MRl and MRS hints for the differentiation of cerebellar multiple system atrophy from spinocerebellar ataxia type II.

Background and objectives: The differentiation of spinocerebellar ataxia type II (SCA 2) from idiopathic multiple systemic atrophy of the cerebellar type (MSA-C) is often difficult in patients with cerebellar ataxia when molecular testing is not available. Besides genetic testing, magnetic resonance imagining (MRI) and magnetic resonance spectroscopy (MRS) prove to be beneficial. Nevertheless, the characteristics observed through radiology change as the disease advances. Different radiological criteria may be needed across different stages of the disease. This study aimed to assess the radiological characteristics of MSA-C or SCA 2 patients across various stages of the disease and to identify potential distinguishing factors. Methods: Between January 2000 and January 2020, a total of 390 patients, diagnosed with probable MSA-C according to the second consensus on MSA (317 cases) or with molecularly confirmed SCA 2 (73 cases), who had undergone at least one brain MRI and MRS targeting the cerebellar hemispheres, were enrolled in the study. The clinical parameters and neuroimaging features between these two diseases were compared and analyzed. Results: A greater occurrence of a pontine hot cross bun sign (HCBS), higher scores on the scale for the assessment and rating of ataxia, and reduced levels of cerebellar N-acetyl aspartate (NAA)/creatine (Cr), and cerebellar choline (Cho)/Cr were found in MSA-C patients as compared with SCA 2 patients at similar disease durations. For the patients with an HCBS, a cerebellar Cho/Cr level of <0.53 was indicative of the potential presence of MSA-C, with significant level of specificity (85.96%). Discussion: Discerning SCA2 from MSA-C using MRI and MRS appears to be plausible at various disease stages.

Prediction of early-wheelchair dependence in multiple system atrophy based on machine learning algorithm: A prospective cohort study.

Objective: The predictive factors for wheelchair dependence in patients with multiple system atrophy (MSA) are unclear. We aimed to explore the predictive factors for early-wheelchair dependence in patients with MSA focusing on clinical features and blood biomarkers. Methods: This is a prospective cohort study. This study included patients diagnosed with MSA between January 2014 and December 2019. At the deadline of October 2021, patients met the diagnosis of probable MSA were included in the analysis. Random forest (RF) was used to establish a predictive model for early-wheelchair dependence. Accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. Results: Altogether, 100 patients with MSA including 49 with wheelchair dependence and 51 without wheelchair dependence were enrolled in the RF model. Baseline plasma neurofilament light chain (NFL) levels were higher in patients with wheelchair dependence than in those without (P = 0.037). According to the Gini index, the five major predictive factors were disease duration, age of onset, Unified MSA Rating Scale (UMSARS)-II score, NFL, and UMSARS-I score, followed by C-reactive protein (CRP) levels, neutrophil-to-lymphocyte ratio (NLR), UMSARS-IV score, symptom onset, orthostatic hypotension, sex, urinary incontinence, and diagnosis subtype. The sensitivity, specificity, accuracy, and AUC of the RF model were 70.82 %, 74.55 %, 72.29 %, and 0.72, respectively. Conclusion: Besides clinical features, baseline features including NFL, CRP, and NLR were potential predictive biomarkers of early-wheelchair dependence in MSA. These findings provide new insights into the trials regarding early intervention in MSA.

Ataxia in a Movement Disorders Outpatient Clinic: a Single-Center Experience in Turkey.

The etiology may not be determined in patients with ataxia despite detailed evaluations. The aim of this study was to investigate the clinical and laboratory characteristics of a large cohort of patients with adult-onset ataxia of different etiologies, particularly, undetermined etiologies despite extensive clinical, genetic, laboratory, electrophysiological, and imaging investigations. The medical records of all patients diagnosed with ataxia of subacute-chronic onset between January 2011 and March 2021 were reviewed retrospectively. The records of patients with symptom onset after 16 years of age were included in the study. In all patients, clinical and demographic findings were noted. Etiologies were classified as acquired, hereditary, degenerative (multiple system atrophy-cerebellar, MSA-C), functional, and undetermined. During the study period, we determined 74 patients with ataxia and 59 (35 males) patients met the study criteria. The age range was 22-87 years. The etiologies were hereditary (n = 19), acquired (n = 14), MSA-C (n = 9), functional (n = 2), and undetermined (n = 15). The patients with hereditary etiologies and undetermined causes were significantly younger at admission and at symptom onset (p = 0.001 and p = 0.000). There was a significant delay until diagnosis in patients with hereditary etiologies compared to other etiologies. In acquired etiologies, axial findings (71.4%) were more prominent whereas extremity and axial findings were more common in patients with hereditary etiologies (83.3%, p = 0.030). There were systemic and radiological indicators such as hearing loss, juvenile cataract, or dentate hyperintensity in certain disorders. Hereditary etiologies are as common as acquired or degenerative etiologies in adults. However, they have an earlier onset and delayed diagnosis. Therefore, we should recognize the extracerebellar neurological, systemic, and neuroimaging findings.

Cognition in Patients With Multiple System Atrophy (MSA) and Its Neuroimaging Correlation: A Prospective Case-Control Study.

Objective Cognition has been reported to be involved in patients with multiple system atrophy (MSA), although initially it was considered an exclusion in the diagnosis of MSA. We assessed cognition in these patients and compared it with age and education matched healthy controls and correlated with the gray matter volume using voxel-based morphometry (VBM). Materials and methods This was a prospective, case-control, single-center study. Thirty patients with MSA (20 MSA-C (cerebellar variant) and 10 MSA-P (Parkinsonian variant)) and 25 age- and educational level-matched healthy controls were included. All the patients and controls underwent detailed neuropsychological tests and MRI brain. A battery of neuropsychological tests like Stroop test, digit span forward and backward, digit symbol substitution time test, animal naming test, color trail test and auditory verbal learning test were used to assess the various domain of cognition, which include mainly attention, executive function, memory, new learning, mental and motor speed. The gray matter volume was determined using VBM and correlated with neuropsychological scores. Results Attention, execution, verbal and visual memory, verbal fluency, and new learning were impaired in patients with MSA. MSA-P had more impairment in motor and mental speed, working memory, executive functions, and focused attention compared to MSA-C. Patients with MSA-C had more impairment in new learning, immediate recall, verbal fluency, and sustained attention compared to MSA-P. However, it was not statistically significant. There was a significant correlation between the various cognitive domains and atrophy of frontotemporal cortical areas, insula, caudate, thalamus, and cerebellum. Conclusion Cognition is impaired in patients with MSA-C and MSA-P and is likely due to the neurodegenerative process involving the cortical and subcortical structures. Long-term follow-up studies are required to find out the progression of these cognitive changes.

Differential value of external anal- and urethral-sphincter electromyography in multiple system atrophy cerebellar type and spinocerebellar ataxias.

OBJECTIVE: Clinically differentiating multiple system atrophy cerebellar type (MSA-C) and spinocerebellar ataxias (SCAs) is challenging, especially at early disease stages, because of their similarities in clinical manifestation and imaging results. The purpose of this study was to explore the value of external anal-sphincter electromyography (EAS-EMG) and urethral-sphincter electromyography (US-EMG) for distinguishing between MSA-C and SCAs. METHODS: A total of 51 subjects, including 33 MSA-C and 18 SCAs, were recruited. Average duration and amplitude of motor unit potentials (MUPs), percentage of polyphasic MUPs, amplitude during strong contraction and recruitment pattern during maximal voluntary contraction were recorded and analyzed to identify differential diagnostic results of EAS-EMG and US-EMG for MSA-C and SCAs. RESULTS: Significant differences in average MUP duration, percentage of polyphasic MUPs, and ratio of simple phase and simple-mix phase using EAS-EMG were noted between patients with MSA-C and SCAs. These same parameters also differed significantly between MSA-C and SCAs male patients using US-EMG. CONCLUSIONS: EAS-EMG may serve as a potential method for early differential diagnosis between patients with MSA-C and SCAs. Furthermore, US-EMG could be a supplementary method for males when EAS-EMG is not available.

Quantifying iron deposition in the cerebellar subtype of multiple system atrophy and spinocerebellar ataxia type 6 by quantitative susceptibility mapping.

We used quantitative susceptibility mapping (QSM) to assess the brain iron deposition in 28 patients with the cerebellar subtype of multiple system atrophy (MSA-C), nine patients with spinocerebellar ataxia type 6 (SCA6), and 23 healthy controls. Two reviewers independently measured the mean QSM values in brain structures including the putamen, globus pallidus, caudate nucleus, red nucleus, substantia nigra, and cerebellar dentate nucleus. A receiver operating characteristics (ROC) analysis was performed to assess the diagnostic usefulness of the QSM measurements. The QSM values in the substantia nigra were significantly higher in the MSA-C group compared to the HC group (p = .007). The QSM values in the cerebellar dentate nucleus were significantly higher in MSA-C than those in the SCA6 and HC groups (p < .001), and significantly lower in the SCA6 patients compared to the HCs (p = .027). The QSM values in the cerebellar dentate nucleus were correlated with disease duration in MSA-C, but inversely correlated with disease duration in SCA6. In the ROC analysis, the QSM values in the cerebellar dentate nucleus showed excellent accuracy for differentiating MSA-C from SCA6 (area under curve [AUC], 0.925), and good accuracy for differentiating MSA-C from healthy controls (AUC 0.834). QSM can identify increased susceptibility of the substantia nigra and cerebellar dentate nucleus in MSA-C patients. These results suggest that an increase in iron accumulation in the cerebellar dentate nucleus may be secondary to the neurodegeneration associated with MSA-C.

Genetic and clinical analyses of spinocerebellar ataxia type 8 in mainland China.

BACKGROUND: Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by CTA/CTG repeat expansion in the ATXN8/ATXN8OS gene. METHODS: To analyze the frequency and clinical characteristics of SCA8 patients in mainland China, we combined polymerase chain reaction (PCR) and triplet repeat-primed PCR (TRP-PCR) to detect the CTA/CTG expansion. We studied a cohort of 362 ataxia patients in which the other known causative genes had been previously excluded, from among 1294 index patients. Positive samples were validated by southern blotting. RESULTS: The CTA/CTG expansion was observed in six probands, accounting for approximately 0.46% (6/1294) in all patients, and 1.66% (6/362) in patients without definite molecular diagnosis. Clinically, aside from the typical SCA8 phenotype, some patients carrying the CTA/CTG expansion exhibited the cerebellar form of multisystem atrophy (MSA-C) and ataxia with paroxysmal kinesigenic dyskinesia (PKD). CONCLUSION: For the first time, we described the PKD phenotype in association with CTA/CTG expansion, suggesting that CTA/CTG expansion might play a role in the pathogenesis of paroxysmal dyskinesia symptoms.

Serum neurofilament light is increased in multiple system atrophy of cerebellar type and in repeat-expansion spinocerebellar ataxias: a pilot study.

Blood biomarkers in degenerative ataxias are still largely missing. Here, we aimed to provide piloting proof-of-concept that serum Neurofilament light (NfL) could offer a promising peripheral blood biomarker in degenerative ataxias. Specifically, as a marker of neuronal damage, NfL might (1) help to differentiate multiple system atrophy of cerebellar type (MSA-C) from sporadic adult-onset ataxia (SAOA), and (2) show increases in repeat-expansion spinocerebellar ataxias (SCAs) which might be amenable to treatment in the future. To explore these two hypotheses, we measured serum NfL levels by single-molecule array (Simoa) technique in 115 subjects, comprising patients with MSA-C (n = 25), SAOA (n = 25), the most frequent repeat-expansion SCAs (SCA 1, 2, 3 and 6) (n = 20), and age-matched controls (n = 45). Compared to controls, NfL was significantly increased in MSA-C, with levels significantly higher than in SAOA (AUC = 0.74 (0.59-0.89), mean and 95% confidence interval, p = .004). NfL was also significantly increased in SCA patients as compared to controls (AUC = 0.91 (0.81-1.00), p < .001), including NfL increases in SCA1 and SCA3. These findings provide first proof-of-concept that NfL might provide a promising peripheral biomarker in degenerative ataxias, e.g. supporting the differentiation of MSA-C from SAOA, and indicating neuronal damage in repeat-expansion SCAs.

Does the Type of Multisystem Atrophy, Parkinsonism, or Cerebellar Ataxia Impact on the Nature of Sleep Disorders?

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by a combination of autonomic failure, parkinsonism, and/or cerebellar ataxia. The cause of MSA is unknown, but neuropathologically the disease is characterized by widespread α-synuclein-positive glial cytoplasmic inclusions and striatonigral and/or olivopontocerebellar neurodegeneration. Two motor phenotypes have been clinically identified: parkinsonian (MSA-P) and cerebellar (MSA-C). In order to elucidate if in addition to the motor abnormalities there are other significant differences between these two phenotypes, we performed a review of the studies on sleep disorders in the two MSA subtypes. Substantially, any significant difference in the sleep structure, as well as in the frequency and severity of the sleep disorders, has been found between MSA-P and MSA-C patients. Recent studies clearly showed similarities between the two MSA subtypes in terms of demographic distributions, natural history of the disease, and survivals. These findings suggest that although the dominant clinical presentations differ between MSA-C and MSA-P, a common pathophysiology may underlie both subtypes of MSA.

Early clinical features of patients with progressive supranuclear palsy with predominant cerebellar ataxia.

BACKGROUND: Patients who develop progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) develop cerebellar ataxia as the initial and principal symptom, may be misdiagnosed as having multiple system atrophy with predominant cerebellar features (MSA-C). Therefore, we investigated the clinical signs and symptoms between PSP-C and MSA-C early in their disease course. METHODS: We reviewed the medical records of 15 consecutive patients with pathologically proven PSP-C (4) and MSA-C (11). We recorded the presence or absence of clinical features that developed within 2 years of disease onset. RESULTS: The age at onset of PSP-C patients was older than that of MSA-C patients (p = 0.009). The frequencies of falls were higher in PSP-C patients than in MSA-C patients (p = 0.026). Additionally, the development of supranuclear vertical gaze palsy was higher in PSP-C patients than in MSA-C patients (p = 0.011), whereas the frequency of dysautonomia was lower in PSP-C patients than in MSA-C patients (p = 0.035). CONCLUSIONS: Older onset, early falls, and supranuclear vertical gaze palsy without dysautonomia may predict the diagnosis of PSP-C in patients with late-onset sporadic cerebellar ataxia.

Oligodendroglial alpha-synucleinopathy and MSA-like cardiovascular autonomic failure: experimental evidence.

Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with limited symptomatic treatment options. Discrimination of MSA from other degenerative disorders crucially depends on the presence of early and severe cardiovascular autonomic failure (CAF). We have previously shown that neuropathologic lesions in the central autonomic nuclei similar to the human disease are present in transgenic MSA mice generated by targeted oligodendroglial overexpression of α-syn using the PLP promoter. We here explore whether such lesions result in abnormalities of heart rate variability (HRV) and circadian rhythmicity which are typically impaired in MSA patients. HRV analysis was performed in five month old transgenic PLP-α-syn (tg) MSA mice and age-matched wild type controls. Decreased HRV and alterations in the circadian rhythmicity were detected in the tg MSA group. The number of choline-acetyltransferase-immunoreactive neurons in the nucleus ambiguus was significantly decreased in the tg group, whereas the levels of arginine-vasopressin neurons in the suprachiasmatic and paraventricular nucleus were not affected. Our finding of impaired HRV and circadian rhythmicity in tg MSA mice associated with degeneration of the nucleus ambiguus suggests that a cardinal non-motor feature of human MSA can be reproduced in the mouse model strengthening its role as a valuable testbed for studying selective vulnerability and assessing translational therapies.