. His status was documented in longitudinal follow-up at our clinic. He had a total of 14 clinical evaluations and four videos made over 6 years. Autopsy of the brain and spinal cord was performed. Results The resting head tremor improved on antiparkinsonian drugs and resolved completely after four years. Coincident with RHT remission, the upper limb tremor worsened and interfered with feeding, and his lower limb resting tremor became more pronounced. During his course he developed slow, scanning speech and all the cardinal motor findings of parkinsonism. There was no ophthalmoplegia. Post-mortem neuropathological examination revealed prominent progressive supranuclear palsy (PSP) changes and minor Lewy body pathology. Conclusion This is the first autopsy confirmed case of parkinsonism with RHT. He had dual pathology. Dissociation between RHT and RLT indicates that the oscillatory brain centers for the two were different in this case.

Objective:To identify the significance of baseline motor features to the lifelong prognostic motor subtypes in a Parkinson disease (PD) cohort.Methods:In a previous study of 166 PD cases, we observed different prognosis in tremor-dominant, akinetic-rigid, and mixed subtypes. This study includes the same cases, but we excluded 10 cases with symptoms of ≥15 years duration at baseline. Relative severity of tremor, bradykinesia/akinesia, and rigidity at baseline were evaluated as predictors of the motor subtypes, which are known to have different prognosis.Results:The most common motor subtype was mixed, followed by akinetic-rigid and then the tremor-dominant. Seventy cases were not receiving antiparkinsonian drugs at baseline. The prognostic subtypes could be predicted at baseline in 85% of all and in 91% of the treatment-naive cases. Sensitivity, specificity, and positive predictive values were strong for the mixed and the akinetic-rigid but weak for the tremor-dominant subtype.Conclusions:Our data show that motor profile at baseline can predict prognosis in most PD cases. These findings can be incorporated into clinical practice.

Introduction Neurodegeneration is known basis of several different Parkinson syndromes. The most common Parkinson syndrome is the Parkinson's disease. Distinction between different Parkinson syndromes is based on pathology or genetic findings. Recent studies indicate that several major variants of PS have some characteristics of a prion disease and may therefore be transmissible. Married couples offer a unique opportunity to study person-to-person transmission and the role of shared environments as the cause of parkinsonism. Methods Autopsy is offered to patients seen at the Movement Disorders Clinic Saskatchewan at no cost. Five couples seen in our clinic, where each spouse had a clinical diagnosis of parkinsonism, came to autopsy. Results Median duration of marriage was 42 years before the Parkinson syndrome first manifested in a spouse. Three couples were pathologically or genetically discordant for Parkinson variant. Each spouse in the other two couples had Parkinson's disease. One couple had onset separated by 20 years and one partner had a strong family history of Parkinson's disease. Conclusion Our data indicate that neither of the Parkinson's disease, Progressive Supranuclear Palsy and Multiple System Atrophy are transmitted by sexual or other intimate contact. The data also indicate against shared environments as the cause of these disorders.

Background Elevated brain iron has been observed in Idiopathic Parkinson's disease (IPD) within the deep gray matter. Using quantitative susceptibility mapping (QSM) and a thresholded high-iron region, we quantified iron content in the midbrain of patients with Parkinson's disease as a function of age. Methods We used MRI to scan 24 IPD patients at 3-Tesla. Susceptibility-weighted images were collected with the following parameters, TE: 6 and 20 ms, TR: 30 ms, FA: 15°, and resolution: 0.5 × 0.5 × 2.0 mm3. QSM images were reconstructed from the source phase images. Whole-region and thresholded high-iron (RII) region boundaries for the Substantia Nigra (SN) and Red Nucleus (RN) were traced. Iron content was measured via mean susceptibilities and volumes, which were compared between the groups, as well as between right and left side of the structures within groups. Results Twenty patients with mild to moderate IPD were used in this study. For the SN, mean RII and whole-region iron and volumes were higher in the IPD group compared to HC, as well as mean RII for the RN, while no differences were seen between the groups when considering whole-region mean susceptibility bilaterally for the RN. Conclusion Using a two-region of interest analysis on QSM, we showed that abnormal iron occurs in IPD patients in the SN and with greater volumes compared to HC. This method may have application as a biomarker for disease diagnosis and early intervention.

Background Drug-induced parkinsonism is a well-known complication of several different drugs—the most common being neuroleptic-induced parkinsonism. However, very few autopsies have been reported in such cases. Methods Patients assessed at Movement Disorders Clinic Saskatchewan are offered brain autopsy. Detailed clinical records are kept. Results Brains were obtained from 7 drug-induced parkinsonism patients with parkinsonian symptom onset coinciding with use of drugs known to produce parkinsonism. Six were on antipsychotics and 1 was on metoclopramide. Three cases were treated with levodopa for parkinsonism. In two cases, parkinsonian features reversed after stopping the offending agent. Both had autopsy evidence of preclinical PD. In 4 of the remaining 5, dopamine-blocking drugs were continued until death. In 4 of those 5, brain histology revealed no cause for the parkinsonism, but 1 had mild SN neuronal loss without Lewy bodies. Conclusion This study shows that reversal of parkinsonism after discontinuing offending drugs does not indicate absence of underlying pathology. Neuroleptics can unmask preclinical PD in patients with insufficient SN damage for the disease to manifest clinically. Though the mechanism of sustained parkinsonian features after discontinuing neuroleptics remains to be established, it is unlikely that dopamine receptor block leads to retrograde SN neuronal degeneration. Furthermore, l-dopa does not appear to be toxic to SN. © 2015 International Parkinson and Movement Disorder Society

Background Definite diagnosis of idiopathic Parkinson's disease is based on histological findings of marked substantia nigra neuronal loss and Lewy body inclusions. Almost all cases with clinical diagnosis of idiopathic Parkinson's disease are treated with levodopa. Because there is no biological marker for the diagnosis, erroneous clinical diagnosis and treatment of such cases with levodopa are well known. There is very limited literature on levodopa treated cases that had normal substantia nigra at autopsy. Methods Patients seen at Movement Disorders Clinic Saskatchewan are offered autopsy at no cost to the family/estate of the patient. Autopsy studies are performed by certified neuropathologists. Notation on the status of substantia nigra is made in every autopsied case. Results Between 1968 and 2014, 21 cases treated with levodopa had normal substantia nigra at autopsy. Eleven patients continued levodopa until death and 9 received the drug for four years or longer. No objective motor symptom benefit, dyskinesia or motor response fluctuations on levodopa were observed in any case. The most common final diagnosis was essential tremor. Conclusion Individuals with normal substantia nigra do not benefit from levodopa and do not manifest motor response fluctuations or dyskinesia. Long-term use of levodopa is not toxic to normal human substantia nigra.

Background:Several studies have compared early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD) but most are not based on autopsy confirmed cases.Methods:We compared clinical and pharmacological profiles, time to reach irreversible Hoehn and Yahr (H&Y) Stage 3 and levodopa motor complications in autopsy confirmed EOPD and LOPD cases.Results:At first clinic visit EOPD cases were younger but had longer disease duration and they died at a younger age (all pConclusions:Our observations indicate that progression of PD is slower in EOPD and suggest that the pre-clinical interval in this group is longer. These findings can be used for case selection for drug trials and studies of the pathogenesis of PD.

We review the Saskatchewan Movement Disorders Program, which started in 1968 and has had the dual goals of patient care and research. The clinics are structured to collect research-worthy data including videos, longitudinal follow-up, and autopsy studies of patients seen in the clinics. At every clinic visit, the patient is evaluated by one or both authors. A total of 25% to 30% of the deceased come to autopsy. Frozen half-brain and formalin-fixed remnants from autopsy are preserved in our laboratories. Patients not seen in our clinic are not included in research, which makes it different from brain banks. So far, 515 cases have come to autopsy. So far, there have been 17 collaborating scientific teams from Canada, the United States, Europe, and Japan. The collaborators are not charged for access to our resources. This program offers a unique opportunity to study multiple aspects of movement disorder patients seen in clinical practice.

The phenotypic variability of progressive supranuclear palsy (PSP) may account for its frequent misdiagnosis, in particular in early stages of the disease. However, large multicenter studies to define the frequency and natural history of PSP phenotypes are missing. In a cohort of 100 autopsy-confirmed patients we studied the phenotypic spectrum of PSP by retrospective chart review. Patients were derived from five brain banks with expertise in neurodegenerative disorders with referrals from multiple academic hospitals. The clinical characteristics of the 100 cases showed remarkable heterogeneity. Most strikingly, only 24% of cases presented as Richardson's Syndrome (RS), and more than half of the cases either showed overlapping features of several predescribed phenotypes, or features not fitting proposed classification criteria for PSP phenotypes. Classification of patients according to predominant clinical features in the first 2 years of the disease course allowed a more comprehensive description of the phenotypic spectrum. These predominance types differed significantly with regard to survival time and frequency of cognitive deficits. In summary, the phenotypic spectrum of PSP may be broader and more variable than previously described in single-center studies. Thus, too strict clinical criteria defining distinct phenotypes may not reflect this variability. A more pragmatic clinical approach using predominance types could potentially be more helpful in the early recognition of and for making prognostic predictions for these patients. Given the limitations arising from the retrospective nature of this analysis, a systematic validation in a prospective cohort study is imperative.

Background Families of Dutch-German-Russian Mennonite descent with multi-incident parkinsonism have been identified as harboring a pathogenic DNAJC13 p.N855S mutation and are awaiting clinical and pathophysiological characterization. Methods Family members were examined clinically longitudinally, and 5 underwent dopaminergic PET imaging. Four family members came to autopsy. Results Of the 16 symptomatic DNAJC13 mutation carriers, 12 had clinically definite, 3 probable, and 1 possible Parkinson's disease (PD). Symptoms included bradykinesia, tremor, rigidity, and postural instability, with a mean onset of 63 years (range, 40-85) and slow progression. Eight of ten subjects who required treatment had a good levodopa response; motor complications and nonmotor symptoms were observed. Dopaminergic PET imaging revealed rostrocaudal striatal deficits typical for idiopathic PD in established disease and subtle abnormalities in incipient disease. Pathological examinations revealed Lewy body pathology. Conclusion PD associated with a DNAJC13 p.N855S mutation presents as late-onset, often slowly progressive, usually dopamine-responsive typical PD. © 2014 International Parkinson and Movement Disorder Society

L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson's disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain α7 nACh receptors might be a potential therapeutic target for PD. This study used [(125)I]α-Bungarotoxin autoradiography to investigate α7 nACh receptors in LID in post-mortem brains from PD patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [(125)I]α-Bungarotoxin specific binding to striatal and pallidal α7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding. The total group of Parkinsonian patients had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus but not in the putamen. PD patients without motor complications had higher [(125)I]α-Bungarotoxin specific binding compared to controls only in the caudate nucleus. PD patients with LID only had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus and compared to those without motor complications and controls in the putamen. PD patients with wearing-off only, had [(125)I]α-Bungarotoxin specific binding at control values in the caudate nucleus and lower in the putamen. Reduced motor complications were associated with normal striatal α7 nACh receptors, suggesting the potential of this receptor to manage motor complications in PD.

Background and purpose: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson’s disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer’s disease. Methods: Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson’s disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson’s disease, 344 controls) and five separate Caucasian series’ (combined sample size 1962 Parkinson’s disease patients, 1900 controls). Results: We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson’s disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model. Conclusion: These specific DAPK1 intronic variants do not increase the risk of Parkinson’s disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.

Alpha-synuclein gene (SNCA) mutations cause familial Parkinsonism but the role of SNCA variability in idiopathic Parkinson's disease (PD) remains incompletely defined. We report a study of SNCA genetic variation in 452 idiopathic PD cases and 245 controls. SNCA copy number mutations were not associated with early-onset disease in this population. The minor allele "G" at rs356165 was associated with increased odds of PD (P = 0.013) and genetic variation in D4S3481 (Rep1) was associated with age of disease onset (P = 0.007). There was a trend toward association between variation at rs2583988 and rapid PD progression.

Background—Purkinje cell axonal swellings (“torpedoes”), described in several cerebellar disorders as well as essential tremor (ET), have not been quantified in common neurodegenerative conditions.

Modulation of basal ganglia group II metabotropic glutamate receptors (mGluR2/3) is a potential therapeutic alternative to levodopa in Parkinson disease (PD). We used receptor-binding autoradiography of the mGluR2/3-selective radioligand [H]LY341495 in postmortem brain specimens from PD patients (n = 14) and controls (n=11) to investigate possible contributions of changes in ligand binding of this receptor to levodopa-associated motor complications experienced premortem in PD patients. The PD patients included those with and without histories of dyskinesias and those with and without "wearing off," which is defined as a reduced period of benefit from levodopa. Specific binding of [H]LY341495 to mGluR2/3 in the basal ganglia was higher in the caudate nucleus than the putamen and lower by approximately half in the external and internal globus pallidus (GPi) in controls. [H]LY341495-specific binding was reduced in the caudate and GPi in patients without wearing-off (-22% caudate, -30% GPi), compared with controls and with patients who had experienced wearing-off; there were no differences among PD patients with or without dyskinesias. These data suggest that an adaptive downregulation of mGluR2/3 in PD patients without wearing-off may compensate for increased glutamate. They indicate a key role for mGluR2/3 in control of movement and the potential for mGluR2/3-targeted drugs in the management of wearing-off fluctuations in PD.

The long-term administration of low doses of rotenone has been used to produce a model of Parkinson disease (PD) in rats. However, only about 50% of similarly treated rats develop the PD-like syndrome, with many dying during the first few days of treatment. The lesions in male Lewis rats that became moribund or died after short-term, low-dose rotenone administration are described. Dosed rats had fibrinoid change and acute hemorrhage involving small arteries and arterioles of the brain and lungs. The thalamus, hypothalamus, and medulla oblongata were most frequently and severely affected. Blood vessels in the brain of some male Lewis rats appeared acutely susceptible to the effects of rotenone. Understanding the selective nature of the fibrinoid change and hemorrhage might explain how rotenone produces PD-like signs and lesions in rats, and it might also provide the basis for a model of intraparenchymal hemorrhagic cerebrovascular disease (i.e., hemorrhagic strokes) in humans.

L-DOPA-induced dyskinesias (LID) are abnormal involuntary movements limiting the chronic use of L-DOPA, the main pharmacological treatment of Parkinson's disease. Serotonin receptors are implicated in the development of LID and modulation of basal ganglia 5-HT1B receptors is a potential therapeutic alternative in Parkinson's disease. In the present study, we used receptor-binding autoradiography of the 5-HT1B-selective radioligand [3H]GR125743 to investigate possible contributions of changes in ligand binding of this receptor in LID in post-mortem brain specimens from Parkinson's disease patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist and has been shown to reduce the development of LID in these monkeys in a chronic treatment of one month. [3H]GR125743 specific binding to striatal and pallidal 5-HT1B receptors respectively were only increased in L-DOPA-treated MPTP monkeys (dyskinetic monkeys) as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesias scores correlated positively with this binding. Parkinson's disease patients with motor complications (L-DOPA-induced dyskinesias and wearing-off) had higher [3H]GR125743 specific binding compared to those without motor complications and controls in the basal ganglia. Reduction of motor complications was associated with normal striatal 5-HT1B receptors, suggesting the potential of this receptor for the management of motor complications in Parkinson's disease.

Up to 6% of the general population have essential tremor (ET). In a number of couples both partners may have ET. The clinical profile of ET in children and the parents where both parents and the child have ET remains to be established. We report on two families where both parents and one child have ET. The severity of ET was greater in the children than in either parent. Such families could provide special opportunity to determine relation between genotype and phenotypic expression of ET.

Background and purpose Exome sequencing analysis has recently identified a nonsense mutation in fused in sarcoma (FUS) segregating with essential tremor (ET) within a large French-Canadian family. Further characterization of FUS resulted in the identification of additional mutations in ET patients; however, their pathogenicity still remains to be confirmed. The role of FUS in an independent cohort of ET patients from Canada was evaluated. Methods The entire coding sequence of FUS in 217 patients diagnosed with ET was analyzed and two missense variants in 219 healthy controls were genotyped by Sanger sequencing. Results Sequencing of FUS identified a previously reported non-pathogenic mutation p.G174_G175del in one ET patient and two healthy controls, and a novel p.R377W in one patient with family history of disease. This mutation is highly conserved and strongly predicted to be damaging by in silico analysis. Conclusion This study has identified a novel FUS p.R377W substitution in ET patients. Additional genotyping studies in a large number of ET patients and controls are necessary to conclusively define its pathogenicity.

Objective:To correlate autopsy findings with the clinical course and disability profile in clinically diagnosed longitudinally followed autopsied essential tremor (ET) patients.Methods:All ET patients followed by one neurologist between 1970 and 2001 who came to autopsy were included. Clinical features and disability were recorded prospectively. Autopsy studies were performed by a qualified neuropathologist.Results:Twenty cases (10 men and 10 women) had ET onset between childhood and age 68 (median 46.5 years). Six cases had additional features of Parkinson syndrome (PS), with presence of bradykinesia, rigidity, and rest tremor (RT). These included progressive supranuclear palsy (PSP; n = 2), drug-induced parkinsonism (n = 2), idiopathic Parkinson disease (PD; n = 1), and basal ganglia status cribrosus (n = 1). Of the remaining 14 ET cases, 6 had additional RT but no bradykinesia or rigidity. Ten of these 14 (71%) reported physical disability. Eleven of the 14 (79%) had only upper limb (UL) tremor at onset, and 8 of these 11 (73%) had subsequent cranial extension of tremor. Two patients clinically had mild cerebellar ataxia but no cerebellar histologic abnormality. There was no consistent brain pathology in the ET or ET + RT cases.Conclusions:UL tremor was the most common onset, which often progressed to the cranial musculature. Functional disability and psychological distress were common in these patients. Functional disability was related to the UL tremor. Six of 20 (30%) had additional features of PS. Six of the remaining 14 (43%) had ET and RT; there was no identifiable pathology in these cases. The risk of PD in ET cases was comparable with that in the general population. PSP in two cases was incidental comorbidity.

The pathophysiology of essential tremor (ET) is unknown but recent studies report that the majority of ET cases has cerebellar Purkinje cell (PC) degeneration and its sequelae. Objective To perform PC counts in ET, and normal and Parkinson's disease (PD) controls to determine the relationship of PC loss to ET. Methods All ET cases and PD controls were followed at our clinic. Normal controls had no history of neurological disease and had normal standard neuropathological studies. The PC counts were done by a neuropathologist who was blinded to the clinical diagnosis. Three different methods were used for counting PC; section through any part of the PC, through any part of the PC nucleus, and through any part of PC nucleolus. The counts were done in five non-contiguous microscopic fields. Results 59 brains were studied. These included 12 ET, 41 PD controls, and six normal controls. The mean age at death was 82.7 in ET, 79.1 in PD, and 75.7 years in the normal controls. The mean duration of symptoms was 34 years in ET and 15.7 years in the PD cases. The mean PC counts through any part of the neuron were 64.8 in ET, 56.2 in PD, and 58.0 in normal controls. Differences were not significant. Conclusion Cerebellar PC loss does not distinguish ET from controls. It is concluded that PC loss is neither a pathological basis for, nor the distinctive feature of ET.

The study of the neuropathological underpinnings of essential tremor (ET) is a relatively new undertaking. The purpose of this paper is three-fold. The first is to comment on methodological problems in a recently-published paper by Rajput et al, the major one being the small sample size of that study, which resulted in a Type II statistical error. Hence, one cannot conclude based on their data that there is no Purkinje cell (PC) loss in ET. Secondly, we comment on conceptual problems with that study, which suggested that PC loss might not be a featured characteristic of ET because it is also found in other disease states. We discuss why this is an erroneous conclusion. Our third purpose is to more broadly discuss the role of the cerebellum in ET, giving consideration to the wealth of clinical and postmortem data that have accumulated over recent years. In this discussion, we make the following points: (1) it is now generally recognized that ET is a disease of cerebellar systems dysfunction, (2) given the nature of the postmortem work, revealing the presence of several types of structural-anatomical changes within the cerebellum and absence of detectable changes in other brain regions, the most empirically-based explanation is that the primary problem in ET is in the cerebellum itself, (3) that the collection of cellular changes in the cerebellum in ET are also present in other cerebellar degenerations should add to rather than detract from the notion that ET is a disease of cerebellar degeneration.

Mutations in the microtubule-associated protein tau gene ( MAPT ) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).1 In addition, the major common MAPT- containing H1 haplotype is associated with increased risk for 2 parkinsonian disorders: progressive supranuclear palsy (PSP) characterized by 4-repeat tau pathology and Parkinson disease (PD) with α-synuclein pathology.2,3 However, the role of MAPT variation in other disorders with similar pathology or disease phenotype is unclear. We investigated the frequency of the MAPT H1 haplotype in both essential tremor (ET) and multiple system atrophy (MSA). ET is the most common movement disorder, and prior evidence has indicated a common link between ET and PD from clinical, epidemiologic, and pathologic studies as well as some reports of brainstem Lewy bodies at autopsy in patients with ET.4 MSA is a neurodegenerative disorder with α-synuclein pathology with a mixed clinical presentation combining autonomic dysfunction, parkinsonism, and cerebellar or pyramidal symptoms. The initial clinical signs of MSA with prominent parkinsonism can make it difficult to differentially diagnose it from early PD. In addition, up to 30% of patients with MSA with prominent parkinsonism may have a transient response to levodopa therapy.5 ### Methods. Genotyping of the MAPT H1 discriminating SNP (rs1052553) and H1c subhaplotype SNP (rs242557) was performed on a Sequenom MassArray iPLEX platform (San Diego, CA) (primer sequences are available on request) and analyzed with Typer 4.0 software. The rate of genotype calls was ≥95% in each population. The series contained 356 patients with clinical ET, 61 patients with pathologically confirmed MSA, and 409 US control subjects; all samples are North American Caucasians. Numerical variables were summarized with the sample mean, SD, and range (table e-1 on the …

Clinicogenetic and pathological studies have shown that mutations of the glucocerebrosidase gene (GBA) are a risk factor for Parkinson’s disease and Lewy body disorders. In the present study, we have identified GBA mutations in 6.8% (4/59) of cases with a pathological diagnosis of diffuse Lewy body disease. Taken with previous studies, it appears that GBA mutations are associated with a more diffuse pattern of Lewy body distribution involving the cerebral cortex than the brainstem/limbic distribution observed in typical Parkinson’s disease.

Essential tremor (ET) is the most common pathological tremor characterized by upper limb action—postural tremor (PT)/kinetic tremor (KT). There are no specific neuropathological or biochemical abnormalities in ET. The disability is consequent to amplitude of KT, which may remain mild without handicap or may become disabling. The most effective drugs for sustained tremor control are propranolol and primidone. Symptomatic drug treatment must be individualized depending on the circumstances that provoke the tremor-related disability. Broad guidelines for treatment are discussed in this review. Patients may be treated intermittently only on stressful occasions with propranolol, clonazepam, or primidone monotherapy, or an alcoholic drink. Those with persistently disabling tremor need continued treatment.

Attempts at replicating the first genome-wide association study (GWAS) in Parkinson's disease (PD) have not successfully identified genetic risk factors. The present study reevaluates data from the GWAS and focuses on the SNP (rs11155313, located in the Phactr2 gene) with the lowest P-value in the Tier 2 patient-control series of the first PD GWAS. We employed four case-control series to examine the nominated SNP rs11155313 and identified association in US (OR: 1.39, P=0.032), Canadian (OR: 1.41, P=0.014) and Irish (OR: 1.44, P=0.034) patient-control series, but not in the Norwegian series (OR: 1.15, P=0.27). When combining all four series the observed trend was statistically significant (OR: 1.30, P

Lrrk2 G2019S is predominantly associated with alpha-synuclein-immunopositive Lewy body pathology. We have identified Family SK where Lrrk2 G2019S segregates with slowly progressive parkinsonism and the affected proband has tau-immunopositive neurofibrillary tangle pathology. Thus alpha-synucleinopathy and tauopathy, the predominant pathologies associated with parkinsonism, may be alternate outcomes of the same underlying genetic cause. Intriguingly, we observe no evidence of a direct interaction between either the tau or alpha-synuclein protein with Lrrk2.

The incidence of Parkinson syndrome in North America is 20.5/10(5), adjusted to 1970 US population, and there has been no significant change between 1935 and 1979. The composition of different Parkinson variants in the general population, however, has altered remarkably during recent decades. Arteriosclerotic Parkinsonism is very rarely diagnosed now, post-encephalitic Parkinsonism is extinct and drug induced Parkinsonism, first identified in the 1950s, is now the second most common variant in the combined community and institutionalised population survey. There has been a trend to higher incidence of Parkinson's disease in recent decades and it is predicted that the incidence would rise further if the current population survival trends continue. There is no race or gender difference for the risk of Parkinson's disease. Survival in Parkinson's disease has increased since the widespread use of levodopa. The prevalence rate of Parkinson syndrome in North America is estimated at 300/105. Increased risk of Parkinson's disease in essential tremor patients and the reported protective effect of smoking are artifactual. Twin studies show a concordance rate of 10.5% in monozygotic and 10.8% in dizygotic twins, indicating against a major genetic basis for Parkinson's disease. Several large Parkinson's disease families with autosomal dominant inheritance are well documented. In one such family, linkage to chromosome 4 is reported and mutation in the a-synuclein gene has been identified. In several other families, linkage to that region was not detected. These families are believed to inherit a Parkinson's disease susceptibility trait.

Amantadine has been used for more than 20 years in the symptomatic treatment of Parkinson's disease (PD).Several recent discoveries suggest that amantadine could also have a neuroprotective effect in PD. We studied survival in all parkinsonism (including PD and other parkinsonian syndromes) patients attending a single clinic, employing standard survival curves and a Cox regression model, to identify independent predictive variables for survival (while taking into account factors potentially associated with both outcome and treatment selection). Amantadine-treated patients (n = 250) were similar to the patients not treated with amantadine (n = 586) in terms of age, gender, type of parkinsonism, Hoehn and Yahr stage and dementia status at initial neurological visit. Amantadine use was an independent predictor of improved survival (p < 0.01). Improved survival was also associated with a higher 10-year expected survival (based on age, gender, and birth year), absence of dementia, type of parkinsonism = PD, and low Hoehn and Yahr stage (I or II) at initial neurologic visit (all p < 0.01); these additional factors occurred in statistically similar proportions in the groups that were and were not treated with amantadine. The association of improved survival with amantadine use may stem from symptomatic benefit or may reflect a "neuroprotective'' effect, mediated through N-methyl-D-aspartate (NMDA) receptor antagonism, dopamine uptake blockade activity, or other mechanisms. Our preliminary findings suggest that a prospective, controlled, randomized trial of amantadine's effects on PD progression is warranted.NEUROLOGY 1996;46: 1551-1556

SUMMARY The pathophysiology of essential tremor (ET) remains unknown. Standard neuropathological studies have reported no consistent changes but a detailed study found neurodegeneration in all ET cases – 24% demonstrated lower brainstem Lewy body (LB) inclusions and 76% experienced a loss of cerebellar Purkinje cells (PCs) and its sequelae. We review the evidence on neurodegeneration in ET. The prevalence of LB inclusions in ET brains is similar to that in the asymptomatic general population. These incidental LB disease cases have evidence for reduced striatal tyrosine hydroxylase levels, as found in Parkinson’s disease, but there is no evidence for reduced tyrosine hydroxylase levels in ET patients. Reduced mean PC counts in ET cases compared with the controls reported by some studies could not be replicated by others. Most ET cases have the same number of PCs as controls of a comparable age. Neither the lower brainstem LB inclusions nor the cerebellar PC loss represent the neurodegenerative basis of ET. Further studies are needed to determine the pathophysiology of ET.

Idiopathic Parkinson's disease (IPD) and Alzheimer's disease (AD) are common neurologic diseases of old age. Parkinson syndrome is easy to recognize even at an early stage, but identifying early AD is often difficult. Accurate clinical diagnosis is important for assigning the prognosis and for studies aimed at assessing the efforts to slow down progression of these diseases. During 22 years, we identified six patients who had clinical features of parkinsonism and dementia and who at autopsy had both IDP and AD and 20 parkinsonian patients without dementia who at autopsy had only IPD. The clinical profile in these two groups was compared. The onset of Parkinson syndrome in the patients with dual pathology had a bimodal distribution—before or after age 65 years. In the three cases with onset before age 65 years, there was sequential evolution of IPD and AD. In contrast, those older than 65 years at onset manifested the clinical features of both IPD and AD simultaneously. The mode of onset and the dominant parkinsonian features in the three patients with sequential clinical evolution were similar to those seen in the nondemented IPD cases; however, lack of self-confidence and inability to make decisions resulted in considerably greater functional disability than could be accounted for by parkinsonism alone. These characteristics may be helpful in early recognition of dual IPD and AD pathology. Psychiatric side effects of levodopa therapy were more common in those with dual pathology than in those with IPD alone.

Neurologists are well known for their outstanding clinical skills. Those skills are especially important in the practice of movement disorders whereby the diagnostic tools are limited.

Metabotropic glutamate receptors type 5 (mGluR5) are implicated in regulation of synaptic plasticity and learning, and were the focus of our investigation in human Parkinson's disease (PD) patients with dyskinesias and wearing-off, and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys with dyskinesias. Using the selective mGluR5 ligand [ 3 H]ABP688 autoradiography, we measured mGluR5 in brain slices from 11 normal and 14 PD patients and from MPTP monkeys, in relation to motor complications (dyskinesias and wearing-off) associated with treatment with l -dopa. In 16 monkeys with a bilateral MPTP lesion and four controls, [ 3 H]ABP688 specific binding was elevated in the striatum of dyskinetic l -dopa-treated MPTP monkeys but not in MPTP monkeys without dyskinesias compared to controls. PD patients with motor complications (either dyskinesias or wearing-off) had higher [ 3 H]ABP688 specific binding compared to those without motor complications and controls in putamen, external and internal globus pallidus. Elevated glutamatergic transmission as measured with increased mGluR5 specific binding was associated with motor complications and its antagonism could be targeted for their treatment.

A National Conference on Parkinson's disease was held on September 7th-8th, 1990 in Victoria, British Columbia. The scientific program included 11 formal presentations, 10 small group workshops and video presentations of interesting examples of movement disorders. The subjects discussed ranged from epidemiology and etiology to current and possible future modes of management of Parkinson's disease.

Chronic low-dose (2-3 mg/kg/day) rotenone infusion produces clinical features and biological markers of Parkinson's disease (PD) in some rats. A significant proportion of rats, however, die of acute rotenone toxicity. Most studies have focused on chronic rotenone-infused rats. It has not been established if the animals that die of acute low-dose rotenone toxicity manifest clinical or pathological evidence of PD. In the present study, six rats that received continuous 3 mg/kg/day subcutaneous rotenone infusion, became moribund and were euthanized after five days were compared with ten vehicle infused animals sacrificed 14, 28 or 56 days after placebo infusion. All rotenone-infused rats had significant motor function decline beginning one day after the infusion and progressive worsening in the physical condition until they became severely akinetic, at which point they were euthanized. In the substantia nigra of rotenone-treated rats, four of six had reduced numbers of tyrosine hydroxylase-positive neurons and all six had increased nigral alpha-synuclein expression. Our observations show that even a short duration of low-dose subcutaneous rotenone infusion can induce clinical and pathological markers of PD in some rats. The pathophysiology of the enhanced susceptibility to PD in some animals remains to be established.