[Neuropathology of the Neurodegenerative Diseases].

A definite diagnosis of neurodegenerative diseases is required for neuropathological examination during an autopsy. Each neurodegenerative disease has specific vulnerable regions and affected systems (system degeneration), and is typified by an accumulation of abnormal protein with the formation of characteristic morphological aggregates in the nerve and glial cells, called proteinopathy. The most common neurodegenerative diseases are tauopathy, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD); α-synucleinopathy, including multiple system atrophy (MSA); and TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). PSP and CBD show characteristic tau-positive astrocytic inclusions known as tufted astrocytes and astrocytic plaques, respectively. PiD shows tau-positive neuronal inclusions termed Pick bodies. MSA is characterized by α-synuclein-positive oligodendroglial inclusions, called glial cytoplasmic inclusions. ALS- and FTLD-TDP show TDP-43-positive neuronal inclusions, such as skein-like and round inclusions. Huntington's disease shows polyglutamine-positive neuronal inclusions, and Creutzfeldt-Jakob disease shows diffuse deposition of granular prions in the neuropil. The atypical proteins in these diseases have abnormal conformational properties. A comprehensive comparison of the clinical findings and neuropathological observations, including neuroanatomy and images acquired during life, is important to improve the sensitivity of clinical diagnosis.

The potential of phosphorylated α-synuclein as a biomarker for the diagnosis and monitoring of multiple system atrophy.

INTRODUCTION: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by the presence of glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-Syn). Accurate diagnosis and monitoring of MSA present significant challenges, which can lead to potential misdiagnosis and inappropriate treatment. Biomarkers play a crucial role in improving the accuracy of MSA diagnosis, and phosphorylated α-synuclein (p-syn) has emerged as a promising biomarker for aiding in diagnosis and disease monitoring. METHODS: A literature search was conducted on PubMed, Scopus, and Google Scholar using specific keywords and MeSH terms without imposing a time limit. Inclusion criteria comprised various study designs including experimental studies, case-control studies, and cohort studies published only in English, while conference abstracts and unpublished sources were excluded. RESULTS: Increased levels of p-syn have been observed in various samples from MSA patients, such as red blood cells, cerebrospinal fluid, oral mucosal cells, skin, and colon biopsies, highlighting their diagnostic potential. The α-Syn RT-QuIC assay has shown sensitivity in diagnosing MSA and tracking its progression. Meta-analyses and multicenter investigations have confirmed the diagnostic value of p-syn in cerebrospinal fluid, demonstrating high specificity and sensitivity in distinguishing MSA from other neurodegenerative diseases. Moreover, combining p-syn with other biomarkers has further improved the diagnostic accuracy of MSA. CONCLUSION: The p-syn stands out as a promising biomarker for MSA. It is found in oligodendrocytes and shows a correlation with disease severity and progression. However, further research and validation studies are necessary to establish p-syn as a reliable biomarker for MSA. If proven, p-syn could significantly contribute to early diagnosis, disease monitoring, and assessing treatment response.

Revisiting the relevance of Hirano bodies in neurodegenerative diseases.

AIMS: Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. METHODS: This cross-sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (n = 91), Lewy body disease (LBD, n = 87), progressive supranuclear palsy (PSP, n = 36), multiple system atrophy (MSA, n = 14) and controls (n = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions. RESULTS: The morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod-shaped HB (CHB), (2) balloon-shaped HB (BHB) and the newly described (3) string-shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP-43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA. CONCLUSIONS: This study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Clinical Characteristics and Outcomes in Young-Onset Multiple System Atrophy.

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.

The Vocal Flutter of Multiple System Atrophy: A Parkinsonian-Type Phenomenon?

BACKGROUND: Early features of multiple system atrophy (MSA) are similar to those in Parkinson's disease (PD), which can challenge differential diagnosis. Identifying clinical markers that help distinguish MSA from forms of parkinsonism is essential to promptly implement the most appropriate management plan. In the context of a thorough neurological evaluation, the presence of a vocal flutter might be considered a potential feature of MSA-parkinsonian type (MSA-P). CASES: This case series describes clinical histories of 3 individuals with MSA-P. In each case, vocal flutter was detected during neurological and motor speech evaluations. It seemed to be a concomitant feature with the constellation of other signs and symptoms that led to the clinical diagnosis. LITERATURE REVIEW: The vocal flutter may be described as pitch and loudness fluctuations during phonation. Different from a vocal tremor, the flutter phenomenon has higher oscillation frequencies. The neuropathological underpinnings of vocal flutter may be related to generalized laryngeal dysfunction that is commonly described in MSA-P. CONCLUSION: Vocal flutter may be a unique speech feature in some individuals who have MSA-P. Future studies using perceptual and acoustic measures of speech are warranted to quantify these observations and directly compare to other MSA variants, PD, and a control group.

[Recent clinical advances in hereditary spinocerebellar degeneration].

Spinocerebellar degeneration (SCD) is a neurodegenerative disorder characterized by cerebellar ataxia and other multisystem manifestations, such as Parkinsonism and pyramidal tract symptoms. No effective treatment is available for SCD. Approximately one-third of the cases of SCD are inherited, and the remaining two-third are sporadic, including multiple system atrophy. This article provides an overview of hereditary SCD, its clinical features, recent treatment advances, biomarkers, role of genomic medicine, and future treatment prospects.

Reliability of the unified multiple system atrophy rating scale using the telephone.

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.

Associations of sleep-related variables with reverse dipping patterns of blood pressure in α-synucleinopathies.

INTRODUCTION: The reverse dipping blood pressure (BP) pattern is very common in α-synucleinopathies. We aimed to explore the associations of sleep-related variables with abnormal BP circadian rhythms in Parkinson's disease (PD) and multiple system atrophy (MSA). METHODS: A total of 126 patients, 76 with PD and 50 with MSA, were included. All participants underwent ambulatory BP monitoring and full-night polysomnography (PSG). We analyzed abnormal dipping patterns and sleep-related parameters, including moderate to severe obstructive sleep apnea (OSA), rapid eye movement behavior disorder (RBD), average oxygen saturation (SaO2%), lowest SaO2%, duration of SaO2% <90%, and apnea-hypopnea index (AHI). Binary logistic regression was performed to explore the associations between paraclinical variables, sleep-related variables, and reverse dipping patterns. RESULTS: Reverse dipping patterns were predominant in patients with PD (58.5 %) and MSA (68.0 %). Patients with MSA had higher AHI, RBD, and lower average SaO2% than those with PD. Taking both diseases together as a whole group of α-synucleinopathies, logistic regression analysis indicates the Hoehn-Yahr stage (odds ratio [OR] = 2.00 for reverse systolic and 2.34 for reverse diastolic dipping patterns), moderate to severe OSA (OR = 2.71 for reverse systolic and 2.53 for reverse diastolic dipping patterns), average SaO2% (OR = 1.35 for reverse systolic dipping patterns), and male sex (OR = 2.70 for reverse diastolic dipping patterns) were independently associated with reverse dipping patterns. CONCLUSIONS: Reverse dipping patterns were common in patients with PD and MSA. Hoehn-Yahr stage, moderate to severe OSA, average SaO2%, and male sex were associated with reverse dipping patterns in α-synucleinopathy.

Putaminal T1/T2-weighted ratio is increased in PSP compared to PD and healthy controls, a multi-cohort study.

INTRODUCTION: Differentiating Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is a common clinical problem. We aimed to apply the T1-/T2-weighted ratio imaging technique, based on standard clinical MRI, to reveal differences in neurodegeneration in three large cohorts. METHODS: Three cohorts, with a total of 405 participants (269 PD, 44 PSP, 38 MSA, 54 controls), were combined and T1/T2-weighted ratio image analyses were carried out. A combination of automatic segmentation and atlas-based ROI were used in this study. The cohorts were combined using the ComBat batch correction procedure. RESULTS: Group differences were found in the putamen (p = 0.040), with higher T1/T2-weighted ratio in this region in PSP compared to PD and healthy controls (p-values 0.010 and 0.007 respectively). Using putaminal T1/T2-weighted ratio for diagnostic separation, a fair performance was found in separating PSP from healthy controls, with an area under the receiver operating characteristic curve of 0.701. CONCLUSION: Different patterns of T1/T2-weighted ratio, reflecting differences in underlying pathophysiology, were found between the groups. Since T1/T2-weighted ratio can be applied to standard clinical MRI sequences to allow more quantitative analyses, this seems to be a promising biomarker for diagnostics and treatment evaluation of parkinsonian disorders for clinical trials.

Stochastic Optical Reconstruction Microscopy Imaging of Multiple System Atrophy Inclusions Suggests Stepwise α-Synuclein Aggregation.

BACKGROUND: The architecture and composition of glial (GCI) and neuronal (NCI) α-synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease. METHODS: Here, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) α-synuclein inclusions in cryopreserved brain sections from MSA patients. RESULTS: STORM revealed a dense cross-linked internal structure of α-synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p-αSyn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process. CONCLUSIONS: These first STORM images of GCI and NCI suggest stepwise α-synuclein aggregation in MSA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Extracellular vesicles contain filamentous alpha-synuclein and facilitate the propagation of Parkinson's pathology.

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.

CSF1R-mediated myeloid cell depletion shifts the ratio of motor cortical excitatory to inhibitory neurons in a multiple system atrophy model.

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.

Support needs of people with Multiple System Atrophy.

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.

Recent Advances in Clinical Trials in Multiple System Atrophy.

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.

Does Spinocerebellar ataxia 27B mimic cerebellar multiple system atrophy?

BACKGROUND: Whether spinocerebellar ataxia 27B (SCA27B) may present as a cerebellar multiple system atrophy (MSA-C) mimic remains undetermined. OBJECTIVES: To assess the prevalence of FGF14 (GAA)≥250 expansions in patients with MSA-C, to compare SCA27B and MSA-C clinical presentation and natural history. METHODS: FGF14 expansion screening combined with longitudinal deep-phenotyping in a prospective cohort of 195 patients with sporadic late-onset cerebellar ataxia. RESULTS: After a mean disease duration of 6.4 years, 111 patients were not meeting criteria for MSA-C while 24 and 60 patients had a final diagnosis of possible and probable MSA-C, respectively. 16 patients carried an FGF14 (GAA)≥250 expansion in the group not meeting MSA-C criteria (14.4%), 3 patients in the possible MSA-C group (12.5%), but none among probable MSA-C cases. SCA27B patients were evolving more slowly than probable MSA-C patients. CONCLUSIONS: FGF14 (GAA)≥250 expansion may account for MSA look-alike cases and should be screened among slow progressors.

Toward the quantification of α-synuclein aggregates with digital seed amplification assays.

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.