RESUMO
Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease.
Assuntos
Testes Genéticos , Glucosilceramidase , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , alfa-Sinucleína , Humanos , Doença de Parkinson/genética , Doença de Parkinson/diagnóstico , Testes Genéticos/métodos , Masculino , Feminino , Glucosilceramidase/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , alfa-Sinucleína/genética , Idoso , Pessoa de Meia-Idade , Ubiquitina-Proteína Ligases/genética , Proteínas Quinases/genética , Proteína Desglicase DJ-1/genética , Proteínas de Transporte Vesicular/genética , América do Norte , Variação Genética/genética , Predisposição Genética para Doença/genética , Adulto , Revelação , Aconselhamento Genético , Canadá , Estados UnidosRESUMO
The rate of medical cannabis use has increased in parallel with the number of states legalizing its use. Parkinson's disease (PD) patients are of particular concern due to their higher cannabis use rate than in the general US population (25-40â¯% PD patient cannabis users vs. â¼18â¯% in the general population), as well as their susceptibility to environmental contaminants in cannabis, including pesticides, toxic elements, solvents, microbes, and mycotoxins. In order to address the complex nature of this industry, we examined the changes in PD-related qualifying conditions in the U.S. from 2019 to 2023. We also conducted an online survey to gain insight into the knowledge, risk perceptions, and opinions regarding medical cannabis and contamination issues from physicians who treated PD patients. The number of states including PD-related qualifying conditions increased over the past 5 years from 28 to 36 states. These conditions included PD (increasing from 14 to 16 states), muscle spasms (14 to 24), anxiety (1 to 5), and pain (17 to 35). State-by-state comparisons revealed high variability in the language used to describe the different qualifying conditions. Online surveys were sent out to 45 neurologists and movement disorder specialists who primarily treated PD patients. The response rate was 44â¯% from nine states (AZ, CA, FL, MA, MN, WI, PA, IL, and NM). When asked if they were aware of any contaminants in cannabis products, we found that 65â¯% of the physicians were unaware of any contaminants commonly found in cannabis and only 25â¯%, 15â¯%, and 15â¯% of them were aware of pesticide, toxic element, and solvent contaminants, respectively. In their free-text opinion response on the health impact of cannabis-borne contaminants, "long-term effect" (35â¯%) and "comorbidities and PD prognosis" (40â¯%) were identified as the two most common themes. These results point to the need for further regulatory deliberation regarding risks and susceptibility to cannabis contaminants. Additionally, education is needed to inform physicians on cannabis safety issues. Further research will identify the implementation strategies to reduce contaminant exposure and protect patient health.
Assuntos
Maconha Medicinal , Doença de Parkinson , Humanos , Maconha Medicinal/uso terapêutico , Maconha Medicinal/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Estados Unidos/epidemiologia , Médicos/psicologia , Inquéritos e Questionários , Atitude do Pessoal de SaúdeRESUMO
Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
Assuntos
Progressão da Doença , Corpos de Lewy , Doença por Corpos de Lewy , alfa-Sinucleína , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , alfa-Sinucleína/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Tronco Encefálico/patologia , Tronco Encefálico/metabolismo , Corpos de Lewy/patologia , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/metabolismo , Bulbo Olfatório/patologia , Bulbo Olfatório/metabolismoRESUMO
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder resulting from the deposition of misfolded and neurotoxic forms of tau protein in specific areas of the midbrain, basal ganglia, and cortex. It is one of the most representative forms of tauopathy. PSP presents in several different phenotypic variations and is often accompanied by the development of concurrent neurodegenerative disorders. PSP is universally fatal, and effective disease-modifying therapies for PSP have not yet been identified. Several tau-targeting treatment modalities, including vaccines, monoclonal antibodies, and microtubule-stabilizing agents, have been investigated and have had no efficacy. The need to treat PSP and other tauopathies is critical, and many clinical trials investigating tau-targeted treatments are underway. In this review, the PubMed database was queried to collect information about preclinical and clinical research on PSP treatment. Additionally, the US National Library of Medicine's ClinicalTrials.gov website was queried to identify past and ongoing clinical trials relevant to PSP treatment. This narrative review summarizes our findings regarding these reports, which include potential disease-modifying drug trials, modifiable risk factor management, and symptom treatments.
RESUMO
BACKGROUND: The G2019S leucine-rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological findings associated with this mutation have thus far been varied but are most often associated with Lewy body (LB) pathology. OBJECTIVE: Describe a case of clinical Parkinson's disease with levodopa responsiveness found to have LRRK2 mutations and the absence of Lewy bodies. METHOD: We present an 89-year-old man with a 10-year history of slowly progressive parkinsonism suspected to be secondary to Parkinson's disease. RESULTS: Neuropathological evaluation revealed nigral degeneration without Lewy bodies or Lewy neurites, but there were frequent tau-immunopositive neurites and astrocytes in the putamen and substantia nigra, neocortical glial tau positive astrocytes associated with aging-related tau astrogliopathy (ARTAG), as well as neurofibrillary tangles, beta amyloid plaques, and amyloid angiopathy typical of advanced Alzheimer's disease. G2019S LRRK2 homozygous mutations were found. CONCLUSION: This case illustrates that levodopa-responsive clinical PD caused by G2019S LRRK2 mutations can occur without Lewy bodies.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Corpos de Lewy , Mutação , Doença de Parkinson , Proteínas Serina-Treonina Quinases , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Masculino , Doença de Parkinson/genética , Doença de Parkinson/patologia , Idoso de 80 Anos ou mais , Corpos de Lewy/patologia , Corpos de Lewy/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Levodopa/uso terapêuticoRESUMO
Background: The Essential Tremor Rating Assessment Scale (TETRAS) is a popular scale for essential tremor (ET), but its activities of daily living (ADL) and performance (P) subscales are based on a structured interview and physical exam. No patient-reported outcome (PRO) scale for ET has been developed according to US regulatory guidelines. Objective: Develop and validate a TETRAS PRO subscale. Methods: Fourteen items, rated 0-4, were derived from TETRAS ADL and structured cognitive interviews of 18 ET patients. Convergent validity analyses of TETRAS PRO versus TETRAS ADL, TETRAS-P, and the Quality of Life in Essential Tremor Questionnaire (QUEST) were computed for 67 adults with ET or ET plus. Test-retest reliability was computed at intervals of 1 and 30 days. The influence of mood (Hospital Anxiety and Depression Scale, HADS) and coping behaviors (Essen Coping Questionnaire, ECQ) was examined with multiple linear regression. Results: TETRAS PRO was strongly correlated (r > 0.7) with TETRAS ADL, TETRAS-P, and QUEST and exhibited good to excellent reliability (Cronbach alpha 95%CI = 0.853-0.926; 30-day test-retest intraclass correlation 95%CI = 0.814-0.921). The 30-day estimate of minimum detectable change (MDC) was 6.6 (95%CI 5.2-8.0). TETRAS-P (rsemipartial = 0.607), HADS depression (rsemipartial = 0.384), and the coping strategy of information seeking and exchange of experiences (rsemipartial = 0.176) contributed statistically to TETRAS PRO in a multiple linear regression (R2 = 0.67). Conclusions: TETRAS PRO is a valid and reliable scale that is influenced strongly by tremor severity, moderately by mood (depression), and minimally by coping skills. The MDC for TETRAS PRO is probably sufficient to detect clinically important change.
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Atividades Cotidianas , Tremor Essencial , Medidas de Resultados Relatados pelo Paciente , Humanos , Tremor Essencial/fisiopatologia , Tremor Essencial/psicologia , Tremor Essencial/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Reprodutibilidade dos Testes , Idoso de 80 Anos ou mais , Qualidade de Vida , Adulto , Inquéritos e QuestionáriosRESUMO
BACKGROUND: While preclinical studies have shown that alpha-synuclein can spread through cell-to-cell transmission whether it can be transmitted between humans is unknown. OBJECTIVES: The aim was to assess the presence of a synucleinopathy in autopsied conjugal couples. METHODS: Neuropathological findings in conjugal couples were categorized as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease with Lewy bodies (ADLB), incidental Lewy body disease (ILBD), or no Lewy bodies. RESULTS: Ninety conjugal couples were included; the mean age of death was 88.3 years; 32 couples had no Lewy bodies; 42 couples had 1 spouse with a synucleinopathy: 10 PD, 3 DLB, 13 ADLB, and 16 ILBD; 16 couples had both spouses with a synucleinopathy: in 4 couples both spouses had PD, 1 couple had PD and DLB, 4 couples had PD and ADLB, 2 couples had PD and ILBD, 1 couple had DLB and ADLB, in 3 couples both had ADLB, and 1 couple had ADLB and ILBD. No couples had both spouses with ILBD. CONCLUSIONS: This large series of 90 autopsied conjugal couples found 16 conjugal couples with synucleinopathies, suggesting transmission of synucleinopathy between spouses is unlikely. © 2024 International Parkinson and Movement Disorder Society.
Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Sinucleinopatias , Humanos , Feminino , Masculino , Idoso de 80 Anos ou mais , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/metabolismo , Idoso , Sinucleinopatias/patologia , Autopsia , alfa-Sinucleína/metabolismo , Cônjuges , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Corpos de Lewy/patologiaRESUMO
The olfactory bulb is involved early in the pathophysiology of Parkinson's disease (PD), which is consistent with the early onset of olfactory dysfunction. Identifying the molecular mechanisms through which PD affects the olfactory bulb could lead to a better understanding of the pathophysiology and etiology of olfactory dysfunction in PD. We specifically aimed to assess gene expression changes, affected pathways and co-expression network by whole transcriptomic profiling of the olfactory bulb in subjects with clinicopathologically defined PD. Bulk RNA sequencing was performed on frozen human olfactory bulbs of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative disorders and the Brain and Body Donation Program. Differential expression analysis (19 PD vs 19 controls) revealed 2164 significantly differentially expressed genes (1090 upregulated and 1074 downregulated) in PD. Pathways enriched in downregulated genes included oxidative phosphorylation, olfactory transduction, metabolic pathways, and neurotransmitters synapses while immune and inflammatory responses as well as cellular death related pathways were enriched within upregulated genes. An overrepresentation of microglial and astrocyte-related genes was observed amongst upregulated genes, and excitatory neuron-related genes were overrepresented amongst downregulated genes. Co-expression network analysis revealed significant modules highly correlated with PD and olfactory dysfunction that were found to be involved in the MAPK signaling pathway, cytokine-cytokine receptor interaction, cholinergic synapse, and metabolic pathways. LAIR1 (leukocyte associated immunoglobulin like receptor 1) and PPARA (peroxisome proliferator activated receptor alpha) were identified as hub genes with a high discriminative power between PD and controls reinforcing an important role of neuroinflammation in the olfactory bulb of PD subjects. Olfactory identification test score positively correlated with expression of genes coding for G-coupled protein, glutamatergic, GABAergic, and cholinergic receptor proteins and negatively correlated with genes for proteins expressed in glial olfactory ensheathing cells. In conclusion, this study reveals gene alterations associated with neuroinflammation, neurotransmitter dysfunction, and disruptions of factors involved in the initiation of olfactory transduction signaling that may be involved in PD-related olfactory dysfunction.
Assuntos
Transtornos do Olfato , Bulbo Olfatório , Doença de Parkinson , Análise de Sequência de RNA , Humanos , Bulbo Olfatório/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Masculino , Transtornos do Olfato/genética , Feminino , Idoso , Análise de Sequência de RNA/métodos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Perfilação da Expressão Gênica/métodos , TranscriptomaRESUMO
BACKGROUND: Peripheral tissue biopsy in Parkinson's disease (PD) may be valuable for clinical care, biomarker validation, and as research enrollment criteria. OBJECTIVE: Determine whether submandibular gland pathologic alpha-synuclein (aSyn) density is symmetrical and whether previous needle biopsy caused tissue damage. METHODS: Thirty autopsy-confirmed PD cases having fixed submandibular gland tissue from one side and frozen submandibular gland tissue from the contralateral side were studied. Tissue was stained for phosphorylated aSyn and density (0-4 semiquantitative scale) was determined. Three previously biopsied cases were also assessed for tissue damage at subsequent autopsy. RESULTS: Mean (SD) age was 80.9 (5.5) years and disease duration 12.5 (9.3). Submandibular gland aSyn staining had a mean score of 2.13 for both the initially fixed and the initially frozen submandibular glands. The correlation between aSyn density of the two sides was r = 0.63. Correlation of aSyn density, in the originally fixed submandibular gland, with disease duration was good (r = 0.49, p =.006). No permanent tissue damage was found in the three previously biopsied cases. CONCLUSIONS: This study found good correlation between aSyn density in both submandibular glands of patients with PD and found no evidence of significant tissue damage in previously biopsied subjects.
Assuntos
Doença de Parkinson , Humanos , Idoso de 80 Anos ou mais , Doença de Parkinson/patologia , Glândula Submandibular/patologia , alfa-Sinucleína , Biópsia , Biomarcadores , AutopsiaRESUMO
Lewy body (LB) disorders, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. By applying data-driven disease progression modelling to regional neuropathological LB density scores from 814 brain donors, we describe three inferred trajectories of LB pathology that were characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) showed earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) exhibited the first abnormalities in brainstem regions. Early limbic pathology was associated with Alzheimer's disease-associated characteristics. Meanwhile, brainstem-first pathology was associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in LBDs.
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Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Diagnóstico Precoce , AutopsiaRESUMO
INTRODUCTION: We examined the progression of extrapyramidal symptoms and signs in autopsy-confirmed dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and Alzheimer's disease dementia (AD). METHODS: Longitudinal data were obtained from Arizona Study of Aging and Neurodegenerative Disease, with PDD (n = 98), AD (n = 47) and DLB (n = 48) further sub-grouped as with or without parkinsonism (DLB+ and DLB-). Within-group Unified Parkinson's Disease Rating Scale (UPDRS) -II and UPDRS-III trajectories were analyzed using non-linear mixed effects models. RESULTS: In DLB, 65.6% had parkinsonism. Baseline UPDRS-II and III scores (off-stage) were highest (P < 0.001) for PDD (mean ± SD 14.3 ± 7.8 and 27.4 ± 16.3), followed by DLB+ (6.0 ± 8.8 and 17.2 ± 17.1), DLB- (1.1 ± 1.3 and 3.3 ± 5.5) and AD (3.2 ± 6.1 and 8.2 ± 13.6). Compared to PDD, the DLB+ group had faster UPDRS-III progression over 8-years (Cohen's-d range 0.98 to 2.79, P < 0.001), driven by gait (P < 0.001) and limb bradykinesia (P = 0.02) subscales. DISCUSSION: Motor deficits progress faster in DLB+ than PDD, providing insights about expected changes in motor function. HIGHLIGHTS: Dementia with Lewy bodies has faster motor progression than Parkinson's disease dementia Linear and non-linear mixed modeling analysis of longitudinal data was utilized Findings have implications for clinical prognostication and trial design.
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Doença de Alzheimer , Demência , Doença por Corpos de Lewy , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , AutopsiaRESUMO
The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological study using Rainwater criteria to define neuropathological PSP. Of 954 autopsy cases, 101 met Rainwater criteria for the neuropathologic diagnosis of PSP. Of these, 87 were termed clinicopathological PSP as they also had either dementia or parkinsonism or both. The prevalence of clinicopathologically defined PSP subjects in the entire autopsy dataset was 9.1%, while the incidence rate was estimated at 780 per 100â000 persons per year, roughly 50-fold greater than most previous clinically determined PSP incidence estimates. A clinical diagnosis of PSP was 99.6% specific but only 9.2% sensitive based on first examination, and 99.3% specific and 20.7% sensitive based on the final clinical exam. Of the clinicopathologically defined PSP cases, 35/87 (â¼40%) had no form of parkinsonism at first assessment, while this decreased to 18/83 (21.7%) at final assessment. Our study confirms a high specificity but low sensitivity for the clinical diagnosis of PSP. The low clinical sensitivity for PSP is likely primarily responsible for previous underestimates of the PSP population incidence rate.
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Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/epidemiologia , Paralisia Supranuclear Progressiva/patologia , Incidência , AutopsiaRESUMO
Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.
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Doença de Alzheimer , Transtornos Cerebrovasculares , Demência Vascular , Substância Branca , Feminino , Humanos , Substância Branca/patologia , Encéfalo/patologia , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Demência Vascular/patologiaRESUMO
BACKGROUND: Essential tremor (ET) is a common movement disorder in which cerebellar microscopic and volume alterations have been repeatedly reported although with disagreement between studies. However, pronounced heterogeneity was found with regard to cerebellar volume alterations. OBJECTIVE: This study aimed to assess postmortem cerebellar volume in subjects with or without ET, as compared with subjects with multiple system atrophy (MSA), a well-established cerebellar neurodegeneration. METHODS: Cases with ET (nâ=â29), MSA (nâ=â7), and non-demented control cases without any movement disorder (nâ=â22) were selected from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study with annual research-dedicated clinical assessments by neuropsychologists, subspecialist movement disorders, and cognitive/behavioral neurologists, with comprehensive neuropathological examinations after death. Group comparisons were controlled for common age-related neurodegenerative and cerebrovascular pathologies. Cerebellar volumes were calculated using digital images of slices taken at the time of autopsy, immediately after brain removal and before fixation. RESULTS: Cerebellar volume was not reduced in ET subjects compared to controls. The two groups did not differ in terms of incidental cerebrovascular and Alzheimer's disease neuropathology. In contrast, cerebellar volume was significantly reduced in subjects with MSA when compared to ET and control subjects. CONCLUSION: In a well-characterized cohort, postmortem cerebellar volume measurements suggest that there are no volume alterations in ET when compared to controls, in contrast to significant cerebellar atrophy in subjects with MSA.
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Tremor Essencial , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , Atrofia de Múltiplos Sistemas/patologia , Autopsia , Doença de Parkinson/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologiaRESUMO
Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.
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COVID-19 , SARS-CoV-2 , Encéfalo , Expressão Gênica , Humanos , ImunidadeRESUMO
The Alzheimer disease (AD) neuropathological hallmarks amyloid ß (Aß) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aß throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aß and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aß was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aß and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aß pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology.
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Doença de Alzheimer , Amiloidose , Disfunção Cognitiva , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/patologia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Humanos , Bulbo Olfatório/metabolismo , Proteínas tau/metabolismoRESUMO
Decline of olfactory function is frequently observed in aging and is an early symptom of neurodegenerative diseases. As the olfactory bulb (OB) is one of the first regions involved by pathology and may represent an early disease stage, we specifically aimed to evaluate the contribution of OB pathology to olfactory decline in cognitively normal aged individuals without parkinsonism or dementia. This clinicopathological study correlates OB tau, amyloid ß (Aß) and α-synuclein (αSyn) pathology densities and whole brain pathology load to olfactory identification function as measured with the University of Pennsylvania Smell Identification Test (UPSIT) and clinical data measured proximate to death in a large autopsy study including 138 cases considered non-demented controls during life. Tau pathology was frequently observed in the OB (95% of cases), while both Aß (27% of cases) and αSyn (20% of cases) OB pathologies were less commonly observed. A weak correlation was only observed between OB tau and olfactory performance, but when controlled for age, neither OB tau, Aß or αSyn significantly predict olfactory performance. Moreover, whole brain tau and αSyn pathology loads predicted olfactory performance; however, only αSyn pathology loads survived age correction. In conclusion, OB tau pathology is frequently observed in normally aging individuals and increases with age but does not appear to independently contribute to age-related olfactory impairment suggesting that further involvement of the brain seems necessary to contribute to age-related olfactory decline.