Publications by authors named "Wassilios Meissner"

142 Publications

The European Reference Network for Rare Neurological Diseases.

Front Neurol 2020 14;11:616569. Epub 2021 Jan 14.

Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseases, were formed to improve the care for patients with an RD. One major aim is to have "the knowledge travel instead of the patient," which has been put into practice by the implementation of the Clinical Patient Management System (CPMS) that enables clinicians to perform pan-European virtual consultations. The European Reference Network for Rare Neurological Diseases (ERN-RND) provides an infrastructure for knowledge sharing and care coordination for patients affected by a rare neurological disease (RND) involving the most common central nervous system pathological conditions. It covers the following disease groups: (i) Cerebellar Ataxias and Hereditary Spastic Paraplegias; (ii) Huntington's disease and Other Choreas; (iii) Frontotemporal dementia; (iv) Dystonia, (non-epileptic) paroxysmal disorders, and Neurodegeneration with Brain Iron Accumulation; (v) Leukoencephalopathies; and (vi) Atypical Parkinsonian Syndromes. At the moment, it unites 32 expert centers and 10 affiliated partners in 21 European countries, as well as patient representatives, but will soon cover nearly all countries of the European Union as a result of the ongoing expansion process. Disease expert groups developed and consented on diagnostic flowcharts and disease scales to assess the different aspects of RNDs. ERN-RND has started to discuss diagnostically unclear patients in the CPMS, is one of four ERNs that serve as foundation of Solve-RD, and has established an RND training and education program. The network will facilitate trial readiness through the establishment of an ERN-RND registry with a minimal data of all patients seen at the ERN-RND centers, thus providing a unique overview of existing genotype-based cohorts. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based on this objective, ERNs are monitored by the European Commission on a regular basis to provide transparency and reassurance to the RD community and the general public.
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http://dx.doi.org/10.3389/fneur.2020.616569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840612PMC
January 2021

A Modified Progressive Supranuclear Palsy Rating Scale.

Mov Disord 2021 Jan 29. Epub 2021 Jan 29.

Department of Neurology, Technische Universität München, Munich, Germany.

Background: The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status.

Objective: The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones.

Methods: Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy.

Results: The modified scale retained 14 items (yielding 0-2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months).

Conclusions: The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28470DOI Listing
January 2021

A Phase 2 Randomized Trial of Asleep versus Awake Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

Stereotact Funct Neurosurg 2020 Nov 30:1-11. Epub 2020 Nov 30.

CHU de Bordeaux, Service de Neurochirurgie B, Bordeaux, France.

Objective: Asleep deep brain stimulation (DBS) for Parkinson's disease (PD) is being performed more frequently; however, motor outcomes and safety of asleep DBS have never been assessed in a prospective randomized trial.

Methods: We conducted a prospective, randomized, noncomparative trial to assess the motor outcomes of asleep DBS. Leads were implanted in the subthalamic nucleus (STN) according to probabilistic stereotactic coordinates with a surgical robot under O-arm© imaging guidance under either general anesthesia without microelectrode recordings (MER) (20 patients, asleep group) or local anesthesia with MER and clinical testing (9 patients, awake group).

Results: The mean motor improvement rates on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-3) between OFF and ON stimulation without medication were 52.3% (95% CI: 45.4-59.2%) in the asleep group and 47.0% (95% CI: 23.8-70.2%) in the awake group, 6 months after surgery. Except for a subcutaneous hematoma, we did not observe any complications related to the surgery. Three patients (33%) in the awake group and 8 in the asleep group (40%) had at least one side effect potentially linked with neurostimulation.

Conclusions: Owing to its randomized design, our study supports the hypothesis that motor outcomes after asleep STN-DBS in PD may be noninferior to the standard awake procedure.
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http://dx.doi.org/10.1159/000511424DOI Listing
November 2020

Cerebrospinal Fluid Levels of Kininogen-1 Indicate Early Cognitive Impairment in Parkinson's Disease.

Mov Disord 2020 11 15;35(11):2101-2106. Epub 2020 Aug 15.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Cognitive impairment is common in patients with PD. Core markers of Alzheimer's dementia have been related also to PD dementia, but no disease-specific signature to predict PD dementia exists to date.

Objectives: The aim of this study was to investigate CSF markers associated with cognition in early PD.

Methods: A high-throughput suspension bead array examined 216 proteins in CSF of 74 PD patients in the AETIONOMY project. Cognitive function was assessed with Repeatable Battery for the Assessment of the Neuropsychological Status, Montreal Cognitive Assessment, and Mini-Mental State Examination.

Results: Of 69 patients with complete data, 34 had high (≥90) and 35 had low Repeatable Battery for the Assessment of the Neuropsychological Status total score (<90). Of 14 proteins in CSF that differed in levels between groups, increased kininogen-1, validated with several antibodies, was independently associated with lower Repeatable Battery for the Assessment of the Neuropsychological Status and Montreal Cognitive Assessment scores after adjustment for confounders.

Conclusions: Kininogen-1 levels in CSF may serve as a marker of cognitive impairment in PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28192DOI Listing
November 2020

Overexpression of α-Synuclein by Oligodendrocytes in Transgenic Mice Does Not Recapitulate the Fibrillar Aggregation Seen in Multiple System Atrophy.

Cells 2020 10 29;9(11). Epub 2020 Oct 29.

CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33076 Bordeaux, France.

The synucleinopathy underlying multiple system atrophy (MSA) is characterized by the presence of abundant amyloid inclusions containing fibrillar α-synuclein (α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinson's disease (PD) where the pathological α-syn aggregates are almost exclusively neuronal, the α-syn inclusions in MSA are principally observed in oligodendrocytes (OLs) where they form glial cytoplasmic inclusions (GCIs). This is intriguing because differentiated OLs express low levels of α-syn, yet pathogenic amyloid α-syn seeds require significant amounts of α-syn monomers to feed their fibrillar growth and to eventually cause the buildup of cytopathological inclusions. One of the transgenic mouse models of this disease is based on the targeted overexpression of human α-syn in OLs using the PLP promoter. In these mice, the histopathological images showing a rapid emergence of S129-phosphorylated α-syn inside OLs are considered as equivalent to GCIs. Instead, we report here that they correspond to the accumulation of phosphorylated α-syn monomers/oligomers and not to the appearance of the distinctive fibrillar α-syn aggregates that are present in the brains of MSA or PD patients. In spite of a propensity to co-sediment with myelin sheath contaminants, the phosphorylated forms found in the brains of the transgenic animals are soluble (>80%). In clear contrast, the phosphorylated species present in the brains of MSA and PD patients are insoluble fibrils (>95%). Using primary cultures of OLs from PLP-αSyn mice we observed a variable association of S129-phosphorylated α-syn with the cytoplasmic compartment, the nucleus and with membrane domains suggesting that OLs functionally accommodate the phospho-α-syn deriving from experimental overexpression. Yet and while not taking place spontaneously, fibrillization can be seeded in these primary cultures by challenging the OLs with α-syn preformed fibrils (PFFs). This indicates that a targeted overexpression of α-syn does not model GCIs in mice but that it can provide a basis for seeding aggregation using PFFs. This approach could help establishing a link between α-syn aggregation and the development of a clinical phenotype in these transgenic animals.
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http://dx.doi.org/10.3390/cells9112371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693764PMC
October 2020

Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease.

Mov Disord 2021 Feb 27;36(2):449-459. Epub 2020 Oct 27.

Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.

Background: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci.

Methods: Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls.

Results: We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts.

Conclusion: Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28338DOI Listing
February 2021

Caregiver Burden in Late-Stage Parkinsonism and Its Associations.

J Geriatr Psychiatry Neurol 2020 Oct 23:891988720968263. Epub 2020 Oct 23.

UCL Queen Square Institute of Neurology, 61554University College London, United Kingdom.

Background: Patients in the late stages of parkinsonism are highly dependent on others in their self-care and activities of daily living. However, few studies have assessed the physical, psychological and social consequences of caring for a person with late-stage parkinsonism.

Patients And Methods: Five hundred and six patients and their caregivers from the Care of Late Stage Parkinsonism (CLaSP) study were included. Patients' motor and non-motor symptoms were assessed using the UPDRS and Non-motor symptom scale (NMSS), Neuropsychiatric inventory (NPI-12), and caregivers' health status using the EQ-5D-3 L. Caregiver burden was assessed by the Zarit Burden Interview (ZBI).

Results: The majority of caregivers were the spouse or life partner (71.2%), and were living with the patient at home (67%). Approximately half of caregivers reported anxiety/depression and pain/discomfort (45% and 59% respectively). The factors most strongly associated with caregiver burden were patients' neuropsychiatric features on the total NPI score (r = 0.38, < 0.0001), total NMSS score (r = 0.28, < 0.0001), caring for male patients and patients living at home. Being the spouse, the hours per day assisting and supervising the patient as well as caregivers' EQ-5D mood and pain scores were also associated with higher ZBI scores (all < 0.001).

Conclusion: The care of patients with late stage parkinsonism is associated with significant caregiver burden, particularly when patients manifest many neuropsychiatric and non-motor features and when caring for a male patient at home.
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http://dx.doi.org/10.1177/0891988720968263DOI Listing
October 2020

Correction to: Excessive buccal saliva in patients with Parkinson's disease of the French COPARK cohort.

J Neural Transm (Vienna) 2020 Oct 21. Epub 2020 Oct 21.

Biomedical Research Center, Interamerican Open University (CAECIHS-UAI), National Research Council (CONICET), Buenos Aires, Argentina.

The original version of this article unfortunately contained a mistake in Fig. 2 caption.
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http://dx.doi.org/10.1007/s00702-020-02264-1DOI Listing
October 2020

Can Autonomic Testing and Imaging Contribute to the Early Diagnosis of Multiple System Atrophy? A Systematic Review and Recommendations by the Movement Disorder Society Multiple System Atrophy Study Group.

Mov Disord Clin Pract 2020 Oct 3;7(7):750-762. Epub 2020 Sep 3.

Department of Neurology Innsbruck Medical University Innsbruck Austria.

Background: In the current consensus diagnostic criteria, the diagnosis of probable multiple system atrophy (MSA) is based solely on clinical findings, whereas neuroimaging findings are listed as aid for the diagnosis of possible MSA. There are overlapping phenotypes between MSA-parkinsonian type and Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and between MSA-cerebellar type and sporadic adult-onset ataxia resulting in a significant diagnostic delay and misdiagnosis of MSA during life.

Objectives: In light of an ongoing effort to revise the current consensus criteria for MSA, the Movement Disorders Society Multiple System Atrophy Study Group performed a systematic review of original articles published before August 2019.

Methods: We included articles that studied at least 10 patients with MSA as well as participants with another disorder or control group for comparison purposes. MSA was defined by neuropathological confirmation, or as clinically probable, or clinically probable plus possible according to consensus diagnostic criteria.

Results: We discuss the pitfalls and benefits of each diagnostic test and provide specific recommendations on how to evaluate patients in whom MSA is suspected.

Conclusions: This systematic review of relevant studies indicates that imaging and autonomic function tests significantly contribute to increasing the accuracy of a diagnosis of MSA.
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http://dx.doi.org/10.1002/mdc3.13052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533961PMC
October 2020

Insulin resistance, diabetes and Parkinson's disease: The match continues.

Parkinsonism Relat Disord 2020 11 6;80:199-200. Epub 2020 Oct 6.

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France; Service de Neurologie des Maladies Neurodégénératives, CHU Bordeaux, 33000, Bordeaux, France; Dept. Medicine, University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2020.10.013DOI Listing
November 2020

Brain 5-HT1A Receptor Binding in Multiple System Atrophy: An [ F]-MPPF PET Study.

Mov Disord 2021 01 21;36(1):246-251. Epub 2020 Sep 21.

Service de Neurologie, CHU Bordeaux, Bordeaux, France.

Background: Loss of medullary serotonin (5-hydroxytryptamine) neurons has been linked to respiratory disturbances in multiple system atrophy (MSA). Broader 5-hydroxytryptamine dysfunction may contribute to additional motor/nonmotor symptoms in MSA. The objective of this study was to compare brain 5-hydroxytryptamine receptor binding between MSA and healthy controls. Secondary objectives were to compare 5-hydroxytryptamine receptor binding between MSA and Parkinson's disease (PD) and to assess potential associations with motor/nonmotor symptoms in MSA.

Methods: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine positron emission tomography was performed in matched MSA patients (n = 16), PD patients (n = 15), and healthy controls (n = 18).

Results: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios were lower in MSA patients versus healthy controls in several brain regions including the caudate, raphe nuclei, thalamus, and brain stem. Distribution volume ratios were also lower in brain stem and amygdala in MSA versus PD. Moderate associations were found between 2'-methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios and fatigue, pain, and apathy in MSA.

Conclusion: Our results demonstrate 5-hydroxytryptamine dysfunction in several brain regions in MSA, which may contribute to fatigue, pain, and apathy. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28295DOI Listing
January 2021

Clinical Conditions "Suggestive of Progressive Supranuclear Palsy"-Diagnostic Performance.

Mov Disord 2020 12 11;35(12):2301-2313. Epub 2020 Sep 11.

Department of Neurology, Technische Universität München, Munich, Germany.

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.
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http://dx.doi.org/10.1002/mds.28263DOI Listing
December 2020

A Phase 1 Randomized Trial of Specific Active α-Synuclein Immunotherapies PD01A and PD03A in Multiple System Atrophy.

Mov Disord 2020 11 3;35(11):1957-1965. Epub 2020 Sep 3.

Université de Toulouse 3, CHU de Toulouse, INSERM, Centre de Reference AMS, Service de Neurologie et de Pharmacologie Clinique, Centre d'Investigation Clinique CIC1436, Réseau NS-Park/FCRIN et Centre of Excellence for Neurodegenerative Disorders (COEN) de Toulouse, Toulouse, France.

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease with limited symptomatic treatment options. Aggregation of α-synuclein in oligodendrocytes is believed to be a central mechanism of the neurodegenerative process. PD01A and PD03A are 2 novel therapeutic vaccine candidates containing short peptides as antigenic moieties that are designed to induce a sustained antibody response, specifically targeting pathogenic assemblies of α-synuclein. The objectives of the current study were to evaluate primarily the safety and tolerability of PD01A and PD03A in patients with early MSA. Thirty patients (11 women) were randomized to receive 5 subcutaneous injections of either PD01A (n = 12), PD03A (n = 12), or placebo (n = 6) in this patient- and examiner-blinded, placebo-controlled, 52-week phase 1 clinical trial (ClinicalTrial.gov identifier: NCT02270489). Immunogenicity and clinical scores were assessed as secondary objectives. Twenty-nine patients reported a total of 595 treatment-emergent adverse events (mild or moderate, n = 555; severe, n = 40). Treatment-related adverse events included 190 injection-site reactions typically observed in vaccination trials with similar per-subject incidence in the treatment groups over time. Sustained IgG titers were observed in the PD01A-treated group, and 89% of treated patients developed a PD01-specific antibody response after receiving all injections. Induced antibodies displayed clear reactivity to the α-synuclein target epitope. Titers and antibody responder rate (58%) were lower in the PD03A-treated group. In conclusion, both PD01A and PD03A were safe and well tolerated. PD01A triggered a rapid and long-lasting antibody response that specifically targeted the α-synuclein epitope. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754431PMC
November 2020

Excessive buccal saliva in patients with Parkinson's disease of the French COPARK cohort.

J Neural Transm (Vienna) 2020 Dec 2;127(12):1607-1617. Epub 2020 Sep 2.

Biomedical Research Center, Interamerican Open University (CAECIHS-UAI), National Research Council (CONICET), Buenos Aires, Argentina.

We describe excessive buccal saliva (EBS) prevalence in patients with Parkinson's Disease (PD) and controls of the COPARK study, its changes between "ON" and OFF" conditions and over time, its impact on Health-related Quality of life (HRQoL), and factors associated with this condition. We studied 671 ambulatory PD patients and 177 age/sex-matched controls. We defined "sialorrhea" as UPDRS item #6 (salivation) = 1 or 2; and "drooling" as item #6 = 3 or 4. SCOPA-Aut drooling score (item #2) was also available in a subset (45%) of the cohort. HRQoL was assessed by the PDQ-39 and SF-36 scales. Twenty-four months' follow-up data were available in 401/671 patients. EBS as assessed by UPDRS was present in 38% of PD patients in the "ON" condition ("Sialorrhea": 35%; "drooling": 3%). There were also more PD patients reporting "drooling" than controls according to the SCOPA-Aut (49% vs 19%, p < 0.01). UPDRS salivation score was worse in the "OFF" vs "ON" condition in PD patients with motor fluctuations (0.90 ± 0.94 vs 0.54 ± 0.79, p < 0.01). UPDRS salivation score worsened after ~ 24 months of follow-up (0.47 ± 0.70 vs 0.64 ± 0.81, p < 0.01). Worse PDQ-39 scores were observed in PD patients with EBS in bivariate but not in multivariate analyses. EBS was directly related to PD duration and severity, male gender, dysphagia, hypomimia, and autonomic dysfunction (logistic regression). EBS was more frequent in PD patients than controls, worsened in the "OFF" condition and after ~ 24 months of follow-up, moderately affected HRQoL, and was correlated with indices of bradykinesia, dysphagia, and autonomic dysfunction.
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http://dx.doi.org/10.1007/s00702-020-02249-0DOI Listing
December 2020

Early cognitive decline after bilateral subthalamic deep brain stimulation in Parkinson's disease patients with GBA mutations.

Parkinsonism Relat Disord 2020 07 9;76:56-62. Epub 2020 Jun 9.

Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France. Electronic address:

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles.

Objective: To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS.

Methods: Patients with STN-DBS were screened for LRRK2, GBA, and PRKN mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes.

Results: We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations. PRKN patients were younger and had a longer disease duration at baseline. A GBA mutation was the only significant genetic factor associated with MDRS change (β = -2.51, p = 0.009). GBA mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with LRRK2 (0.9 ± 4.8), PRKN (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups.

Conclusion: GBA mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.
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http://dx.doi.org/10.1016/j.parkreldis.2020.04.002DOI Listing
July 2020

Addressing knowledge gaps in Parkinson's disease: a report on the Movement Disorder Society's Centre-to-Centre initiative to improve Parkinson's disease services in Lao People's Democratic Republic.

BMC Med Educ 2020 Jul 29;20(1):239. Epub 2020 Jul 29.

Chulalongkorn Centre of Excellence for Parkinson's Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Thai Red Cross Society, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand.

Background: Lao People's Democratic Republic (Lao PDR) has only nine neurologists for seven million people; none have formal training in Parkinson's disease (PD). Medical specialists require sufficient PD knowledge to provide high-quality care.

Methods: This study outlines a Centre-to-Centre programme for developing PD expertise in underserved regions through a tailored two-year educational enterprise between an established movement disorder mentor centre at Chulalongkorn University in Thailand and mentee centres in Lao PDR. Background knowledge of 80 Laotian physicians was assessed using a validated PD knowledge questionnaire containing 26 questions divided into 3 sections (diagnosis, therapeutic options, disease course) before and immediately after one-day kick-start training. Responses were compared across physicians' demographic groups.

Results: Of 80 respondents, 50 (62.5%) were board-certified physicians, of which 27 (54%) specialised in internal medicine. Apparent knowledge gaps were shown by a 51.2% correct response rate for total score, 52.8% for diagnosis, 50.6% for therapeutic options, and 48.2% for disease course. No significant differences in total score or any domain sub-scores between neurologists and other specialties were found. Many did not know which non-motor symptoms could occur as prodromal symptoms or late in course of PD. Incorrect responses mainly reflected a lack of knowledge of the impact of medication on disease. Total and domain sub-scores significantly improved after the course (p < 0.05, each). The size of difference of the means was significant for the total score (d = 0.82), therapeutic option (d = 0.56), and disease course (d = 0.68) sub-scores.

Conclusions: Significant improvement of PD knowledge amongst Laotian physicians is demonstrated after a training course, focusing on practical management of PD. Our findings highlight the importance of continued medical education, especially PD-specific training.
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http://dx.doi.org/10.1186/s12909-020-02161-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392705PMC
July 2020

Characteristics of Patients with Late-Stage Parkinsonism Who are Nursing Home Residents Compared with those Living at Home.

J Am Med Dir Assoc 2021 Feb 25;22(2):440-445.e2. Epub 2020 Jul 25.

UCL Queen Square Institute of Neurology, University College London, London, UK. Electronic address:

Objectives: To determine clinical characteristics and treatment complications of patients with late-stage Parkinsonism living in nursing homes compared with those living at home.

Design: Cross-sectional analysis.

Setting And Participants: This study is an analysis of 692 patients with late stage Parkinsonism recruited to an in-depth international study, Care of Late-Stage Parkinsonism (CLaSP).

Measures: Sociodemographic characteristics were compared between patients who were living in a nursing home (n = 194) and those living at home (n = 498). Clinical assessments included the Unified Parkinson's Disease Rating Scale (UPDRS), the nonmotor symptom scale, the neuropsychiatric inventory, and a structured interview of patients and carers. Predictors of nursing home status were determined in a multivariate analysis.

Results: Nursing home placement was strongly associated with more severe cognitive impairment, worse UPDRS motor scores and disability, and with being unmarried and older. Although nursing home residents had significantly higher axial scores, falls were less common. Despite similar levodopa equivalence doses, they had less dyskinesia. Nonmotor symptom burden, particularly delusion, hallucination, and depression scores were higher in nursing home residents, and they were more frequently on psychotropic medication. They had lower rates of dopamine agonist use and lower rates of impulse control disorders. In multivariate analysis, being unmarried, presence of cognitive impairment, worse disease severity as assessed on the UPDRS parts II and III, severity of delusions, and lower rate of dyskinesia were associated with nursing home placement.

Conclusions And Implications: These clinical characteristics suggest that in patients with Parkinsonsim who are nursing home residents, presence of cognitive impairment and delusions particularly add to the higher overall symptom burden, and more often require specific treatments, including clozapine. Despite similar levodopa equivalent daily dose, motor severity is higher, and dyskinesias, indicative of a response to levodopa, are less common. Falls, however, also occur less commonly, and dopamine agonists are less frequently used, with lower rates of impulse control disorder.
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http://dx.doi.org/10.1016/j.jamda.2020.06.025DOI Listing
February 2021

The Prevalence and Determinants of Neuropsychiatric Symptoms in Late-Stage Parkinsonism.

Mov Disord Clin Pract 2020 Jul 21;7(5):531-542. Epub 2020 May 21.

University College London, Queen Square Institute of Neurology, University College London London United Kingdom.

Background: Late-stage parkinsonism and Parkinson's disease (PD) are insufficiently studied population. Although neuropsychiatric symptoms (eg, psychosis, depression, anxiety, behavioral problems) are frequently present, their prevalence and clinical predictors remain unknown.

Objective: To determine the prevalence and predictors of neuropsychiatric symptoms in late-stage PD.

Methods: We conducted a multinational study of patients with PD with ≥7 years disease duration and either a Hoehn and Yahr stage ≥4 or a Schwab and England score ≤ 50% in the stage. Neuropsychiatric symptoms were assessed through interviews with carers using the Neuropsychiatric Inventory, with a frequency × severity score ≥ 4, indicating clinically relevant symptoms. The determinants analyzed were demographic characteristics, medication, and motor and nonmotor symptoms. Univariate and multivariate logistic analyses were performed on predictors of clinically relevant neuropsychiatric symptoms.

Results: A total of 625 patients were recruited in whom the Neuropsychiatric Inventory could be completed. In 92.2% (576/625) of the patients, at least 1 neuropsychiatric symptom was present, and 75.5% (472/625) had ≥1 clinically relevant symptom. The most common clinically relevant symptoms were apathy (n = 242; 38.9%), depression (n = 213; 34.5%), and anxiety (n = 148; 23.8%). The multivariate analysis revealed unique sets of predictors for each symptom, particularly the presence of other neuropsychiatric features, cognitive impairment, daytime sleepiness.

Conclusion: Neuropsychiatric symptoms are common in late-stage PD. The strongest predictors are the presence of other neuropsychiatric symptoms. Clinicians involved in the care for patients with late-stage PD should be aware of these symptoms in this specific disease group and proactively explore other psychiatric comorbidities once a neuropsychiatric symptom is recognized.
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http://dx.doi.org/10.1002/mdc3.12968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328429PMC
July 2020

Optimizing Treatment in Undertreated Late-Stage Parkinsonism: A Pragmatic Randomized Trial.

J Parkinsons Dis 2020 ;10(3):1171-1184

UCL Queen Square Institute of Neurology, University College London, Royal Free Campus, Rowland Hill Street, London, UK.

Background: Treatment of patients with late-stage parkinsonism is often sub-optimal.

Objective: To test the effectiveness of recommendations by a movement disorder specialist with expertise in late-stage parkinsonism.

Methods: Ninety-one patients with late-stage parkinsonism considered undertreated were included in apragmatic a pragmatic multi-center randomized-controlled trial with six-month follow-up. The intervention group received a letter with treatment recommendations to their primary clinician based on an extensive clinical assessment. Controls received care as usual. The primary outcome was the Unified Parkinson Disease Rating Scale (UPDRS)part-II (Activities of Daily Living). Other outcomes included quality-of-life (PDQ-8), mental health (UPDRS-I), motor function (UPDRS-III), treatment complications (UPDRS-IV), cognition (Mini-mental-state-examination), non-motor symptoms (Non-Motor-Symptoms-scale), health status (EQ-5D-5L) and levodopa-equivalent-daily-dose (LEDD). We also assessed adherence to recommendations. In addition to intention-to-treat analyses, a per-protocol analysis was conducted.

Results: Sample size calculation required 288 patients, but only 91 patients could be included. Treating physicians followed recommendations fully in 16 (28%) and partially in 21 (36%) patients. The intention-to-treat analysis showed no difference in primary outcome (between-group difference = -1.2, p = 0.45), but there was greater improvement for PDQ-8 in the intervention group (between-group difference = -3.7, p = 0.02). The per-protocol analysis confirmed these findings, and showed less deterioration in UPDRS-part I, greater improvement on UPDRS-total score and greater increase in LEDD in the intervention group.

Conclusions: The findings suggest that therapeutic gains may be reached even in this vulnerable group of patients with late-stage parkinsonism, but also emphasize that specialist recommendations need to be accompanied by better strategies to implement these to further improve outcomes.
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http://dx.doi.org/10.3233/JPD-202033DOI Listing
January 2020

Reduced oligodendrocyte exosome secretion in multiple system atrophy involves SNARE dysfunction.

Brain 2020 06;143(6):1780-1797

Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.

Transportation of key proteins via extracellular vesicles has been recently implicated in various neurodegenerative disorders, including Parkinson's disease, as a new mechanism of disease spreading and a new source of biomarkers. Extracellular vesicles likely to be derived from the brain can be isolated from peripheral blood and have been reported to contain higher levels of α-synuclein (α-syn) in Parkinson's disease patients. However, very little is known about extracellular vesicles in multiple system atrophy, a disease that, like Parkinson's disease, involves pathological α-syn aggregation, though the process is centred around oligodendrocytes in multiple system atrophy. In this study, a novel immunocapture technology was developed to isolate blood CNPase-positive, oligodendrocyte-derived enriched microvesicles (OEMVs), followed by fluorescent nanoparticle tracking analysis and assessment of α-syn levels contained within the OEMVs. The results demonstrated that the concentrations of OEMVs were significantly lower in multiple system atrophy patients, compared to Parkinson's disease patients and healthy control subjects. It is also noted that the population of OEMVs involved was mainly in the size range closer to that of exosomes, and that the average α-syn concentrations (per vesicle) contained in these OEMVs were not significantly different among the three groups. The phenomenon of reduced OEMVs was again observed in a transgenic mouse model of multiple system atrophy and in primary oligodendrocyte cultures, and the mechanism involved was likely related, at least in part, to an α-syn-mediated interference in the interaction between syntaxin 4 and VAMP2, leading to the dysfunction of the SNARE complex. These results suggest that reduced OEMVs could be an important mechanism related to pathological α-syn aggregation in oligodendrocytes, and the OEMVs found in peripheral blood could be further explored for their potential as multiple system atrophy biomarkers.
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http://dx.doi.org/10.1093/brain/awaa110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296853PMC
June 2020

Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.

Neurology 2020 05 12;94(21):e2189-e2202. Epub 2020 May 12.

From the Neurology Department (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital; National Reference Centre for Wilson's Disease (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital, Paris; Hepatobiliary Centre (R.S., D.C., D.S., J.-C.D.-V.), DHU Hepatinov, UMR-1193, AP-HP, Paul Brousse Hospital, Villejuif; Service de Neurologie (W.G.M.), CHU Bordeaux; Université de Bordeaux (W.G.M.), Institut des Maladies Neurodégénératives, CNRS UMR 5393, France; Department of Medicine (W.G.M.), University of Otago and New Zealand Brain Research Institute (W.G.M.), Christchurch; Hepatology, Gastroenterology and Nutrition Department (A.-S.B., A.L.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon; National Reference Centre for Wilson's Disease (A.-S.B., E.B., C.L., L.L.-F., O.G., A.L.), Hospices Civils de Lyon; Neurology Department (E.B., C.L.), Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon; CNRS (E.B., C.L.), UMR 5229, Institut des Sciences Cognitives Marc-Jeannerod, Bron; Faculté de Médecine Lyon Sud Charles-Mérieux (E.B., C.L., A.L.), Université Claude-Bernard Lyon 1; Neurology and Paediatrics Department (L.L.-F.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron; Hepatogastroenterology Department (O.G.), Edouard Herriot Hospital, Hospices Civils de Lyon; Internal Medicine Department (F.M.), National Reference Centre for Inborn Errors of Metabolism, Université François Rabelais; Neurology Department (J.B.), CHRU Bretonneau, Tours; Surgery, Oncology and Liver Transplantation Department (E.S.), CHRU Tours; Hepatology and Gastroenterology Department (C.V.) and Surgery and Liver Transplantation Department (B.H.), CHU Besançon; Neurology and Paediatrics Department (C. Bellesme), AP-HP, Bicêtre University Hospital, Kremlin-Bicetre; Pediatric Hepatology and Pediatric Liver Transplantation Unit (U.H) and National Reference Centre for Rare Pediatric Liver Diseases (U.H), Bicêtre University Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, DHU Hepatinov, AP-HP, Le Kremlin Bicêtre; INSERM (D.H.), UMR-S1174, Hepatinov, University of Paris Sud 11, Orsay; Hepatology and Gastroenterology Department (C. Bureau) and Neurology Department (F.O.-M.), CHU Toulouse; Centre D'investigation de la Fibrose Hépatique (V.L.), Hôpital Haut-Lévêque, CHU Bordeaux; and INSERM U1053 (V.d.L.), Université de Bordeaux, France. A. Poujois is currently at Neurology Department, Rothschild Foundation Hospital, and National Reference Centre for Wilson's Disease, Rothschild Foundation Hospital, Paris.

Objective: To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.

Methods: French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.

Results: Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved ( < 0.0001 and = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved ( = 0.0007). Severe sepsis ( = 0.011) and intensive care unit admission ( = 0.001) before LT were significantly associated with death.

Conclusions: LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.

Classification Of Evidence: This study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.
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http://dx.doi.org/10.1212/WNL.0000000000009474DOI Listing
May 2020

Looking into the prediagnostic phase of progressive supranuclear palsy.

Parkinsonism Relat Disord 2020 05 15;74:74-75. Epub 2020 Apr 15.

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Department of Neurology, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1016/j.parkreldis.2020.04.006DOI Listing
May 2020

Nilotinib Fails to Prevent Synucleinopathy and Cell Loss in a Mouse Model of Multiple System Atrophy.

Mov Disord 2020 07 14;35(7):1163-1172. Epub 2020 Apr 14.

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France.

Background: Multiple system atrophy (MSA) is a rare, untreatable neurodegenerative disorder characterized by accumulation of α-synuclein in oligodendroglial inclusions. As such, MSA is a synucleinopathy along with Parkinson's disease (PD) and dementia with Lewy bodies. Activation of the abelson tyrosine kinase c-Abl leads to phosphorylation of α-synuclein at tyrosine 39, thereby promoting its aggregation and subsequent neurodegeneration. The c-Abl inhibitor nilotinib used for the treatment of chronic myeloid leukemia based on data collected in preclinical models of PD might interfere with pathogenic mechanisms that are relevant to PD and dementia with Lewy bodies, which motivated its assessment in an open-label clinical trial in PD and dementia with Lewy bodies patients. The objective of this study was to assess the preclinical efficacy of nilotinib in the specific context of MSA.

Methods: Mice expressing human wild-type α-synuclein in oligodendrocytes received daily injection of nilotinib (1 or 10 mg/kg) over 12 weeks. Postmortem analysis included the assessment of c-Abl activation, α-synuclein burden, and dopaminergic neurodegeneration.

Results: α-Synuclein phosphorylated at tyrosine 39 was detected in glial cytoplasmic inclusions in MSA patients. Increased activation of c-Abl and α-synuclein phosphorylation at tyrosine 39 were found in transgenic mice. Despite significant inhibition of c-Abl and associated reduction of α-synuclein phosphorylation at tyrosine 39 by 40%, nilotinib failed to reduce α-synuclein aggregate burden (including phosphorylation at serine 129) in the striatum and cortex or to lessen neurodegeneration in the substantia nigra.

Conclusions: This preclinical study suggests that partial inhibition of c-Abl and reduction of α-synuclein phosphorylation at tyrosine 39 may not be a relevant target for MSA. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28034DOI Listing
July 2020

Disease progression and prognostic factors in multiple system atrophy: A prospective cohort study.

Neurobiol Dis 2020 06 20;139:104813. Epub 2020 Feb 20.

French Reference Centre for MSA, University Hospital Bordeaux, Bordeaux, France; Institut des Maladies Neurodégénératives, CNRS, UMR 5293, Bordeaux University, Bordeaux, France; Dept. Medicine, University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand.

Multiple system atrophy (MSA) is a rare neurodegenerative disease, with limited understanding of disease progression and prognostic factors. We leveraged the data of a large prospective cohort of MSA to study both clinical progression and survival and assess their determinants. All consecutive patients seen at the French Reference Centre for MSA since 2007 were included in a prospective cohort with an annual follow-up including the Unified MSA Rating Scale (UMSARS). We used joint models to evaluate the risk of death, the mean trajectory of each UMSARS subscale and to determine the potential factors. Investigated factors included gender, age at baseline, MSA subtype, diagnosis certainty, type of first symptoms and the duration between symptom onset and the first visit. Among the 261 MSA patients included in our cohort, the median duration of clinical follow-up was 2.1 years (up to 10.3 years) and the median survival was 4.0 years since the first visit. Main factors for poor survival were the progression over time of UMSARS score (I + II and IV) and the severity of orthostatic hypotension. MSA subtype had no effect on progression or survival. The UMSARS I + II score progressed faster over time in subjects with autonomic dysfunction as the initial feature and in women. Despite a faster progression, women and men had similar survival. From this large MSA cohort, we confirm the rapid progression and poor prognosis of MSA. We provide additional evidence for a negative impact of early autonomic dysfunction and the severity of orthostatic hypotension on both disease progression and survival.
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http://dx.doi.org/10.1016/j.nbd.2020.104813DOI Listing
June 2020

Utilization Patterns of Amantadine in Parkinson's Disease Patients Enrolled in the French COPARK Study.

Drugs Aging 2020 03;37(3):215-223

Institute of Cardiology Research, University of Buenos Aires, National Research Council (CONICET-ININCA), Buenos Aires, Argentina.

Introduction: Immediate-release (IR) amantadine has been marketed for Parkinson's disease (PD) therapy for 50 years, while two novel extended-release formulations have only recently reached the market in the US.

Objectives: The aim of this study was to describe amantadine IR utilization patterns in the French COPARK cohort, at baseline and after 2 years of follow-up.

Methods: Overall, 683 PD patients from the COPARK survey were evaluated. All patients were assessed in a standardized manner (demographics, treatments, Unified Parkinson's Disease Rating Scale [UPDRS], Hospital Anxiety and Depression Scale, Pittsburg Questionnaire and health-related quality-of-life scales (Short Form-36 [SF-36], 39-item Parkinson's Disease Questionnaire [PDQ-39]). Longitudinal data were only available for 401/683 patients (59%) with a median (P25-75) follow-up period of 23 months (18-31). Patients were assessed in the same way as in the baseline visit.

Results: At baseline, amantadine was prescribed to 61/683 (9%) patients (median dose 200 mg/day, range 100-300 mg/day). Amantadine was initiated after a median of 7 years from PD diagnosis, and its prescription was correlated with the presence of dyskinesia (logistic regression odds ratio [OR] 3.72, 95% confidence interval [CI] 1.95-7.08) and hallucinations (UPDRS I.2) [OR 1.57, 95% CI 1.08-2.29]. After 2 years, the amantadine prescription increased from 33 (8%) patients at baseline to 54 (14%) patients in the subset of 401 patients analysed twice (p = 0.001). Among the 33 patients receiving amantadine at baseline, 9 (27%) stopped amantadine, 5 (15%) increased the dose, 6 (18%) reduced the dose and 13 (40%) stayed at the same doses. Treatment was initiated in 30/54 new patients (55%). Patients who started amantadine or increased its dose (n = 35) had more levodopa-induced dyskinesias at baseline (OR 7.02, 95% CI 3.09-15.90) and higher Mini-Mental State Examination score at follow-up (OR 1.37, 95% CI 1.06-1.79). Undergoing deep brain stimulation was related to stopping or downtitrating amantadine (OR 22.02, 95% CI 4.24-114.44; n = 15).

Conclusions: In this cohort, amantadine was used in 10% of patients. Its use increased during follow-up, despite the fact that one-third of patients who received amantadine at baseline stopped taking it. Amantadine prescription was mainly correlated with the presence of dyskinesia.
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http://dx.doi.org/10.1007/s40266-019-00740-2DOI Listing
March 2020

Multiple System Atrophy: Recent Developments and Future Perspectives.

Mov Disord 2019 11 6;34(11):1629-1642. Epub 2019 Nov 6.

Services de Neurologie et de Pharmacologie Clinique, Centre de Reference AMS, Centre d'Investigation Clinique, Réseau NS-Park/FCRIN et Centre of Excellence for Neurodegenerative Disorders (COEN) de Toulouse, CHU de Toulouse, Toulouse 3 University, Toulouse, France.

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. The pathologic hallmark is the accumulation of aggregated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions, which qualifies MSA as a synucleinopathy together with Parkinson's disease and dementia with Lewy bodies. The underlying pathogenesis is still not well understood. Some symptomatic treatments are available, whereas neuroprotection remains an urgent unmet treatment need. In this review, we critically appraise significant developments of the past decade with emphasis on pathogenesis, diagnosis, prognosis, and treatment development. We further discuss unsolved questions and highlight some perspectives. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27894DOI Listing
November 2019

Validation of the movement disorder society criteria for the diagnosis of 4-repeat tauopathies.

Mov Disord 2020 01 30;35(1):171-176. Epub 2019 Sep 30.

Department of Neurology, Technische Universität München, Munich, Germany.

Background: The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category "probable 4-repeat (4R)-tauopathy" for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration.

Objectives: To validate the accuracy of these clinical criteria for "probable 4R-tauopathy" to predict underlying 4R-tauopathy pathology.

Methods: Diagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies).

Results: We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of "probable 4R-tauopathy" was 10% and 99% in the first year and 59% and 88% at final record.

Conclusions: The new diagnostic category "probable 4R-tauopathy" showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27872DOI Listing
January 2020

Stridor in multiple system atrophy: Consensus statement on diagnosis, prognosis, and treatment.

Neurology 2019 10;93(14):630-639

From the IRCCS (P.C., G.C.-B., G.G., F.P., L.V.), Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Dipartimento di Scienze Biomediche e Neuromotorie (P.C., G.C.-B., G.G., P.M., F.P.), Università di Bologna, Bologna, Italy; Department of Neurology (E.E.B., P.A.L.), Mayo Clinic, Rochester, MN; Multidisciplinary Sleep Unit (A.I.), Neurology Service, Hospital Clinic de Barcelona, IDIBAPS CIBERNED, Barcelona, Spain; UCL Queen Square Institute of Neurology (N.Q.), Queen Square, London; Parkinson's Disease and Movement Disorders Unit (E.T.), Neurology Service, Hospital Clinic de Barcelona; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (E.T.), University of Barcelona (UB), and Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Department of Neurology (G.K.W.), Innsbruck Medical University, Innsbruck, Austria; Department of Neuroscience (G.A.), Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genoa, Genoa, Italy; The Multiple System Atrophy Coalition, Inc. (P.B.), Charlotte, NC; Neurophysiopathology Unit (E.A.), IRCCS "C. Mondino" Foundation, Pavia, Italy; Department of Clinical Neurophysiology (I.G.), CHU de Bordeaux, Bordeaux, France; Université de Bordeaux (I.G.), Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Bordeaux, France; CNRS (I.G.), Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Bordeaux, France; Department of Neurology (T.O.), Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minami Uonuma, Niigata, Japan; Parkinson's Disease and Movement Disorders Unit (C.P., N.G.P.), IRCCS "C. Mondino" Foundation, Pavia; Dipartimento di Medicina Specialistica (C.V.), Diagnostica e Sperimentale (DIMES), University of Bologna, Bologna, Italy; Dipartimento di Scienze biomediche e chirurgico specialistiche (C.V.), University of Ferrara, Ferrara, Italy; Department of Neurosciences (A.A.), University of Padua, Padua, Italy; Department of Clinical and Motor Neuroscience (A.P.B.), UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London; Spinal Unit (J.B.), Montecatone Rehabilitation Institute, Imola, Italy; Department of Neurology (H.K.), New York University School of Medicine, New York, NY; Department of Medicine (M.T.P.), Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy; "Luigi Sacco" Department of Biomedical and Clinical Sciences (N.P., A.S.), University of Milan, Milan, Italy; Service de Neurologie (F.T., W.G.M.), CRMR Atrophie Multisystématisée, CHU Bordeaux, Bordeaux, France; Univ. de Bordeaux (F.T., W.G.M.), Institut des Maladies Neurodégénératives, Bordeaux, France; and Department Medicine (W.G.M.), University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor is an additional feature for MSA diagnosis, showing a high diagnostic positive predictive value, and its early occurrence might contribute to shorten survival. A consensus definition of stridor in MSA is lacking, and disagreement persists about its diagnosis, prognosis, and treatment. An International Consensus Conference among experts with methodological support was convened in Bologna in 2017 to define stridor in MSA and to reach consensus statements for the diagnosis, prognosis, and treatment. Stridor was defined as a strained, high-pitched, harsh respiratory sound, mainly inspiratory, occurring only during sleep or during both sleep and wakefulness, and caused by laryngeal dysfunction leading to narrowing of the rima glottidis. According to the consensus, stridor may be recognized clinically by the physician if present at the time of examination, with the help of a witness, or by listening to an audio recording. Laryngoscopy is suggested to exclude mechanical lesions or functional vocal cord abnormalities related to different neurologic conditions. If the suspicion of stridor needs confirmation, drug-induced sleep endoscopy or video polysomnography may be useful. The impact of stridor on survival and quality of life remains uncertain. Continuous positive airway pressure and tracheostomy are both suggested as symptomatic treatment of stridor, but whether they improve survival is uncertain. Several research gaps emerged involving diagnosis, prognosis, and treatment. Unmet needs for research were identified.
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http://dx.doi.org/10.1212/WNL.0000000000008208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814413PMC
October 2019

Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies.

JCI Insight 2019 08 22;4(16). Epub 2019 Aug 22.

Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.

The synucleinopathies Parkinson's disease (PD) and Multiple system atrophy (MSA) - characterized by α-synuclein intracytoplasmic inclusions into, respectively, neurons and oligodendrocytes - are associated with impairment of the autophagy-lysosomal pathways (ALP). Increased expression of the master regulator of ALP, transcription factor EB (TFEB), is hypothesized to promote the clearance of WT α-synuclein and survival of dopaminergic neurons. Here, we explore the efficacy of targeted TFEB overexpression either in neurons or oligodendrocytes to reduce the pathological burden of α-synuclein in a PD rat model and a MSA mouse model. While TFEB neuronal expression was sufficient to prevent neurodegeneration in the PD model, we show that only TFEB oligodendroglial overexpression leads to neuroprotective effects in the MSA model. These beneficial effects were associated with a decreased accumulation of α-synuclein into oligodendrocytes through recovery of the ALP machinery. Our study demonstrates that the cell type where α-synuclein aggregates dictates the target of TFEB overexpression in order to be protective, paving the way for adapted therapies.
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http://dx.doi.org/10.1172/jci.insight.129719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777809PMC
August 2019

Four-repeat tauopathies.

Prog Neurobiol 2019 09 22;180:101644. Epub 2019 Jun 22.

Dept. of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Dept. of Neurology, Technical University of Munich, School of Medicine, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany; Dept. of Neurology, Hannover Medical School, 30625 Hannover, Germany. Electronic address:

Tau is a microtubule-associated protein with versatile functions in the dynamic assembly of the neuronal cytoskeleton. Four-repeat (4R-) tauopathies are a group of neurodegenerative diseases defined by cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains. Progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease or glial globular tauopathy belong to the group of 4R-tauopathies. The present review provides an introduction in the current concept of 4R-tauopathies, including an overview of the neuropathological and clinical spectrum of these diseases. It describes the genetic and environmental etiological factors, as well as the contemporary knowledge about the pathophysiological mechanisms, including post-translational modifications, aggregation and fragmentation of tau, as well as the role of protein degradation mechanisms. Furthermore, current theories about disease propagation are discussed, involving different extracellular tau species and their cellular release and uptake mechanisms. Finally, molecular diagnostic tools for 4R-tauopathies, including tau-PET and fluid biomarkers, and investigational therapeutic strategies are presented. In summary, we report on 4R-tauopathies as overarching disease concept based on a shared pathophysiological concept, and highlight the challenges and opportunities on the way towards a causal therapy.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101644DOI Listing
September 2019