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Virginia M.-y. Lee - One of the best experts on this subject based on the ideXlab platform.
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Distinct α-Synuclein strains and implications for heterogeneity among α-Synucleinopathies.
Neurobiology of disease, 2017Co-Authors: Chao Peng, Ronald J. Gathagan, Virginia M.-y. LeeAbstract:The deposition of misfolded β-sheet enriched amyloid protein is a shared feature of many neurodegenerative diseases. Recent studies demonstrated the existence of conformationally diverse strains as a common property for multiple amyloidogenic proteins including α-Synuclein (α-Syn). α-Syn is misfolded and aggregated in a group of neurodegenerative diseases collectively known as α-Synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy body, multiple system atrophy and also a subset of Alzheimer's disease patients with concomitant PD-like Lewy bodies and neurites. While sharing the same pathological protein, different α-Synucleinopathies demonstrate distinct clinical and pathological phenotypes, which could result from the existence of diverse pathological α-Syn strains in patients. In this review, we summarized the characteristics of different α-Synucleinopathies and α-Syn strains generated with recombinant α-Syn monomers. We also make predictions of α-Syn strains that could potentially exist in patients based on the knowledge from other amyloid proteins and the clinical and pathological features of different α-Synucleinopathies.
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α-Synuclein Induced Aggregation of Cytoplasmic Vesicles in Saccharomyces cerevisiae
Molecular biology of the cell, 2008Co-Authors: James H. Soper, Subhojit Roy, Anna Stieber, Eliza Lee, Robert B. Wilson, John Q. Trojanowski, Christopher G. Burd, Virginia M.-y. LeeAbstract:Aggregated -synuclein (-syn) fibrils form Lewy bodies (LBs), the signature lesions of Parkinson’s disease (PD) and related Synucleinopathies, but the pathogenesis and neurodegenerative effects of LBs remain enigmatic. Recent studies have shown that when overexpressed in Saccharomyces cerevisiae, -syn localizes to plasma membranes and forms cytoplasmic accumulations similar to human -syn inclusions. However, the exact nature, composition, temporal evolution, and underlying mechanisms of yeast -syn accumulations and their relevance to human Synucleinopathies are unknown. Here we provide ultrastructural evidence that -syn accumulations are not comprised of LB-like fibrils, but are associated with clusters of vesicles. Live-cell imaging showed -syn initially localized to the plasma membrane and subsequently formed accumulations in association with vesicles. Imaging of truncated and mutant forms of -syn revealed the molecular determinants and vesicular trafficking pathways underlying this pathological process. Because vesicular clustering is also found in LB-containing neurons of PD brains, -syn–mediated vesicular accumulation in yeast represents a model system to study specific aspects of neurodegeneration in PD and related Synucleinopathies.
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Oxidative Damage Linked to Neurodegeneration by Selective α-Synuclein Nitration in Synucleinopathy Lesions
Science (New York N.Y.), 2000Co-Authors: Benoit I. Giasson, John Q. Trojanowski, John E. Duda, Ian V. J. Murray, Qiping Chen, José M. Souza, Howard I. Hurtig, Harry Ischiropoulos, Virginia M.-y. LeeAbstract:Aggregated α-synuclein proteins form brain lesions that are hallmarks of neurodegenerative Synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in α-synuclein, we demonstrate extensive and widespread accumulations of nitrated α-synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated α-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of Synucleinopathies. The selective and specific nitration of α-synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative Synucleinopathies.
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Transgenic models of tauopathies and Synucleinopathies.
Brain pathology (Zurich Switzerland), 1999Co-Authors: John Q. Trojanowski, Virginia M.-y. LeeAbstract:Rapidly emerging concepts about the pathobiology and defining phenotypes of two major classes of neurodegenerative disease known as tauopathies and Synucleinopathies are bringing these diseases into shaper focus. Significantly, recent research has substantially advanced understanding of these neurodegenerative disorders thereby providing fresh opportunities for the development of transgenic (TG) mouse models. Since the availability of such animal models will accelerate efforts to discover more effective therapies, we review the current status of efforts to generate informative TG mouse models for tauopathies and Synucleinopathies and other neurodegenerative disorders characterized by prominent filamentous brain lesions.
Rodolfo Savica - One of the best experts on this subject based on the ideXlab platform.
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alpha synuclein oligomers and neurofilament light chain in spinal fluid differentiate multiple system atrophy from lewy body Synucleinopathies
Annals of Neurology, 2020Co-Authors: Wolfgang Singer, Bradley F. Boeve, Ann M Schmeichel, Mohammad Shahnawaz, James D Schmelzer, David M Sletten, Tonette L Gehrking, Jade A Gehrking, Anita D Olson, Rodolfo SavicaAbstract:Objective To explore the role of alpha-synuclein (αSyn) oligomers and neurofilament light chain (NFL) in cerebrospinal fluid (CSF) as markers of early multiple system atrophy (MSA) and to contrast findings with Lewy body Synucleinopathies. Methods In a discovery cohort of well-characterized early MSA patients (n = 24) and matched healthy controls (CON, n = 14), we utilized enzyme-linked immunosorbent assay to measure NFL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF. We confirmed findings in a separate prospectively enrolled cohort of patients with early MSA (n = 38), Parkinson disease (PD, n = 16), and dementia with Lewy bodies (DLB, n = 13), and CON subjects (n = 15). Results In the discovery cohort, NFL was markedly elevated in MSA patients, with perfect separation from CON. αSyn-PMCA was nonreactive in all CON, whereas all MSA samples were positive. In the confirmatory cohort, NFL again perfectly separated MSA from CON, and was significantly lower in PD and DLB compared to MSA. PMCA was again nonreactive in all CON, and positive in all but 2 MSA cases. All PD and all but 2 DLB samples were also positive for αSyn aggregates but with markedly different reaction kinetics from MSA; aggregation occurred later, but maximum fluorescence was higher, allowing for perfect separation of reactive samples between MSA and Lewy body Synucleinopathies. Interpretation NFL and αSyn oligomers in CSF faithfully differentiate early MSA not only from CON but also from Lewy body Synucleinopathies. The findings support the role of these markers as diagnostic biomarkers, and have important implications for understanding pathophysiologic mechanisms underlying the Synucleinopathies. ANN NEUROL 2020.
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Infections or Sepsis Preceding Clinically Diagnosed α-Synucleinopathies: A Case-Control Study.
Movement disorders : official journal of the Movement Disorder Society, 2020Co-Authors: Shemonti Hasan, Michelle M. Mielke, J. Eric Ahlskog, James H. Bower, Pierpaolo Turcano, Rodolfo SavicaAbstract:BACKGROUND Several studies have proposed a role for infections to induce an inflammatory response triggering Parkinson's disease. This remains controversial and the influence of severe infections on other α-Synucleinopathies (Dementia with Lewy Bodies, Parkinson's disease dementia, and Multiple System Atrophy) has not been adequately investigated. OBJECTIVES To assess the association between hospitalization-required infections or sepsis and risk of clinically diagnosed α-Synucleinopathies. METHODS Using the medical records-linkage system (Rochester Epidemiology Project), we identified all α-synucleinopathy cases of in Olmsted County (1991-2010). Cases were matched by symptom-onset age and sex to controls. We reviewed complete medical records to detect hospital-required infections or sepsis preceding clinical-motor onset of α-Synucleinopathies. We used conditional logistic regression to calculate the odds ratio of all α-Synucleinopathies, adjusting for medications, coffee, and smoking. RESULTS There was no association between infection-related hospitalization (odds ratio: 1.05; 95% confidence interval: 0.78-1.40; P = 0.76) or sepsis (odds ratio: 0.86; 95% confidence interval: 0.40-1.85; P = 0.70) and all α-Synucleinopathies in multivariable analyses. We did not identify any associations after stratifying for type of α-synucleinopathy, sex, and age at clinical-motor onset. We analyzed sepsis separately with similar results. CONCLUSION We did not observe any associations between infections leading to hospitalization or sepsis and development of any α-Synucleinopathies. © 2020 International Parkinson and Movement Disorder Society.
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Traumatic brain injury preceding clinically diagnosed α-Synucleinopathies: A case-control study.
Neurology, 2020Co-Authors: Shemonti Hasan, Michelle M. Mielke, J. Eric Ahlskog, James H. Bower, Pierpaolo Turcano, Rodolfo SavicaAbstract:Objective To determine the association between traumatic brain injury (TBI) and any clinically diagnosed α-synucleinopathy including Parkinson disease (PD), dementia with Lewy bodies (DLB), PD dementia (PDD), and multiple system atrophy (MSA). Methods Using the medical records-linkage system of the Rochester Epidemiology Project, we identified incident cases of α-Synucleinopathies in Olmsted County, Minnesota, from 1991 to 2010, matching by age (±1 year) at symptom onset and sex to controls. We reviewed records of cases and controls to detect TBI prior to clinical-motor onset of any α-Synucleinopathies. We based severity (possible, probable, and definite) upon the Mayo Classification System for TBI Severity. Using conditional-logistic regression, we calculated the odds ratio (OR) of all α-Synucleinopathies and type, adjusting for coffee intake and smoking. Results TBI frequency was lower among cases (7.0%) than controls (8.2%). No association was found between TBI and all α-Synucleinopathies in multivariable analyses (OR 0.90, 95% confidence interval [CI] 0.54–1.52). No association presented when examining the number of TBIs, TBI severity, time between TBI exposure and index date, age at index date, or sex. When stratifying by each individual α-synucleinopathy, we did not identify any associations between TBI and PD, DLB, or PDD. Among the MSA group, 1 (6.4%) and 0 controls experienced a TBI (OR could not be estimated). Conclusions In this nested case-control population-based analysis, TBI was not associated with subsequent α-Synucleinopathies in general or any individual α-synucleinopathy. This did not change based on the temporality or the severity of the TBI. Our findings may be limited by the study power.
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When Do α-Synucleinopathies Start? An Epidemiological Timeline: A Review
JAMA neurology, 2018Co-Authors: Rodolfo Savica, Bradley F. Boeve, Michelle M. MielkeAbstract:Importance This article reviews the epidemiological evidence of features of α-Synucleinopathies that precede clinical onset of disease, proposes a clinical timeline, and attempts to define the different premotor and clinical phenotypes associated with α-Synucleinopathies. Observations The pathological hallmarks of the α-Synucleinopathies (Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, and multisystem atrophy) begin years before a clinical diagnosis. Epidemiologic studies support the long gap between pathology and symptoms and suggest that certain nonmotor conditions (constipation, anxiety, and rapid eye movement sleep behavior disorder) precede the traditional motor Parkinson disease phenotype by long intervals. Conclusions and Relevance Characterizing the temporal onset of these conditions will help to better recognize the premotor phase of the α-Synucleinopathies and specific clinical phenotypes and will guide the search for predictive biomarkers and risk or protective factors for Parkinson disease and other Synucleinopathies.
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incidence and pathology of Synucleinopathies and tauopathies related to parkinsonism
JAMA Neurology, 2013Co-Authors: Rodolfo Savica, James H. Bower, Brandon R Grossardt, Eric J Ahlskog, Walter A RoccaAbstract:Importance The frequency and distribution of Synucleinopathies and tauopathies manifesting with parkinsonism in the general population are poorly understood, thus affecting health care planning and research. Objective To investigate the incidence and distribution of specific types of parkinsonism and related proteinopathies. Design We used the medical records–linkage system of the Rochester Epidemiology Project to identify all subjects who received a screening diagnostic code related to parkinsonism in Olmsted County, Minnesota, from January 1, 1991, through December 31, 2005 (15 years). A movement disorders specialist reviewed the complete medical records of each subject who screened positive to determine the type of parkinsonism and the presumed proteinopathy using specified criteria. Setting Geographically defined population. Participants All residents of Olmsted County who provided authorization to use their data for medical records research (population-based sample). Main Outcome and Measures Incidence of parkinsonism and specific proteinopathies. Results Among 542 incident cases of parkinsonism, 409 (75.5%) were classified as proteinopathies. Of the 389 patients with presumed Synucleinopathies (71.8%), 264 had Parkinson disease (48.7% of all cases). The incidence rate of Synucleinopathies was 21.0 per 100 000 person-years overall and increased steeply with age. The incidence rate of tauopathies was 1.1 overall (20 cases), and the most common tauopathy was progressive supranuclear palsy (16 cases). Thirty-six subjects had drug-induced parkinsonism (6.6%), 11 had vascular parkinsonism (2.0%), 1 had amyotrophic lateral sclerosis in parkinsonism (0.2%), 1 had parkinsonism secondary to surgery (0.2%), and 84 remained unspecified (15.5%). Men had a higher incidence than women for most types of parkinsonism. Findings at brain autopsy confirmed the clinical diagnosis in 53 of 65 patients who underwent autopsy (81.5%). Conclusions and Relevance The incidence of proteinopathies related to parkinsonism increases steeply with age and is consistently higher in men than women. Clinically diagnosed Synucleinopathies are much more common than tauopathies. Findings at autopsy confirm the clinical diagnosis of presumed proteinopathy. Our findings may guide health care planning and prompt new research directions.
O. Chiba-falek - One of the best experts on this subject based on the ideXlab platform.
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Structural variants in SNCA gene and the implication to Synucleinopathies.
Current opinion in genetics & development, 2017Co-Authors: O. Chiba-falekAbstract:Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed of aggregates of alpha-synuclein protein. Accumulating evidence, including genome-wide association studies, has implicated the alpha-synuclein ( SNCA ) gene in the etiology of Synucleinopathies and it has been suggested that SNCA expression levels are critical for the development of these diseases. This review focuses on genetic variants from the class of structural variants (SVs), including multiplication of large genomic segments and short ( SNCA locus. We provide evidence that SNCA -SVs play a key role in the pathogenesis of Synucleinopathies via their effects on gene expression and on regulatory mechanisms including transcription and splicing.
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Up-regulation of SNCA gene expression: implications to Synucleinopathies
neurogenetics, 2016Co-Authors: L. Tagliafierro, O. Chiba-falekAbstract:Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein ( SNCA ) gene in the etiology of Synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic forms of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other Synucleinopathies and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here, we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of Synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA down-regulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with Synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)—derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis -genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glial lineages involved in Synucleinopathies representing an attractive strategy to elucidate—common and specific— SNCA -genetic variants, regulatory mechanisms, and vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for Synucleinopathies.
Robert L Nussbaum - One of the best experts on this subject based on the ideXlab platform.
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genetics of Synucleinopathies
Cold Spring Harbor Perspectives in Medicine, 2018Co-Authors: Robert L NussbaumAbstract:Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA) constitute the three major neurodegenerative disorders referred to as Synucleinopathies because both genetic and pathological results implicate the α-synuclein protein in their pathogenesis. PD and DLBD are recognized as closely related diseases with substantial clinical and pathological overlap. MSA, on the other hand, has a distinctive clinical presentation and neuropathological profile. In this review, we will summarize the evidence linking α-synuclein to these three disorders. Hundreds of patients with point or copy number mutations in the gene encoding α-synuclein, SNCA, have been reported in the literature in association with hereditary, autosomal dominant forms of PD, DLBD, or neurodegenerative disease with parkinsonism. The copy number mutations show a dosage effect with age at onset and severity correlating with the number of extra copies of SNCA a patient carries. Common variation in and around the SNCA gene has also been found by genome-wide association studies to be associated with increased risk for apparently sporadic PD, with some evidence that these variants exert their effect through modest increases in α-synuclein expression. Complementing the genetic evidence linking α-synuclein to PD and DLBD is the pathological finding that α-synuclein is a major constituent of Lewy bodies and Lewy neurites in the brains of patients with the common sporadic form of PD. On the other hand, there is little genetic evidence linking SNCA to MSA despite strong neuropathological evidence of α-synuclein aggregation in oligodendroglial cells in MSA patients. Evidence is now emerging that α-synuclein aggregates can have different protein conformations, referred to as strains, similar to what has been shown in prion disease. The different phenotypes in hereditary PD/DLBD versus MSA are likely, therefore, to be the result not only of how specific mutations affect protein expression and turnover, but also a more complex interaction between intrinsic and extrinsic factors governing aggregation and strain formation.
Michelle M. Mielke - One of the best experts on this subject based on the ideXlab platform.
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Timeline of REM Sleep Behavior Disorder in Overt Alpha-Synucleinopathies.
Annals of neurology, 2020Co-Authors: Cole D. Stang, Michelle M. Mielke, James H. Bower, Pierpaolo Turcano, Keith A. Josephs, Aidan F. Mullan, Mania Hajeb, Emanuele Camerucci, Peter R. Martin, Erik K. St. LouisAbstract:OBJECTIVE To analyze the timeline, prevalence, and survival of REM sleep-behavior disorder in patients who developed alpha-Synucleinopathies: Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia compared to age- and sex-matched controls in a population-based incident-cohort study. METHODS We used a population-based, 1991-2010 incident-cohort study of alpha-Synucleinopathies. A movement-disorder specialist reviewed medical records to confirm diagnoses. REM sleep-behavior disorder was diagnosed by reported dream-enactment symptoms or polysomnography. Probable RBD and polysomnography- confirmed RBD were analyzed singularly and combined. RESULTS Among the 444 incident cases of alpha-synucleinopathy, 86 were clinically diagnosed with REM sleep-behavior disorder (19.8%) including 30 (35%) by polysomnography and 56(65%) as probable. Idiopathic REM sleep-behavior-disorder prevalence at alpha-synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha-Synucleinopathies patients than controls (OR=53.1, 95% CI: 13.0- 217.2, p
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Infections or Sepsis Preceding Clinically Diagnosed α-Synucleinopathies: A Case-Control Study.
Movement disorders : official journal of the Movement Disorder Society, 2020Co-Authors: Shemonti Hasan, Michelle M. Mielke, J. Eric Ahlskog, James H. Bower, Pierpaolo Turcano, Rodolfo SavicaAbstract:BACKGROUND Several studies have proposed a role for infections to induce an inflammatory response triggering Parkinson's disease. This remains controversial and the influence of severe infections on other α-Synucleinopathies (Dementia with Lewy Bodies, Parkinson's disease dementia, and Multiple System Atrophy) has not been adequately investigated. OBJECTIVES To assess the association between hospitalization-required infections or sepsis and risk of clinically diagnosed α-Synucleinopathies. METHODS Using the medical records-linkage system (Rochester Epidemiology Project), we identified all α-synucleinopathy cases of in Olmsted County (1991-2010). Cases were matched by symptom-onset age and sex to controls. We reviewed complete medical records to detect hospital-required infections or sepsis preceding clinical-motor onset of α-Synucleinopathies. We used conditional logistic regression to calculate the odds ratio of all α-Synucleinopathies, adjusting for medications, coffee, and smoking. RESULTS There was no association between infection-related hospitalization (odds ratio: 1.05; 95% confidence interval: 0.78-1.40; P = 0.76) or sepsis (odds ratio: 0.86; 95% confidence interval: 0.40-1.85; P = 0.70) and all α-Synucleinopathies in multivariable analyses. We did not identify any associations after stratifying for type of α-synucleinopathy, sex, and age at clinical-motor onset. We analyzed sepsis separately with similar results. CONCLUSION We did not observe any associations between infections leading to hospitalization or sepsis and development of any α-Synucleinopathies. © 2020 International Parkinson and Movement Disorder Society.
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Traumatic brain injury preceding clinically diagnosed α-Synucleinopathies: A case-control study.
Neurology, 2020Co-Authors: Shemonti Hasan, Michelle M. Mielke, J. Eric Ahlskog, James H. Bower, Pierpaolo Turcano, Rodolfo SavicaAbstract:Objective To determine the association between traumatic brain injury (TBI) and any clinically diagnosed α-synucleinopathy including Parkinson disease (PD), dementia with Lewy bodies (DLB), PD dementia (PDD), and multiple system atrophy (MSA). Methods Using the medical records-linkage system of the Rochester Epidemiology Project, we identified incident cases of α-Synucleinopathies in Olmsted County, Minnesota, from 1991 to 2010, matching by age (±1 year) at symptom onset and sex to controls. We reviewed records of cases and controls to detect TBI prior to clinical-motor onset of any α-Synucleinopathies. We based severity (possible, probable, and definite) upon the Mayo Classification System for TBI Severity. Using conditional-logistic regression, we calculated the odds ratio (OR) of all α-Synucleinopathies and type, adjusting for coffee intake and smoking. Results TBI frequency was lower among cases (7.0%) than controls (8.2%). No association was found between TBI and all α-Synucleinopathies in multivariable analyses (OR 0.90, 95% confidence interval [CI] 0.54–1.52). No association presented when examining the number of TBIs, TBI severity, time between TBI exposure and index date, age at index date, or sex. When stratifying by each individual α-synucleinopathy, we did not identify any associations between TBI and PD, DLB, or PDD. Among the MSA group, 1 (6.4%) and 0 controls experienced a TBI (OR could not be estimated). Conclusions In this nested case-control population-based analysis, TBI was not associated with subsequent α-Synucleinopathies in general or any individual α-synucleinopathy. This did not change based on the temporality or the severity of the TBI. Our findings may be limited by the study power.
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When Do α-Synucleinopathies Start? An Epidemiological Timeline: A Review
JAMA neurology, 2018Co-Authors: Rodolfo Savica, Bradley F. Boeve, Michelle M. MielkeAbstract:Importance This article reviews the epidemiological evidence of features of α-Synucleinopathies that precede clinical onset of disease, proposes a clinical timeline, and attempts to define the different premotor and clinical phenotypes associated with α-Synucleinopathies. Observations The pathological hallmarks of the α-Synucleinopathies (Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, and multisystem atrophy) begin years before a clinical diagnosis. Epidemiologic studies support the long gap between pathology and symptoms and suggest that certain nonmotor conditions (constipation, anxiety, and rapid eye movement sleep behavior disorder) precede the traditional motor Parkinson disease phenotype by long intervals. Conclusions and Relevance Characterizing the temporal onset of these conditions will help to better recognize the premotor phase of the α-Synucleinopathies and specific clinical phenotypes and will guide the search for predictive biomarkers and risk or protective factors for Parkinson disease and other Synucleinopathies.
