Differentiation of multiple system atrophy subtypes by gray matter atrophy.

The prognostic impact of dysphagia in multiple system atrophy (MSA) remains controversial. This study aimed to investigate the relationship between dysphagia severity and survival in MSA and to elucidate whether this impact differs between MSA-cerebellar ataxia (MSA-C) and MSA-parkinsonism (MSA-P). This retrospective study included 297 patients with MSA: 251 met criteria for clinically established MSA and 46 for clinically probable MSA. Among them, 171 had MSA-C and 126 had MSA-P. We evaluated symptomatic dysphagia within 3years of onset and quantified dysphagia severity using the Hyodo score (0 to 12) through fibreoptic endoscopic evaluation of swallowing (FEES) and clinical features, including autonomic dysfunction and vocal cord paralysis. Patients were followed up until death or tracheostomy, and survival factors were analysed using the log-rank test and multivariate Cox proportional hazards model. Ninety patients developed symptomatic dysphagia within 3years of onset, and 75 were evaluated for dysphagia severity using FEES. Survival from onset was shorter in patients with dysphagia within 3years compared to those without (median: 4.2years vs. 7.3years; p < 0.001). Symptomatic dysphagia within 3years of onset was an independent predictor of shorter survival in the multivariate Cox analysis. While the Hyodo score was higher in MSA-P than in MSA-C patients (p = 0.048), the Hyodo score was associated with survival in both MSA-C and MSA-P patients (log-rank p < 0.001 and p = 0.046, respectively). Symptomatic dysphagia within 3years of onset predicts shorter survival in MSA-C and MSA-P patients.

Differential patterns of central synucleinopathy and catecholaminergic abnormalities in Lewy body diseases and multiple system atrophy.

Cerebral small vessel disease (CSVD) has not been systematically studied in patients with multiple system atrophy (MSA). We sought to explore whether MSA patients suffer from a heavier CSVD burden relative to healthy individuals and whether CSVD has a relationship with motor, cognitive, and emotional dysfunction in patients with MSA. This study consecutively recruited 190 MSA patients and 190 matched healthy controls whose overall CSVD burden and single CSVD imaging markers (including white matter hyperintensity (WMH), microbleeds, lacunes, and enlarged perivascular spaces (EPVS)) were measured. Of the MSA patients, 118 completed multi-dimensional outcome assessments. Spearman's correlations and multivariable linear regressions were performed. We observed a greater burden of overall CSVD, WMH, and EPVS in MSA patients compared with controls, but not for microbleeds and lacunes. Motor dysfunction and cognitive impairment were significantly worse in subjects with severe CSVD than those with none-to-mild CSVD. In patients with MSA, the severity of CSVD burden was positively associated with motor impairments as measured by the Unified Multiple System Atrophy Rating Scale-II (β= 2.430, p = 0.039) and Scale for the Assessment and Rating of Ataxia (β= 1.882, p = 0.015). Of CSVD imaging markers, different associations with MSA outcomes were displayed. WMH was associated with motor, cognitive, and emotional deficits, while the EPVS in the centrum semiovale, basal ganglia, and hippocampus regions was correlated only with motor severity, anxiety, and cognition, respectively. Similar findings were noted in MSA-cerebellar and MSA-parkinsonian patients. Concomitant CSVD may be correlated with worse multi-dimensional dysfunction in patients with MSA.

In this multiparametric, cross-sectional study, we aimed to investigate cognitive impairment and brain structural changes in patients with multiple system atrophy (MSA)-parkinsonian variant (MSA-p). Twenty-six MSA-p patients and 19 controls underwent clinical and neuropsychological evaluation and 1.5T brain MRI scan. Cortical thickness measures and volumes of deep grey matter structures were obtained. A regression analysis correlated MRI metrics with clinical features in MSA-p patients. Almost 46% of MSA-p patients showed a mild cognitive impairment involving mainly attentive-executive and memory domains. Apathy and depression were found in half of MSA-p patients. MSA-p patients showed significant cortical thinning of fronto-temporal-parietal regions and atrophy of periaqueductal grey matter, left cerebellar hemisphere, left pallidum and bilateral putamen, compared to controls. Cortical thinning in temporal regions correlated with global cognitive status and memory impairment. Grey matter cerebellar atrophy correlated with motor deficits. MSA-p patients showed a multidomain cognitive impairment with a prominent cortical damage in anterior more than posterior brain regions and grey matter volume reduction in subcortical structures. Cortical and subcortical structural changes might lead to cognitive dysfunction in MSA-p.

Multiple system atrophy (MSA) is a neurodegenerative disorder that presents as parkinsonism, cerebellar ataxia, and autonomic dysfunction. Magnetic resonance imaging (MRI) findings of MSA are reported to be the atrophy of the putamen/pons/cerebellum, hot cross bun sign, and bright middle cerebellar peduncle (MCP) sign. Here, we assessed the sensitivity of detecting the bright MCP sign in patients with MSA cerebellar variant (MSA-C) using a double inversion recovery (DIR) procedure, comparing it to the sensitivity of detection by T2-weighted image (T2WI) and fluid-attenuated inversion recovery (FLAIR) sequences on conventional MRI. We evaluated 6 MSA-C patients and 6 control patients (multiple sclerosis, neuromyelitis optica, and spinocerebellar atrophy). Characteristics of all the patients were collected, and MRI was analyzed. Two neurologists independently evaluated the visualization of the bright MCP sign using a 4-point visual grade from Grade 0 to Grade 3. Differences in grade between DIR and T2WI or FLAIR were statistically analyzed. Also, as a quantitative analysis, the signal intensity of the MCP lesion was compared with that of the ipsilateral thalamus, and the MCP/thalamus ratio was evaluated. As a result, DIR more sensitively showed the bright MCP signs of MSA-C patients than T2WI or FLAIR. Also, the bright MCP sign deteriorated and expanded over time in the cases we followed with MRI. We also evaluated hot cross bun sign in the pons, but the hot cross bun sign in MSA-C patients was not significantly different between the DIR and conventional MRI sequences. The DIR procedure can be a more sensitive method for detecting the involvement of MCP lesions in MSA-C.

Objective To investigate the resting-state functional connectivity of the two hemispheres between multiple system atrophy (Parkinsonian type, MSA-P) and Parkinson′s disease (PD). Methods A total of 25 MSA-P, 29 PD patients and 29 well-matched healthy controls recruited in the Nanjing Brain Hospital Affiliated to Nanjing Medical University from June 2013 to December 2015 were scanned with resting-state functional magnetic resonance imaging for voxel mirrored homotopic correlation (VMHC) analysis. The Mini Mental State Examination, Montreal Cognitive Assessment, Frontal Assessment Battery and Unified Parkinson′s Disease Rating Scale-Ⅲ (UPDRS-Ⅲ) were used to assess the clinical symptom. Then the relationship between the change of VMHC values and severity of clinical symptoms was investigated. Results Compared with healthy controls, MSA-P and PD patients both showed decreased VMHC in bilateral cerebellum posterior lobe, precuneus gyrus, middle temporal gyrus, and postcentral gyrus. Compared with PD or healthy controls, MSA-P patients exhibited lower VMHC in bilateral putamen. Significant negative correlation between VMHC values of putamen and UPDRS-Ⅲ scores was found in MSA-P patients (r=-0.607, P=0.001). Conclusion These functional changes suggest that the abnormal interhemispheric synchrony probably plays an important role in pathophysiology of both MSA-P and PD, and abnormal VMHC values in putamen of MSA-P may be helpful in differentiating MSA-P from PD. Key words: Multiple system atrophy; Parkinson disease; Magnetic resonance imaging; Voxel mirrored homotopic correlation

Prodromal multiple system atrophy (MSA) has been characterized mainly by retrospective chart reviews. Direct observation and tracking of prodromal markers in MSA have been very limitedObjective:To report the baseline characteristics and evolution of prodromal markers of MSA as they were prospectively measured in patients with idiopathic/isolated REM sleep behavior disorder (iRBD)Methods:Patients with iRBD were evaluated as part of a comprehensive protocol repeated annually. The protocol included assessment of motor, sleep, psychiatric, and autonomic symptoms supplemented by motor examination, quantitative motor testing, neuropsychological examination, orthostatic blood pressure measurement, and tests of olfaction and color vision. Patients who eventually developed MSA were described and compared with those who phenoconverted to Lewy body disease (Parkinson's disease and dementia with Lewy bodies). Of 67 phenocoverters, 4 developed MSA-P and 63 developed Lewy body disease. An additional 2 MSA-C patients were seen at baseline, already with cerebellar signs. Compared to those with Lewy body disease, those with MSA-P were younger, had less severe loss of tonic REM sleep atonia, more insomnia symptoms, and better olfaction. Clinically-evident autonomic dysfunction was not invariable in prodromal stages, often developing proximate to or after motor phenoconversion. Of the autonomic symptoms, genitourinary dysfunction was the first to develop in all cases. Olfaction and cognition remained normal throughout the prodromal and clinical disease course, in clear contrast to patients with Lewy body disease. Prodromal MSA progresses rapidly, often without substantial autonomic dysfunction, and with preserved olfaction and cognition throughout its prodromal course.

Multiple system atrophy, cerebellar type (MSA-C) sometimes shows asymmetrical findings on magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT). To assess the frequency and clinical significance of asymmetrical MRI and (99m)Tc-ethyl cysteinate dimer perfusion (ECD) SPECT findings of the cerebellum, middle cerebellar peduncle (MCP), and pons in MSA-C patients. We retrospectively reviewed 28 patients with MSA-C who underwent MRI and (99m)Tc-ECD SPECT and evaluated laterality of atrophy and signal changes on MRI, and laterality of perfusion on (99m)Tc-ECD SPECT transversely and longitudinally. Laterality was identified for 64%, 61%, and 21% of atrophy in the cerebellum, MCP, and pons, respectively, on MRI and for 71% of atrophy in the cerebellum on perfusion SPECT. Concerning comparisons between the latest MRI and SPECT findings, laterality of cerebellar/MCP atrophy on MRI and decreased cerebellar perfusion on SPECT was matched in 57%, mismatched in 11%, and absent in 25% of patients. On past images, MRI and SPECT showed matched laterality in 33%, mismatched laterality in 27%, no laterality in 13%, and SPECT precedent laterality in 27% of patients. Including the latest and past images, asymmetrical changes were observed in 75% of patients. We could not identify any correlation between laterality of image findings and cerebellar symptoms in most patients. Asymmetrical changes on MRI and perfusion SPECT are common in MSA-C patients. Perfusion SPECT is useful for diagnosing MSA-C in the early stages from a functional perspective.

Clinical studies in patients with MSA document facial motor abnormalities, but no studies have objectively assessed blinking abnormalities in this condition. We enrolled patients diagnosed as having clinically probable MSA, 20 patients of the parkinsonian phenotype (MSA-P) and 10 patients of the cerebellar phenotype (MSA-C) and 20 healthy controls (HCs). Blinking was recorded with a three-dimensional optoelectronic motion system equipped with dedicated software for data analysis. During voluntary blinking, the interphase pause duration between the closing and opening phases lasted longer in MSA-P and in MSA-C patients than in HCs; the opening phase had increased duration and reduced peak velocity in MSA-P. During reflex blinking, the opening blink phase also lasted longer in MSA-P patients than in HCs. During spontaneous blinking, the rate and kinematics of the closing and opening blinking phases were lower in MSA-P and in MSA-C patients than in HCs. Blink reflex recovery was higher in patients than in HCs. No difference was found between MSA-P patients receiving or not receiving dopaminergic medication. Our objective assessment of upper facial movement documents abnormalities of voluntary, spontaneous, and reflex blinking in patients with MSA-P and MSA-C, reflecting cortical-basal ganglia and brainstem dysfunction.

1-P-E-6. Saccade abnormalities in multiple system atrophy – Comparison between MSA-C and MSA-P

The aim of this study was to demonstrate circadian blood pressure trends and to evaluate autonomic function in patients with spinocerebellar degeneration (SCD). We performed 24-h ambulatory blood pressure monitoring (ABPM) on 10 patients from seven Japanese families with spinocerebellar ataxia type 6 (SCA6), 10 patients with idiopathic cerebellar ataxia (ICA), eight patients with multiple system atrophy (MSA) suffering from cerebellar MSA (MSA-C), and 12 age- and gender-matched normal subjects. We also evaluated autonomic function in these patients. Three SCA6 patients (30%), six ICA patients (60%), eight MSA-C patients (100%) and four normal subjects (33%) were non-dippers. The nocturnal reduction rate of blood pressure in MSA patients was significantly less than those in normal subjects, SCA6 patients and ICA patients. There were no abnormal findings in any patient with SCA6 in autonomic function tests. All dipper patients exhibited normal findings on autonomic function tests. This is the first report of ABPM in patients with SCD. Blunted reduction of nocturnal blood pressure may be associated with autonomic dysfunction in patients with SCD.

Autonomic dysfunction in multiple system atrophy (MSA) comprises cardinal symptoms of orthostatic hypotension (OH) and urinary incontinence. Additionally, cardiovagal and sudomotor abnormalities can be present. Previous studies compared hand skin temperature and its response to cooling in subjects with probable MSA and Parkinson's disease (PD). Significant differences were found indicating that disturbed thermoregulation belongs to MSA autonomic features and could be helpful in differentiation of MSA from PD. The objective of this study was to improve our knowledge about impaired thermoregulation of distal extremities in MSA with parkinsonian features (MSA-P) and PD and to assess the possible interrelations for the different subtypes of autonomic dysfunction in a large cohort of MSA-P, PD and control patients. The patients underwent a standard cooling-rewarming procedure, termed ice test (IT). Electroneurography, heart rate variability, sympathetic skin response and orthostatic tests were performed for the subdivision of the patients. The prevalence of pathological IT was slightly increased in MSA compared with PD and control groups. The presence of pathological IT was related with older patient's age in PD and control groups significantly (p<0.05). This relation was absent for the MSA patients, who themselves were significantly younger (p=0.001). Significant association between the presence of pathological IT and OH was determined (p<0.001). Defective thermoregulation of distal extremities seems to be more severe in the MSA patients. The dysfunction of preganglionic sympathetic neurons might be involved in impaired response to cooling for MSA. The results suggest pathophysiological affinity of impaired sympathetic neurovascular regulation between pathological IT and OH.

For this observational study, we evaluated the clinical profile of Parkinsonian features in multiple system atrophy (MSA), as there is no clarity about the specifics of these features in this disease compared to progressive supranuclear palsy (PSP) and Parkinson's disease (PD). Here, we selected 57 patients with MSA based on standard criteria and grouped them into two categories - Parkinsonian variant of MSA (MSA-P) and cerebellar variant of MSA (MSA-C). However, researchers did not distinguish among patients based on the nature of extrapyramidal syndrome or levodopa responsiveness. Then, we examined the patients at the time of their first visit to outpatient clinics or indoor wards and recorded and analyzed the specific extrapyramidal features or their variations. The extrapyramidal features including levodopa responsiveness were highly variable among MSA-C as well as MSA-P patients. A subset of patients presented with features resembling PSP (symmetry [56.1%], axial rigidity [52.6%], backward falls [28.1%], and down-gaze restriction [17.5%]), while others presented with features resembling PD (asymmetry [43.9%], tremors [71.9%], and peripheral rigidity [40.4%]). After grouping patients based on predominant extrapyramidal features, 36.8% of patients had PD-like, 19.3% had PSP-like, and 43.9 % had mixed presentation. Moreover, 86% of patients had a perceptible levodopa response, including a sustained response for more than six months in 64% of patients. Extrapyramidal features in MSA patients may be PD-like, PSP-like, or mixed. Moreover, an initial presentation resembling PSP or PD may be deceptive and one must follow it up for MSA.

Multiple system atrophy (MSA) can clinically be divided into the cerebellar (MSA-C) and the parkinsonian (MSA-P) variant. However, till now, it is unknown whether autonomic dysfunction in these two entities differs regarding severity and profile. We compared the pattern of autonomic dysfunction in 12 patients with MSA-C and 26 with MSA-P in comparison with 27 age- and sex-matched healthy controls using a standard battery of autonomic function tests and a structured anamnesis of the autonomic nervous system. MSA-P patients complained significantly more often about the symptoms of autonomic dysfunctions than MSA-C patients, especially regarding vasomotor, secretomotor, and gastrointestinal subsystems. However, regarding cardiovascular, sudomotor pupil, urogenital, and sleep subsystems, there were no significant quantitative or qualitative differences as analyzed by autonomic anamnesis and testing. Our results suggest that there are only minor differences in the pattern of autonomic dysfunction between the two clinical MSA phenotypes.

Objective: To analyze the PET/CT imaging features of fluoride 18F-fluorodeoxyglucose (18F-FDG) in patients with various types of Parkinson's syndrome (PS), and to establish a "diagnostic tree" model of 18F-FDG PET/CT for PS. Methods: Data of patients with Parkinson's disease (PD), patients with multiple system atrophy cerebellar type (MSA-C), and patients with multiple system atrophy Parkinson's type (MSA-P)admitted to the Neurology Department of Huashan Hospital affiliated to Fudan University from January 2019 to December 2021. 18F-FDG PET/CT examination was conducted in all patients. Clinical and follow-up data was collected to determine clinical diagnosis. The specific patterns of brain glucose metabolism in patients with various types of Parkinsonism were observed and their utility in the differential diagnosis of the disease was analyzed. 18F-FDG PET/CT imaging"diagnostic tree"model was established and its value in the differential diagnosis of Parkinsonism was verified. Results: A total of 320 patients, 187 males and 133 females, aged (62±9) years, were enrolled in our study, including 80 PD, 90 PSP, 114 MSA-C and 36 MSA-P patients. The differential diagnostic features of cerebral glucose metabolism of Parkinsonism were as follows: the metabolism of putamen increased in PD patients, the metabolism of caudate nucleus, thalamus, midbrain, and frontal lobe decreased in PSP patients, the metabolism of cerebellum decreased in MSA-C patients, and the metabolism of putamen and cerebellum decreased in MSA-P patients. The sensitivity and specificity of the"diagnostic tree"model are 88.75% and 91.25% for PD diagnosis, 54.44% and 96.96% for PSP diagnosis, 87.72% and 86.41% for MSA-C diagnosis, and 55.56% and 91.55% for MSA-P diagnosis, respectively. It could correctly classify 75%(240/320) of patients. Conclusions: Characteristic metabolism patterns of brain in 18F-FDG PET/CT imaging is significant for the differential diagnosis of PD, PSP, MSA-C and MSA-P. The"diagnostic tree"model is valuable for clinical diagnosis.