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1.
Mov Disord Clin Pract ; 11(3): 220-226, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38468536

RESUMO

BACKGROUND: Young-onset multiple system atrophy (YOMSA) is defined as the onset of multiple system atrophy (MSA) before the age of 40 years old. YOMSA is rare and there is much uncertainty of the phenotype and natural history in patients with YOMSA. OBJECTIVE: The objective is to evaluate the characteristics and disease course of patients with YOMSA. METHODS: We retrospectively reviewed medical records of patients with MSA who were evaluated at all Mayo Clinic sites from 1998 to 2021. We identified patients with YOMSA and evaluated clinical characteristics, autonomic function testing results, and disease course. RESULTS: Of 1496 patients with a diagnosis of clinically probable or clinically established MSA, 20 patients had YOMSA. The median age of onset was 39.1 (interquartile range [IQR] = 37.1, 40.1) years; 13 patients (65%) were male. MSA-parkinsonism was the most common subtype (65%). The median duration of symptom onset to YOMSA diagnosis was 4.9 (IQR = 3.7, 9) years. At the time of medical record review, 17 patients were deceased with a median survival of 8.3 (IQR = 7, 10.9) years. Univariate analysis showed that initial onset of autonomic failure predicted unfavorable survival (hazard ratio = 2.89, P = 0.04) compared to those who presented with motor impairment only at onset. At the time of YOMSA diagnosis, composite autonomic severity score was available in 19 patients with a median of 5 (IQR = 4, 6.5). CONCLUSIONS: YOMSA resembles MSA in most aspects including phenotype and prognosis, although the diagnosis is usually delayed. The presence of autonomic failure at symptom onset may be a poor predictor for survival.


Assuntos
Atrofia de Múltiplos Sistemas , Insuficiência Autonômica Pura , Humanos , Masculino , Adulto , Feminino , Atrofia de Múltiplos Sistemas/diagnóstico , Estudos Retrospectivos , Sistema Nervoso Autônomo , Prognóstico , Progressão da Doença
2.
Clin Neurol Neurosurg ; 237: 108147, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38325040

RESUMO

OBJECTIVE: The unified multiple system atrophy rating scale (UMSARS) was used to evaluate various symptoms of multiple system atrophy (MSA). And UMSARS part 1 was originally developed for use in interviews, but the need for telemedicine is increasing in COVID-19 pandemic. The purpose of this study is to evaluate the reliability of the UMSARS part 1 telephone survey. METHODS: Thirty-two MSA patients took the UMSARS part 1 face-to-face, followed by two more telephone evaluations. Intraclass correlation coefficients (ICC) and Cronbach's alpha (α) coefficients were calculated, and the inter-rater reliability was determined. At the same time, we asked about the problems in COVID-19 pandemic. RESULTS: The study participants included 15 men and 17 women with mean age of 67.1 years (SD, 8.3). For the total UMSARS part 1 score, the inter-rater ICC and Cronbach's α coefficient were 0.89 to 0.92, and 0.84 to 0.87, respectively. More than half of the items had a relatively high ICC. Cronbach's α coefficients were more than 0.7 for all items. Changes that occurred in COVID-19 pandemic included reduced outings and lack of rehabilitation in about half of the cases. CONCLUSION: The UMSARS part 1 has high inter-rater reliability and internal consistency. Evaluation of subjective symptoms showed that some variability could occur. In addition, there was concern about the influence of lack of rehabilitation due to COVID-19 pandemic.


Assuntos
COVID-19 , Atrofia de Múltiplos Sistemas , Masculino , Humanos , Feminino , Idoso , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/epidemiologia , Reprodutibilidade dos Testes , Pandemias , Índice de Gravidade de Doença
3.
Biochem Biophys Res Commun ; 703: 149620, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38359614

RESUMO

Parkinson's disease (PD) is characterized by the pathological deposition of a-synuclein (a-syn) inclusions, known as Lewy bodies/neurites. Emerging evidence suggests that extracellular vesicles (EVs) play a role in facilitating the spreading of Lewy pathology between the peripheral nervous system and the central nervous system. We analyzed serum EVs obtained from patients with PD (n = 142), multiple system atrophy (MSA) (n = 18), progressive supranuclear palsy (PSP) (n = 28), rapid eye movement sleep behavior disorder (n = 31), and controls (n = 105). While we observed a significant reduction in the number of EVs in PD compared to controls (p = 0.006), we also noted a substantial increase in filamentous α-synuclein within EVs in PD compared to controls (p < 0.0001), MSA (0.012), and PSP (p = 0.03). Further analysis unveiled the role of EVs in facilitating the transmission of filamentous α-synuclein between neurons and from peripheral blood to the CNS. These findings highlight the potential utility of serum α-synuclein filaments within EVs as diagnostic markers for synucleinopathies and underscore the significance of EVs in promoting the dissemination of filamentous α-synuclein throughout the entire body.


Assuntos
Vesículas Extracelulares , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , alfa-Sinucleína , Doença de Parkinson/patologia , Vesículas Extracelulares/patologia , Sistema Nervoso Central
4.
Exp Neurol ; 374: 114706, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38311020

RESUMO

Motor cortical circuit functions depend on the coordinated fine-tuning of two functionally diverse neuronal populations: glutamatergic pyramidal neurons providing synaptic excitation and GABAergic interneurons adjusting the response of pyramidal neurons through synaptic inhibition. Microglia are brain resident macrophages which dynamically refine cortical circuits by monitoring perineuronal extracellular matrix and remodelling synapses. Previously, we showed that colony-stimulating factor 1 receptor (CSF1R)-mediated myeloid cell depletion extended the lifespan, but impaired motor functions of MBP29 mice, a mouse model for multiple system atrophy. In order to better understand the mechanisms underlying these motor deficits we characterized the microglial involvement in the cortical balance of GABAergic interneurons and glutamatergic pyramidal neurons in 4-months-old MBP29 mice following CSF1R inhibition for 12 weeks. Lack of myeloid cells resulted in a decreased number of COUP TF1 interacting protein 2-positive (CTIP2+) layer V pyramidal neurons, however in a proportional increase of calretinin-positive GABAergic interneurons in MBP29 mice. While myeloid cell depletion did not alter the expression of important presynaptic and postsynaptic proteins, the loss of cortical perineuronal net area was attenuated by CSF1R inhibition in MBP29 mice. These cortical changes may restrict synaptic plasticity and potentially modify parvalbumin-positive perisomatic input. Collectively, this study suggests, that the lack of myeloid cells shifts the neuronal balance toward an increased inhibitory connectivity in the motor cortex of MBP29 mice thereby potentially deteriorating motor functions.


Assuntos
Córtex Motor , Atrofia de Múltiplos Sistemas , Camundongos , Animais , Neurônios , Células Piramidais/fisiologia , Interneurônios/fisiologia , Receptores Proteína Tirosina Quinases , Células Mieloides
5.
Parkinsonism Relat Disord ; 120: 106019, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38350294

RESUMO

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disease with presentations including parkinsonism, autonomic disturbances, gait impairment and mood disorders. The progressive nature of MSA results in a significant deterioration in quality of life for patients. OBJECTIVES: To investigate the needs of people with MSA (PwMSA) in the United Kingdom (UK) and the support provided to them. METHODS: A survey of members of the UK's MSA Trust including PwMSA and former carers explored questions on the physical, emotional, personal and financial impact of MSA and on support received. RESULTS: There were 284 valid responses from PwMSA and 371 responses from former carers. Difficulties with movement were universally experienced by PwMSA. The majority of former carers reported these as difficult or very difficult to manage (90 %), followed by autonomic problems (85 %) and breathing, speech or swallowing problems (81 %). PwMSA also reported fatigue (96 %), mood disorders (80 %) and social isolation (82 %). 41 % of former carers felt that the emotional needs of PwMSA had not been met. Many also reported inadequately covered financial needs (48 %). Equipment used most commonly included mobility equipment (90 %). The majority received support from neurologists (95 %) and GPs (92 %), but few from palliative care or mental health professionals. Satisfaction was highest for support from palliative services (95 %) and specialist nurses (91 %). CONCLUSION: This survey demonstrates the high burden of MSA across various aspects of life for PwMSA. It suggests that whilst there is good provision of neurology services and physical equipment, there is a need to improve support for their emotional and social needs.


Assuntos
Atrofia de Múltiplos Sistemas , Qualidade de Vida , Humanos , Cuidados Paliativos , Cuidadores/psicologia , Isolamento Social
6.
Curr Neurol Neurosci Rep ; 24(4): 95-112, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38416311

RESUMO

PURPOSE OF REVIEW: This review summarizes previous and ongoing neuroprotection trials in multiple system atrophy (MSA), a rare and fatal neurodegenerative disease characterized by parkinsonism, cerebellar, and autonomic dysfunction. It also describes the preclinical therapeutic pipeline and provides some considerations relevant to successfully conducting clinical trials in MSA, i.e., diagnosis, endpoints, and trial design. RECENT FINDINGS: Over 30 compounds have been tested in clinical trials in MSA. While this illustrates a strong treatment pipeline, only two have reached their primary endpoint. Ongoing clinical trials primarily focus on targeting α-synuclein, the neuropathological hallmark of MSA being α-synuclein-bearing glial cytoplasmic inclusions. The mostly negative trial outcomes highlight the importance of better understanding underlying disease mechanisms and improving preclinical models. Together with efforts to refine clinical measurement tools, innovative statistical methods, and developments in biomarker research, this will enhance the design of future neuroprotection trials in MSA and the likelihood of positive outcomes.


Assuntos
Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Humanos , Atrofia de Múltiplos Sistemas/terapia , Atrofia de Múltiplos Sistemas/diagnóstico , alfa-Sinucleína/metabolismo , Biomarcadores , Cerebelo
8.
Proc Natl Acad Sci U S A ; 121(3): e2312031121, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38194461

RESUMO

The quantification and characterization of aggregated α-synuclein in clinical samples offer immense potential toward diagnosing, treating, and better understanding neurodegenerative synucleinopathies. Here, we developed digital seed amplification assays to detect single α-synuclein aggregates by partitioning the reaction into microcompartments. Using pre-formed α-synuclein fibrils as reaction seeds, we measured aggregate concentrations as low as 4 pg/mL. To improve our sensitivity, we captured aggregates on antibody-coated magnetic beads before running the amplification reaction. By first characterizing the pre-formed fibrils with transmission electron microscopy and size exclusion chromatography, we determined the specific aggregates targeted by each assay platform. Using brain tissue and cerebrospinal fluid samples collected from patients with Parkinson's Disease and multiple system atrophy, we demonstrated that the assay can detect endogenous pathological α-synuclein aggregates. Furthermore, as another application for these assays, we studied the inhibition of α-synuclein aggregation in the presence of small-molecule inhibitors and used a custom image analysis pipeline to quantify changes in aggregate growth and filament morphology.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Sinucleinopatias , Humanos , alfa-Sinucleína , Anticorpos
9.
Acta Neuropathol Commun ; 12(1): 11, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38238869

RESUMO

Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (α-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of glia cytoplasmic inclusions (GCI) pathology, however it is not known what specifically drives disease pathogenesis. Recent studies have shown that disease pathologies found in post-mortem tissue from MSA patients can be modeled in rodents via a modified AAV overexpressing α-syn, Olig001-SYN, which has a 95% tropism for oligodendrocytes. In the Olig001-SYN mouse model, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs remains unclear. In this study we use genetic and pharmacological approaches in the Olig001-SYN model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFNγ) drives neuroinflammation, demyelination, and neurodegeneration. Furthermore, using an IFNγ reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFNγ in response to α-syn overexpression in oligodendrocytes. Results from these studies indicate that IFNγ expression from CD4+ T cells drives α-syn-mediated neuroinflammation, demyelination, and neurodegeneration. These results indicate that targeting IFNγ expression may be a potential disease modifying therapeutic strategy for MSA.


Assuntos
Doenças Desmielinizantes , Atrofia de Múltiplos Sistemas , Sinucleinopatias , Animais , Humanos , Camundongos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Interferon gama/metabolismo , Atrofia de Múltiplos Sistemas/patologia , Doenças Neuroinflamatórias , Oligodendroglia/patologia , Sinucleinopatias/patologia
11.
Parkinsonism Relat Disord ; 120: 106001, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38217954

RESUMO

AIMS: Parkinson's disease (PD), as the second most common neurodegenerative disorder, often presents diagnostic challenges in differentiation from other forms of Parkinsonism. Recent studies have reported an association between plasma glycoprotein nonmetastatic melanoma protein B (pGPNMB) and PD. METHODS: A retrospective study was conducted, comprising 401 PD patients, 111 multiple system atrophy (MSA) patients, 13 progressive supranuclear palsy (PSP) patients and 461 healthy controls from the Chinese Han population, with an assessment of pGPNMB levels. RESULTS: The study revealed that pGPNMB concentrations were significantly lower in PD and MSA patients compared to controls (area under the receiver operating characteristics curve (AUC) 0.62 and 0.74, respectively, P < 0.0001 for both), but no difference was found in PSP patients compared to controls (P > 0.05). Interestingly, the level of pGPNMB was significantly higher in PD patients than in MSA patients (AUC = 0.63, P < 0.0001). Furthermore, the study explored the association between pGPNMB levels and disease severity in PD and MSA patients, revealing a positive correlation in PD patients but not in MSA patients with both disease severity and cognitive impairment. CONCLUSION: This study successfully replicated prior findings, demonstrating an association between pGPNMB levels and disease severity, and also identified a correlation with cognitive impairment in PD patients of the Chinese Han population. Additionally, this study is the first to identify a significant difference in pGPNMB levels between MSA, PD, and normal controls. The data provide new evidence supporting the potential role of pGPNMB in the diagnosis and differential diagnosis of Parkinsonism.


Assuntos
Disfunção Cognitiva , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Paralisia Supranuclear Progressiva , Humanos , Doença de Parkinson/diagnóstico , Estudos Retrospectivos , Atrofia de Múltiplos Sistemas/diagnóstico , Paralisia Supranuclear Progressiva/diagnóstico , Disfunção Cognitiva/diagnóstico , Diagnóstico Diferencial , Glicoproteínas de Membrana
12.
J Neurol Sci ; 457: 122896, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38290377

RESUMO

BACKGROUND: Information on the incidence and risk factors of deep vein thrombosis (DVT) in neurodegenerative diseases is limited. We aimed to determine the incidence of DVT among neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Parkinson's disease [PD], multiple system atrophy [MSA], and progressive supranuclear palsy [PSP]-corticobasal syndrome [CBS]) and the risk factors for the development of DVT. METHODS: Overall, 229 hospitalized patients with neurodegenerative diseases (65 patients with ALS, 61 with PD, 53 with MSA, and 50 with PSP-CBS) were included in this study. D-dimer value and ultrasonography of the leg vein were assessed to determine the presence or absence of leg DVT. We compared the DVT incidence among each disease group. To identify the risk factors for DVT, a multivariate analysis was performed. RESULTS: Of 229 patients, 34 had leg DVT; the incidence was significantly higher in patients with PD (38%) than in those with ALS (2%), MSA (5%), or PSP-CBS (4%). Patients with DVT were older, had a smaller waist circumference, had a longer disease duration, and had a high blood pressure (BP) variability. Multivariate analysis revealed that a PD diagnosis and female sex, with a high BP variability were predictive of leg DVT. CONCLUSIONS: Among the neurodegenerative diseases, the DVT incidence was markedly higher in PD than in ALS, MSA, and PSP-CBS. Several risk factors have been identified in patients with leg DVT. Recognition of these risk factors will improve patient care and guide the appropriate use of anticoagulants.


Assuntos
Esclerose Amiotrófica Lateral , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Paralisia Supranuclear Progressiva , Trombose Venosa , Humanos , Feminino , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/epidemiologia , Incidência , Fatores de Risco , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/epidemiologia
13.
Neurosci Lett ; 822: 137642, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38228218

RESUMO

Multiple system atrophy (MSA) is a progressive and sporadic neurodegenerative disorder characterized by the histological appearance of glial cytoplasmic inclusions primarily composed of α-synuclein. Recently, complement-mediated neuroinflammation has been proposed as a key factor in the pathogenesis of numerous neurodegenerative disorders. We conducted immunohistochemical/immunofluorescent assays targeting a number of complements to explore the role of complements in MSA pathogenesis using brain samples from deceased patients and controls. Complement deposition was notably increased in the cerebral vasculature and myelin sheath in the MSA brains. Furthermore, fibrinogen leakage resulting from the disruption of the blood-brain barrier (BBB) was observed, along with the presence of C1q-positive microglia clusters surrounding the MSA brain vessels. These immunohistochemical/immunofluorescent findings suggest that complement activation and BBB disruption play critical roles in MSA progression.


Assuntos
Atrofia de Múltiplos Sistemas , Humanos , Atrofia de Múltiplos Sistemas/patologia , Barreira Hematoencefálica/metabolismo , alfa-Sinucleína/metabolismo , Encéfalo/metabolismo , Microglia/metabolismo , Ativação do Complemento
14.
Rev Neurol (Paris) ; 180(1-2): 79-93, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38216420

RESUMO

Autonomic failure is frequently encountered in synucleinopathies such as multiple system atrophy (MSA), Parkinson's disease (PD), Lewy body disease, and pure autonomic failure (PAF). Cardiovascular autonomic failure affects quality of life and can be life threatening due to the risk of falls and the increased incidence of myocardial infarction, stroke, and heart failure. In PD and PAF, pathogenic involvement is mainly post-ganglionic, while in MSA, the involvement is mainly pre-ganglionic. Cardiovascular tests exploring the autonomic nervous system (ANS) are based on the analysis of continuous, non-invasive recordings of heart rate and digital blood pressure (BP). They assess facets of sympathetic and parasympathetic activities and provide indications on the integrity of the baroreflex arc. The tilt test is widely used in clinical practice. It can be combined with catecholamine level measurement and analysis of baroreflex activity and cardiac variability for a detailed analysis of cardiovascular damage. MIBG myocardial scintigraphy is the most sensitive test for early detection of autonomic dysfunction. It provides a useful measure of post-ganglionic sympathetic fiber integrity and function and is therefore an effective tool for distinguishing PD from other parkinsonian syndromes such as MSA. Autonomic cardiovascular investigations differentiate between certain parkinsonian syndromes that would otherwise be difficult to segregate, particularly in the early stages of the disease. Exploring autonomic failure by gathering information about residual sympathetic tone, low plasma norepinephrine levels, and supine hypertension can guide therapeutic management of orthostatic hypotension (OH).


Assuntos
Doenças do Sistema Nervoso Autônomo , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Insuficiência Autonômica Pura , Sinucleinopatias , Humanos , Insuficiência Autonômica Pura/complicações , Insuficiência Autonômica Pura/diagnóstico , Insuficiência Autonômica Pura/terapia , Sinucleinopatias/complicações , Qualidade de Vida , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/terapia , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/terapia , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia
15.
Acta Neuropathol Commun ; 12(1): 1, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167307

RESUMO

The growing recognition of a dichotomous role of astrocytes in neurodegenerative processes has heightened the need for unraveling distinct astrocytic subtypes in neurological disorders. In multiple system atrophy (MSA), a rare, rapidly progressing atypical Parkinsonian disease characterized by increased astrocyte reactivity. However the specific contribution of astrocyte subtypes to neuropathology remains elusive. Hence, we first set out to profile glial fibrillary acidic protein levels in astrocytes across the human post mortem motor cortex, putamen, and substantia nigra of MSA patients and observed an overall profound astrocytic response. Matching the post mortem human findings, a similar astrocytic phenotype was present in a transgenic MSA mouse model. Notably, MSA mice exhibited a decreased expression of the glutamate transporter 1 and glutamate aspartate transporter in the basal ganglia, but not the motor cortex. We developed an optimized astrocyte isolation protocol based on magnetic-activated cell sorting via ATPase Na+/K+ transporting subunit beta 2 and profiled the transcriptomic landscape of striatal and cortical astrocytes in transgenic MSA mice. The gene expression profile of astrocytes in the motor cortex displayed an anti-inflammatory signature with increased oligodendroglial and pro-myelinogenic expression pattern. In contrast, striatal astrocytes were defined by elevated pro-inflammatory transcripts accompanied by dysregulated genes involved in homeostatic functions for lipid and calcium metabolism. These findings provide new insights into a region-dependent, dichotomous astrocytic response-potentially beneficial in the cortex and harmful in the striatum-in MSA suggesting a differential role of astrocytes in MSA-related neurodegenerative processes.


Assuntos
Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Humanos , Camundongos , Animais , Atrofia de Múltiplos Sistemas/patologia , Astrócitos/metabolismo , Transtornos Parkinsonianos/patologia , Corpo Estriado/metabolismo , Substância Negra/metabolismo , Camundongos Transgênicos
16.
Mov Disord Clin Pract ; 11(1): 45-52, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38291837

RESUMO

BACKGROUND: RFC1-related disorder (RFC1/CANVAS) shares clinical features with other late-onset ataxias, such as spinocerebellar ataxias (SCA) and multiple system atrophy cerebellar type (MSA-C). Thinning of cranial nerves V (CNV) and VIII (CNVIII) has been reported in magnetic resonance imaging (MRI) scans of RFC1/CANVAS, but its specificity remains unclear. OBJECTIVES: To assess the usefulness of CNV and CNVIII thinning to differentiate RFC1/CANVAS from SCA and MSA-C. METHODS: Seventeen individuals with RFC1/CANVAS, 57 with SCA (types 2, 3 and 6), 11 with MSA-C and 15 healthy controls were enrolled. The Balanced Fast Field Echo sequence was used for assessment of cranial nerves. Images were reviewed by a neuroradiologist, who classified these nerves as atrophic or normal, and subsequently the CNV was segmented manually by an experienced neurologist. Both assessments were blinded to patient and clinical data. Non-parametric tests were used to assess between-group comparisons. RESULTS: Atrophy of CNV and CNVIII, both alone and in combination, was significantly more frequent in the RFC1/CANVAS group than in healthy controls and all other ataxia groups. Atrophy of CNV had the highest sensitivity (82%) and combined CNV and CNVIII atrophy had the best specificity (92%) for diagnosing RFC1/CANVAS. In the quantitative analyses, CNV was significantly thinner in the RFC1/CANVAS group relative to all other groups. The cutoff CNV diameter that best identified RFC1/CANVAS was ≤2.2 mm (AUC = 0.91; sensitivity 88.2%, specificity 95.6%). CONCLUSION: MRI evaluation of CNV and CNVIII using a dedicated sequence is an easy-to-use tool that helps to distinguish RFC1/CANVAS from SCA and MSA-C.


Assuntos
Atrofia de Múltiplos Sistemas , Ataxias Espinocerebelares , Humanos , Ataxia/patologia , Atrofia/patologia , Cerebelo/patologia , Nervos Cranianos/patologia , Atrofia de Múltiplos Sistemas/diagnóstico , Ataxias Espinocerebelares/diagnóstico
17.
Neurol Sci ; 45(1): 309-313, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37752324

RESUMO

BACKGROUND: Multiple system atrophy (MSA) is considered a primarily sporadic neurodegenerative disease, but the role of genetic is poorly understood. CASE: We present a female patient of Moroccan origin who developed a rapidly progressive non-levodopa responsive parkinsonism, gait and balance problems, and dysautonomia including severe bulbar symptoms. She was diagnosed with MSA Parkinsonian-type (MSA-P) and suddenly died at night at 58 years of age. Reduced striatal DAT-SPECT, putaminal hyperintensity on T2-MRI, and hypometabolism with FDG-PET were present. Genetic testing documented a G2019S mutation in the LRRK2 gene. A skin biopsy was obtained and used to perform alpha-synuclein RT-QuIC, which was negative, and immunohistochemical analysis, which demonstrated abnormal alpha-synuclein deposits in cutaneous nerves. Elevated blood neurofilament light chain levels were also documented. CONCLUSIONS: LRRK2 mutations are the most common cause of monogenic Parkinson's disease (PD) and G2019S is the most frequent variant. Our patient presented with biological, clinical, and radiological features of MSA, but genetic testing revealed a G2019S LRRK2 mutation, which has been previously reported only in one other case of pathologically proven MSA but with mild progression. In our patient, post-mortem confirmation could not be performed, but RT-QuIC and immunohistochemical findings on skin biopsy support the diagnosis of MSA. G2019S LRRK2 may be linked to an increased risk of MSA. Cases of atypical parkinsonism with rapid disease course should be screened for PD-related genes especially in populations with a high prevalence of mutations in known genes.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Feminino , alfa-Sinucleína/genética , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética
18.
Mov Disord ; 39(2): 380-390, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37986699

RESUMO

BACKGROUND: Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood. OBJECTIVE: We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates. METHODS: This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy-related pathology, argyrophilic grain disease, age-related τ astrogliopathy, transactive DNA-binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact. RESULTS: The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was <2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction. CONCLUSIONS: The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α-synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Atrofia de Múltiplos Sistemas , Humanos , Idoso , Idoso de 80 Anos ou mais , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/epidemiologia , Atrofia de Múltiplos Sistemas/diagnóstico , Doença de Alzheimer/metabolismo , Encéfalo/patologia , Comorbidade , Disfunção Cognitiva/complicações
19.
Mov Disord ; 39(1): 130-140, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38013497

RESUMO

BACKGROUND: Multiple system atrophy (MSA) clinically manifests with either predominant nigrostriatal or cerebellopontine degeneration. This corresponds to two different phenotypes, one with predominant Parkinson's symptoms (MSA-P [multiple system atrophy-parkinsonian subtype]) and one with predominant cerebellar deficits (MSA-C [multiple system atrophy-cerebellar subtype]). Both nigrostriatal and cerebellar degeneration can lead to impaired dexterity, which is a frequent cause of disability in MSA. OBJECTIVE: The aim was to disentangle the contribution of nigrostriatal and cerebellar degeneration to impaired dexterity in both subtypes of MSA. METHODS: We thus investigated nigrostriatal and cerebellopontine integrity using diffusion microstructure imaging in 47 patients with MSA-P and 17 patients with MSA-C compared to 31 healthy controls (HC). Dexterity was assessed using the 9-Hole Peg Board (9HPB) performance. RESULTS: Nigrostriatal degeneration, represented by the loss of cells and neurites, leading to a larger free-fluid compartment, was present in MSA-P and MSA-C when compared to HCs. Whereas no intergroup differences were observed between the MSAs in the substantia nigra, MSA-P showed more pronounced putaminal degeneration than MSA-C. In contrast, a cerebellopontine axonal degeneration was observed in MSA-P and MSA-C, with stronger effects in MSA-C. Interestingly, the degeneration of cerebellopontine fibers is associated with impaired dexterity in both subtypes, whereas no association was observed with nigrostriatal degeneration. CONCLUSION: Cerebellar dysfunction contributes to impaired dexterity not only in MSA-C but also in MSA-P and may be a promising biomarker for disease staging. In contrast, no significant association was observed with nigrostriatal dysfunction. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Substância Negra/diagnóstico por imagem
20.
Mov Disord ; 39(1): 119-129, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37933745

RESUMO

OBJECTIVE: To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA). BACKGROUND: Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion. METHODS: Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion. RESULTS: Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively. CONCLUSIONS: Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Atrofia/patologia , Diagnóstico Diferencial
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