Publications by authors named "Anthony E Lang"

630 Publications

Epigenetic Clock Acceleration Is Linked to Age at Onset of Parkinson's Disease.

Mov Disord 2022 Aug 3. Epub 2022 Aug 3.

The First Rehabilitation Hospital of Shanghai, Department of Medical Genetics, School of Medicine, Tongji University, Shanghai, China.

Background: Aging is the strongest risk factor for Parkinson's disease (PD), which is a clinically heterogeneous movement disorder with highly variable age at onset. DNA methylation age (DNAm age) is an epigenetic clock that could reflect biological aging.

Objectives: The aim was to evaluate whether PD age at onset is associated with DNAm-age acceleration (difference between DNAm age and chronological age).

Methods: We used the genome-wide Infinium MethylationEPIC array to assess DNAm age in discovery (n = 96) and replication (n = 182) idiopathic PD cohorts and a unique longitudinal LRRK2 cohort (n = 220) at four time points over a 3-year period, comprising 91 manifesting and 129 nonmanifesting G2019S carriers at baseline. Cox proportional hazard regression and multivariate linear regression were used to evaluate the relation between DNAm-age acceleration and PD age at onset, which was highly variable in manifesting G2019S carriers (36-75 years) and both idiopathic PD cohorts (26-77 and 35-81 years).

Results: DNAm-age acceleration remained steady over the 3-year period in most G2019S carriers. It was strongly associated with age at onset in the LRRK2 cohort (P = 2.25 × 10 ) and discovery idiopathic PD cohort (P = 5.39 × 10 ), suggesting that every 5-year increase in DNAm-age acceleration is related to about a 6-year earlier onset. This link was replicated in an independent idiopathic PD cohort (P = 1.91 × 10 ). In each cohort, the faster-aging group has an increased hazard for an earlier onset (up to 255%).

Conclusions: This study is the first to demonstrate that DNAm-age acceleration is related to PD age at onset, which could be considered in disease-modifying clinical trials. Future studies should evaluate the stability of DNAm-age acceleration over longer time periods, especially for phenoconverters from nonmanifesting to manifesting individuals. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.29157DOI Listing
August 2022

Trial of Cinpanemab in Early Parkinson's Disease.

N Engl J Med 2022 08;387(5):408-420

From the Edmond J. Safra Program in Parkinson's Disease, University Health Network, and the University of Toronto, Toronto (A.E.L.), and the Montreal Neurological Institute, Montreal (R.B.P.); the University of Pennsylvania, Philadelphia (A.D.S.); the Biostatistics Center, Massachusetts General Hospital (E.A.M.), Beth Israel Deaconess Medical Center (D.K.S.), and Harvard Medical School (E.A.M., D.K.S.), Boston, and Biogen, Cambridge (K.F., J.X., K.C.E., D.L.G., I.S., J.I., R.M.H., M.Y., S.B.H., T.D.) - all in Massachusetts; Medizinische Universität Innsbruck, Innsbruck, Austria (W.P.); Newcastle University, Newcastle upon Tyne (D.J.B.), and Biogen, Maidenhead (T.F.) - both in the United Kingdom; Aarhus University, Aarhus, Denmark (D.J.B.); the Center for Neurological Restoration, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine - both in Cleveland (H.H.F.); Clinical Investigation Center 1436, the Departments of Clinical Pharmacology and Neurosciences, NS-PARK-French Clinical Research Infrastructure Network, NeuroToul COEN Center, INSERM, University Hospital of Toulouse, and the University of Toulouse III - both in Toulouse, France (O.R.); Tel Aviv Sourasky Medical Center, and the Sackler School of Medicine and the Sagol School of Neuroscience, Tel Aviv University - both in Tel Aviv, Israel (N.G.); University San Raffaele and IRCCS San Raffaele - both in Rome (F.S.); the University of California, San Diego, La Jolla (C.M.T.), and the San Francisco Veterans Affairs Medical Center, San Francisco (C.M.T.); the University of Barcelona, Barcelona (E.T.); the Department of Neurology, University Medical Center Göttingen, Göttingen, and Paracelsus-Elena-Klinik, Kassel - both in Germany (B.M.); and Coeruleus Clinical Sciences, Woodbridge, CT (J.M.C.).

Background: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease.

Methods: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT).

Results: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls.

Conclusions: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).
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http://dx.doi.org/10.1056/NEJMoa2203395DOI Listing
August 2022

Endoplasmic Reticulum Proteostasis/Protein Trafficking Enhancement: A Novel Synergistic Approach to Tackling α-Synuclein.

Mov Disord 2022 Jul 21. Epub 2022 Jul 21.

Department of Movement Disorders, Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/mds.29156DOI Listing
July 2022

DYT-TUBB4A (DYT4 Dystonia): Clinical Anthology of 11 Cases and Systematized Review.

Mov Disord Clin Pract 2022 Jul 28;9(5):659-675. Epub 2022 Apr 28.

The Edmond J Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital & University of Toronto Toronto Ontario.

Background: DYT-TUBB4A, formerly known as DYT4, has not been comprehensively described as only one large family and three individual cases have been published. We have recently described an in depth genetic and protein structural analysis of eleven additional cases from four families with four new pathogenic variants. We aim to report on the phenomenology of these cases suffering from DYT-TUBB4A and to perform a comprehensive review of the clinical presentation and treatment responses of all DYT-TUBB4A cases reported in the literature.

Cases And Literature Review: The clinical picture was typically characterized by laryngeal dystonia (more than three quarters of all cases), associated with cervical dystonia, upper limb dystonia and frequent generalization. Extension of the dystonia to the lower limbs, creating the famous "hobby horse" gait, was present in more than 20% of cases (in only one of ours). Globus pallidus pars interna (GPi) deep brain stimulation (DBS), performed in 4 cases, led to a good improvement with greatest benefit in motoric and less benefit in laryngeal symptoms. Medical treatment was generally rather poorly effective, except some benefit from propranolol, tetrabenazine and alcohol intake.

Conclusion: Laryngeal involvement is a hallmark of DYT-TUBB4A. Symptomatic treatment with GPi-DBS led to the greatest benefit in motoric symptoms. Nevertheless, mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia and regular screening of mutations for isolated dystonias has a very low yield.
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http://dx.doi.org/10.1002/mdc3.13452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9274350PMC
July 2022

Periodic Limb Movements while Awake () as a Manifestation of Wearing-Off in Parkinson's Disease: A Case Series and Review of the Literature.

Mov Disord Clin Pract 2022 Jul 10;9(5):652-658. Epub 2022 Jun 10.

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada; Division of Neurology University of Toronto Toronto Ontario Canada.

Background: Periodic limb movements while awake (PLMA) are similar to Periodic limb movements in sleep (PLMS) but occurring during wakefulness and seen in association with restless leg syndrome (RLS).

Objectives: To describe PLMA as a wearing-off phenomenon in Parkinson's Disease (PD).

Methods: We describe four individuals with PD and PLMS, who had associated similar periodic and stereotypic lower extremity movements during wakefulness, thought to be secondary to PLMA, and were highly responsive to dopaminergic treatment.

Results: Despite the prevalence of RLS and PLMS in individuals with PD, the presence of similar movements during wakefulness has not been well characterized. The lack of a specific diagnostic criteria poses a significant diagnostic challenge.

Conclusions: We describe, for the first time to our knowledge, PLMA as a wearing-off phenomenon in PD. This entity could be classified in the spectrum of "low-dose dyskinesia," as we found that it was highly responsive to dopaminergic treatment.
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http://dx.doi.org/10.1002/mdc3.13487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9274377PMC
July 2022

The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited.

Mov Disord 2022 Jul 10. Epub 2022 Jul 10.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions.

Objective: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction.

Methods: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1.

Results: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P  = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern.

Conclusions: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 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.29133DOI Listing
July 2022

Vitamins B6 and B12, levodopa, and their complex interactions in patients with Parkinson's disease.

Brain 2022 Jul 8. Epub 2022 Jul 8.

The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto, Ontario M5T 2S6, Canada.

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http://dx.doi.org/10.1093/brain/awac225DOI Listing
July 2022

Commentary on Long-term Effectiveness of Adjuvant Treatment in Parkinson Disease.

JAMA Neurol 2022 Jul;79(7):726

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1001/jamaneurol.2022.1601DOI Listing
July 2022

Pallidal neuronal activity in multiple system atrophy type P and Parkinson's disease.

Parkinsonism Relat Disord 2022 Jun 13;101:15-17. Epub 2022 Jun 13.

Krembil Brain Institute, University Health Network, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Canada; Department of Neurology, University of Toronto, Canada; Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Canada.

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http://dx.doi.org/10.1016/j.parkreldis.2022.06.007DOI Listing
June 2022

The microbiome-gut-brain axis in Parkinson disease - from basic research to the clinic.

Nat Rev Neurol 2022 Aug 24;18(8):476-495. Epub 2022 Jun 24.

Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Ontario, Canada.

Evidence for a close bidirectional link between the brain and the gut has led to a paradigm shift in neurology, especially in the case of Parkinson disease (PD), in which gastrointestinal dysfunction is a prominent feature. Over the past decade, numerous high-quality preclinical and clinical publications have shed light on the highly complex relationship between the gut and the brain in PD, providing potential for the development of new biomarkers and therapeutics. With the advent of high-throughput sequencing, the role of the gut microbiome has been specifically highlighted. Here, we provide a critical review of the literature on the microbiome-gut-brain axis in PD and present perspectives that will be useful for clinical practice. We begin with an overview of the gut-brain axis in PD, including the potential roles and interrelationships of the vagus nerve, α-synuclein in the enteric nervous system, altered intestinal permeability and inflammation, and gut microbes and their metabolic activities. The sections that follow synthesize the proposed roles of gut-related factors in the development and progression of, in responses to PD treatment, and as therapeutic targets. Finally, we summarize current knowledge gaps and challenges and delineate future directions for the field.
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http://dx.doi.org/10.1038/s41582-022-00681-2DOI Listing
August 2022

α-Synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders.

Acta Neuropathol 2022 Aug 24;144(2):167-185. Epub 2022 Jun 24.

Tanz Centre for Research in Neurodegenerative Disease (CRND), University of Toronto, Krembil Discovery Tower, 60 Leonard Ave, Toronto, ON, M5T 0S8, Canada.

Lewy body disorders (LBD), characterized by the deposition of misfolded α-synuclein (α-Syn), are clinically heterogeneous. Although the distribution of α-Syn correlates with the predominant clinical features, the burden of pathology does not fully explain the observed variability in clinical presentation and rate of disease progression. We hypothesized that this heterogeneity might reflect α-Syn molecular diversity, between both patients and different brain regions. Using an ultra-sensitive assay, we evaluated α-Syn seeding in 8 brain regions from 30 LBD patients with different clinical phenotypes and disease durations. Comparing seeding across the clinical phenotypes revealed that hippocampal α-Syn from patients with a cognitive-predominant phenotype had significantly higher seeding capacity than that derived from patients with a motor-predominant phenotype, whose nigral-derived α-Syn in turn had higher seeding capacity than that from cognitive-predominant patients. Interestingly, α-Syn from patients with rapid disease progression (< 3 years to development of advanced disease) had the highest nigral seeding capacity of all the patients included. To validate these findings and explore factors underlying seeding heterogeneity, we performed in vitro toxicity assays, and detailed neuropathological and biochemical examinations. Furthermore, and for the first time, we performed a proteomic-wide profiling of the substantia nigra from 5 high seeder and 5 low seeder patients. The proteomic data suggests a significant disruption in mitochondrial function and lipid metabolism in high seeder cases compared to the low seeders. These observations suggest that distinct molecular populations of α-Syn may contribute to heterogeneity in phenotypes and progression rates in LBD and imply that effective therapeutic strategies might need to be directed at an ensemble of differently misfolded α-Syn species, with the relative contribution of their differing impacts accounting for heterogeneity in the neurodegenerative process.
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http://dx.doi.org/10.1007/s00401-022-02453-0DOI Listing
August 2022

Targeted copy number variant identification across the neurodegenerative disease spectrum.

Mol Genet Genomic Med 2022 Aug 3;10(8):e1986. Epub 2022 Jun 3.

Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Background: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied.

Methods: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519).

Results: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1-5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7-11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies.

Conclusion: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.
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http://dx.doi.org/10.1002/mgg3.1986DOI Listing
August 2022

Case of a Man with Hemichorea and Behavioral Changes: "A Red Herring".

Mov Disord Clin Pract 2022 May 30;9(4):501-507. Epub 2022 Mar 30.

Division of Neurology, Department of Medicine University of Toronto Toronto Ontario Canada.

Background: Progressive supranuclear palsy (PSP)-pallido-nigro-luysian atrophy (PNLA) is a neuropathological entity thought to be a variant of classic PSP. Clinical features and pathologic hallmarks are the same in both conditions; however, age and order of symptom onset, disease duration and prognosis, and distribution and density of pathology differentiate the 2 entities.

Objectives: This study presents a PSP-PNLA case confirmed pathologically with a clinical presentation of hemichorea/ballism, spasticity, progressive hemiparesis, and a frontal behavioral syndrome with relative cognitive sparing early in the disease course.

Methods: We describe the clinical progression in this unique case supplemented with video and imaging findings in the form of magnetic resonance imaging and brain single photon emission computed tomography. Final diagnosis is via pathological analysis at autopsy.

Results: We present an elderly gentleman who manifested a clinical syndrome consisting of subacute onset of chorea that at presentation was distinctly unilateral and a frontal behavioral syndrome in the setting of mild thrombocytopenia and elevated anticardiolipin antibodies. Positive antiphospholipid antibodies resulted in an initial antemortem diagnosis of primary antiphospholipid syndrome as a cause of his chorea. Longitudinal follow-up over 5 years demonstrated a progression of clinical features with hemi-motor impersistence/chorea, disinhibition and impulsivity, and eventually corticospinal distribution weakness on the initially affected side. He required nursing home care and falls necessitated wheelchair use. Postmortem neuropathological study revealed a diagnosis of frontotemporal lobar degeneration-tau, PSP-PNLA.

Conclusions: This case broadens the phenotype of PSP-PNLA and to our knowledge is the only case presenting with unilateral chorea.
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http://dx.doi.org/10.1002/mdc3.13433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092749PMC
May 2022

Spastic Paraplegia Type 7 and Movement Disorders: Beyond the Spastic Paraplegia.

Mov Disord Clin Pract 2022 May 1;9(4):522-529. Epub 2022 Apr 1.

Movement Disorders and Neurodegenerative Diseases Unit Hospital Civil de Guadalajara "Fray Antonio Alcalde" Guadalajara Mexico.

Background: Spastic paraplegia type 7 (SPG7) mutations can present either as a pure form or a complex phenotype with movement disorders.

Objective: Describe the main features of subjects with SPG7 mutations associated with movement disorders.

Methods: We analyzed the clinical and paraclinical information of subjects with SPG7 mutations associated with movement disorders.

Results: Sixteen affected subjects from 11 families were identified. Male sex predominated (10 of 16) and the mean age at onset was 41.25 ± 16.1 years. A cerebellar syndrome was the most frequent clinical movement disorder phenotype (7 of 16); however, parkinsonism (2 of 16), dystonia (1 of 16), and mixed phenotypes between them were also seen. The "ears of the lynx" sign was found in four subjects. A total of nine SPG7 variants were found, of which the most frequent was the c.1529C > T (p.Ala510Val).

Conclusion: This case series expands the motor phenotype associated with SPG7 mutations. Clinicians must consider this entity in single or familial cases with combined movement disorders.
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http://dx.doi.org/10.1002/mdc3.13437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092757PMC
May 2022

Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force - An Update.

Mov Disord 2022 05 28;37(5):905-935. Epub 2022 Apr 28.

The Edmond J. Safra Program in Parkinson's Disease and The Morton and Gloria Shulman Movement Disorder Clinic, Toronto Western Hospital, University of Toronto, Toronto, Canada.

In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion-based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28982DOI Listing
May 2022

Small and Large Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia of Parkinson's Disease Patients.

Mov Disord 2022 06 11;37(6):1304-1309. Epub 2022 Apr 11.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

Background: Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested.

Objective: The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD.

Methods: We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study.

Results: Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P = 0.008) and II (both P = 0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition.

Conclusions: Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.29010DOI Listing
June 2022

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 2: Acquired Disorders.

Mov Disord Clin Pract 2022 Apr 3;9(3):311-325. Epub 2022 Feb 3.

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital-UHN, Division of Neurology University of Toronto Toronto Ontario Canada.

The MDS Video Challenge continues to be the one of most widely attended sessions at the International Congress. Although the primary focus of this event is the presentation of complex and challenging cases through videos, a number of cases over the years have also presented an unusual or important neuroimaging finding related to the case. We reviewed the previous Video Challenge cases and present here a selection of those cases which incorporated such imaging findings. We have compiled these "imaging pearls" into two anthologies. The first focuses on pearls where the underlying diagnosis was a genetic condition. This second anthology focuses on imaging pearls in cases where the underlying condition was acquired. For each case we present brief clinical details along with neuroimaging findings, the characteristic imaging findings of that disorder and, finally, the differential diagnosis for the imaging findings seen.
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http://dx.doi.org/10.1002/mdc3.13415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8974867PMC
April 2022

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 1: Genetic Disorders.

Mov Disord Clin Pract 2022 Apr 3;9(3):297-310. Epub 2022 Feb 3.

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital-UHN, Division of Neurology University of Toronto Toronto Ontario Canada.

We selected several "imaging pearls" presented during the Movement Disorder Society (MDS) Video Challenge for this review. While the event, as implicated by its name, was video-centered, we would like to emphasize the important role of imaging in making the correct diagnosis. We divided this anthology into two parts: genetic and acquired disorders. Genetic cases described herein were organized by the inheritance pattern and the focus was put on the imaging findings and differential diagnoses. Despite the overlapping phenotypes, certain described disorders have pathognomonic MRI brain findings that would provide either the "spot" diagnosis or result in further investigations leading to the diagnosis. Despite this, the diagnosis is often challenging with a broad differential diagnosis, and hallmark findings may be present for only a limited time.
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http://dx.doi.org/10.1002/mdc3.13412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8974871PMC
April 2022

Protracted course progressive supranuclear palsy.

Eur J Neurol 2022 Aug 21;29(8):2220-2231. Epub 2022 Apr 21.

Edmond J. Safra Program in Parkinson's Disease, Rossy Program for PSP Research and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

Background And Purpose: Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD).

Methods: Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology.

Results: We identified four cases with long (>10-15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele.

Conclusions: We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.
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http://dx.doi.org/10.1111/ene.15346DOI Listing
August 2022

A Modified Progressive Supranuclear Palsy Rating Scale for Virtual Assessments.

Mov Disord 2022 06 1;37(6):1265-1271. Epub 2022 Apr 1.

Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.

Background: The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed.

Objectives: To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression.

Methods: We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single-center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS-25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS-21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single-center cohort using proportional hazards models.

Results: The mPSPRS-25 showed excellent agreement (0.99; P < 0.001) with the original PSPRS at baseline, 0.98 (P < 0.001) agreement in measuring change over 6 months, and 0.98 (P < 0.001) over 12 months. The mPSPRS-21 showed agreement of 0.94 (P < 0.001) with the original PSPRS at baseline, 0.92 (P < 0.001) at 6 months, and 0.95 (P < 0.001) at 12 months. Baseline and 6-month change in both modified scales were highly predictive of survival in the single-center cohort.

Conclusions: Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232989PMC
June 2022

Patterns of Mixed Pathologies in Down Syndrome.

J Alzheimers Dis 2022 ;87(2):595-607

Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada.

Background: Down syndrome (DS) is frequently associated with Alzheimer's disease (AD)-related neuropathological changes. There are few observations on the spectrum of mixed proteinopathies in DS patients.

Objective: This study aimed to evaluate multiple disease-associated proteinopathies in a series of DS cases.

Methods: We analyzed the distribution of neurodegenerative disease associated proteins in postmortem brain samples from 11 DS cases (6 females, median age 57, range 38-66 years). Sections were stained for phosphorylated tau, 3-repeat and 4-repeat tau, amyloid-β, alpha synuclein, phosphorylated TDP-43, and p62. A comprehensive anatomical mapping and staging were applied for all proteins.

Results: Tau and amyloid-β pathology was prevalent in all cases and compatible with that typically seen in AD with some subtle deviations. Four of 11 cases presented with Lewy-related pathology (LRP). Two cases followed the Braak staging (stage 4 and 5) whereas 2 cases presented with an atypical distribution. Two cases showed limbic predominant age-related TDP-43 encephalopathy (LATE) (stage 1 and stage 2) neuropathologic change. Two cases exhibited aging-related tau astrogliopathy (ARTAG).

Conclusion: In addition to subtle deviations from AD regarding the morphology of amyloid-β deposition and distribution of neuronal tau pathology, we find that the spectrum of mixed-pathologies in DS show distinctive features such as deviations from the Braak staging of LRP and that LATE neuropathologic change and ARTAG pathology can be seen in individuals younger than in sporadic AD cases. Our observations support the notion that DS has distinctive pathogenic pathways from sporadic AD.
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http://dx.doi.org/10.3233/JAD-215675DOI Listing
January 2022

Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases.

Geroscience 2022 Jun 16;44(3):1575-1598. Epub 2022 Mar 16.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson's disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.
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http://dx.doi.org/10.1007/s11357-022-00539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213606PMC
June 2022

The Role of Insular Cortex in Gut-Inflammation Memory: What Does It Mean for Parkinson's Disease?

Mov Disord 2022 04 1;37(4):700-701. Epub 2022 Mar 1.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/mds.28975DOI Listing
April 2022

Common Data Elements to Facilitate Sharing and Re-use of Participant-Level Data: Assessment of Psychiatric Comorbidity Across Brain Disorders.

Front Psychiatry 2022 7;13:816465. Epub 2022 Feb 7.

Tanz Centre for Research in Neurodegenerative Diseases University of Toronto, Toronto, ON, Canada.

The Ontario Brain Institute's "Brain-CODE" is a large-scale informatics platform designed to support the collection, storage and integration of diverse types of data across several brain disorders as a means to understand underlying causes of brain dysfunction and developing novel approaches to treatment. By providing access to aggregated datasets on participants with and without different brain disorders, Brain-CODE will facilitate analyses both within and across diseases and cover multiple brain disorders and a wide array of data, including clinical, neuroimaging, and molecular. To help achieve these goals, consensus methodology was used to identify a set of core demographic and clinical variables that should be routinely collected across all participating programs. Establishment of Common Data Elements within Brain-CODE is critical to enable a high degree of consistency in data collection across studies and thus optimize the ability of investigators to analyze pooled participant-level data within and across brain disorders. Results are also presented using selected common data elements pooled across three studies to better understand psychiatric comorbidity in neurological disease (Alzheimer's disease/amnesic mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia, and Parkinson's disease).
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http://dx.doi.org/10.3389/fpsyt.2022.816465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859302PMC
February 2022

Lateralized Subthalamic Stimulation for Axial Dysfunction in Parkinson's Disease: A Randomized Trial.

Mov Disord 2022 05 13;37(5):1079-1087. Epub 2022 Feb 13.

The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Hospital Network and Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Patients with Parkinson's disease might develop treatment-resistant axial dysfunction after bilateral subthalamic stimulation.

Objectives: To study whether lateralized stimulation (unilateral 50% amplitude reduction) for ≥21 days results in ≥0.13 m/s faster gait velocity in the dopaminergic ON state in these patients, and its effects on motor and axial function, quantitative gait and speech measures, quality of life, and selected cognitive tasks.

Methods: Randomized, double-blinded, double-crossover trial.

Results: In 22 participants (51-79 years old, 15 women), there were no significant changes in gait velocity, quality of life, cognitive, and speech measures. Reducing left-sided amplitude resulted in a 2.5-point improvement in axial motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (P = 0.005, uncorrected) and a 1.9-point improvement in the Freezing of Gait Questionnaire (P = 0.024, uncorrected).

Conclusions: Lateralized subthalamic stimulation does not result in meaningful improvement in gait velocity in patients with Parkinson's disease who develop treatment-resistant axial dysfunction after bilateral subthalamic stimulation. Left subthalamic overstimulation may contribute to axial deterioration in these patients. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28953DOI Listing
May 2022

Teaching Video NeuroImage: Unilateral Myorhythmia in a Patient With a Midbrain-Diencephalic Junction Cavernous Malformation.

Neurology 2022 04 10;98(14):e1510-e1511. Epub 2022 Feb 10.

From the The Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Canada.

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http://dx.doi.org/10.1212/WNL.0000000000200121DOI Listing
April 2022

Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy.

Transl Neurodegener 2022 02 7;11(1). Epub 2022 Feb 7.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.

Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions.

Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA.

Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders.

Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.
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http://dx.doi.org/10.1186/s40035-022-00283-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819887PMC
February 2022

Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation.

Hum Brain Mapp 2022 05 28;43(7):2089-2108. Epub 2022 Jan 28.

Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.

White matter hyperintensities (WMHs) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D convolutional neural network with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control, and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. Four hundred thirty-two subjects were recruited to train the CNNs from four multisite imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multisite study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on "clinical adversarial cases" simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io.
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http://dx.doi.org/10.1002/hbm.25784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996363PMC
May 2022

Genomic study of a large family with complex neurological phenotype including hearing loss, imbalance and action tremor.

Neurobiol Aging 2022 05 25;113:137-142. Epub 2021 Dec 25.

Tanz Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Neurological disorders are often associated with a variety of symptoms, which can result from the combined action of genetic variants. We conducted a whole-genome analysis of a previously unreported unique multigenerational Dutch-Canadian family with a complex phenotype presenting with a combination of hearing loss, balance issues or action tremor. Ten family members were available for genetic study. The hearing loss and balance problems are explained by a pathogenic p.P51S substitution in COCH, which is a known founder mutation in Dutch and Belgium families affected by non-syndromic progressive sensorineural hearing loss often accompanied by vestibular dysfunction. Notably, p.P51S did not co-segregate with action tremor in our and reported kindreds. In our family, all 5 patients with tremor were carriers of the extremely rare p.R247W substitution in MCM9 (minor allele frequency in European population is 0.00003), which belongs to the top 0.1% of deleterious variants in the human genome. The MCM9 locus has not been previously associated with action tremor and deserves further investigation in future functional and genetic studies of action tremor.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.12.004DOI Listing
May 2022
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