Cognitive impairment and structural brain damage in multiple system atrophy-parkinsonian variant.

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) is a rare adult-onset synucleinopathy that can be divided in two subtypes depending on whether the prevalence of its symptoms is more parkinsonian or cerebellar (MSA-P and MSA-C, respectively). The aim of this work is to investigate the structural MRI changes able to discriminate MSA phenotypes. The sample includes 31 MSA patients (15 MSA-C and 16 MSA-P) and 39 healthy controls. Participants underwent a comprehensive motor and neuropsychological battery. MRI data wereacquired with a 3T scanner (MAGNETOM Trio, Siemens, Germany). FreeSurfer was used to obtain volumetric and cortical thickness measures. A Support Vector Machine (SVM) algorithm was used to assess the classification between patients' group using cortical and subcortical structural data. After correction for multiple comparisons, MSA-C patients had greater atrophy than MSA-P in the left cerebellum, whereas MSA-P showed reduced volume bilaterally in the pallidum and putamen. Using deep gray matter volume ratios and mean cortical thickness as features, the SVM algorithm provided a consistent classification between MSA-C and MSA-P patients (balanced accuracy 74.2%, specificity 75.0%, and sensitivity 73.3%). The cerebellum, putamen, thalamus, ventral diencephalon, pallidum, and caudate were the most contributing features to the classification decision (z>3.28; p<.05 [false discovery rate]). MSA-C and MSA-P with similar disease severity and duration have a differential distribution of gray matter atrophy. Although cerebellar atrophy is a clear differentiator between groups, thalamic and basal ganglia structures are also relevant contributors to distinguishing MSA subtypes.

Asthma as a chronic inflammatory disease can be expected to affect central nervous system structures but little is known about subcortical structures in asthma and their potential association with illness-specific outcomes and anxiety. A total of 40 young adults (20 with asthma and 20 gender- and age-matched controls) underwent high-resolution T1-weighted MRI scan, viewed short distressing film clips, and filled in questionnaires about anxious and depressed mood, as well as asthma history, control, and catastrophizing thoughts about asthma, for those with asthma. The structural scans were processed in FSL's FIRST program to delineate subcortical structures of interest: amygdala, hippocampus, putamen, pallidum, caudate nucleus, nucleus accumbens, and thalamus. Findings showed no general reduction insubcortical gray matter volumes in asthma compared to controls. Asthma duration, asthma control, and catastrophizing of asthma and asthma attacks were negatively associated with volumes of putamen and pallidum, and to a weaker extent thalamus and amygdala, while controlling for gender, age, and corticosteroid inhaler use. In addition, stronger anxiety in response to distressing films was associated with lower volume of the pallidum, whereas general anxious and depressed mood was unrelated to subcortical structures. Thus, although there are no subcortical structural differences between young adults with asthma and healthy controls, longer asthma history, suboptimal management, and illness-related anxiety are reflected in lower gray matter volumes of subcortical structures, further emphasizing the importance of maintaining optimal asthma control.

Introduction: This study aimed to use a novel MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, to assess damage of the white matter and gray matter in multiple system atrophy (MSA). Furthermore, this study investigated whether the sT1w/T2w ratio was associated with cognitive impairment in MSA. Methods: The white matter and gray matter sT1w/T2w ratio of 37 MSA patients and 19 healthy controls were measured. Correlation analyses were used to evaluate the relationship between sT1w/T2w ratio values and clinical variables, and a multivariate analysis was used to identify independent factors associated with cognitive impairment in MSA. Results: MSA patients showed a higher white matter sT1w/T2w ratio value than controls (p < 0.001), and the white matter sT1w/T2w ratio value was significantly correlated with the International Cooperative Ataxia Rating Scale score (r = 0.377, p = 0.021) and the Addenbrooke’s cognitive examination III score (r = −0.438, p = 0.007). Cognitively impaired MSA patients had a significantly higher white matter sT1w/T2w ratio value than cognitively preserved MSA patients (p = 0.010), and the multiple logistic regression analysis revealed that the median white matter sT1w/T2w ratio value was independently associated with cognitive impairment in MSA. Conclusion: The sT1w/T2w ratio is sensitive to degenerative changes in the white matter that is associated with cognitive ability in MSA patients.

Recent post-mortem studies reported 22-37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79.7%) were reported to have had normal cognition in life, whereas the remaining 30 (20.3%) developed cognitive impairment. Twelve of them had pure frontal-subcortical dysfunction, defined as the presence of executive dysfunction, impaired processing speed, personality change, disinhibition or stereotypy; six had pure memory impairment; and 12 had both types of impairment. Semi-quantitative analysis of neuronal cytoplasmic inclusions in the hippocampus and parahippocampus revealed a disease duration-related increase in neuronal cytoplasmic inclusions in the dentate gyrus and cornu ammonis regions 1 and 2 of patients with normal cognition. In contrast, such a correlation with disease duration was not found in patients with cognitive impairment. Compared to the patients with normal cognition, patients with memory impairment (pure memory impairment: n = 6; memory impairment + frontal-subcortical dysfunction: n = 12) had more neuronal cytoplasmic inclusions in the dentate gyrus, cornu ammonis regions 1-4 and entorhinal cortex. In the multiple system atrophy mixed pathological subgroup, which equally affects the striatonigral and olivopontocerebellar systems, patients with the same combination of memory impairment developed more neuronal inclusions in the dentate gyrus, cornu ammonis regions 1, 2 and 4, and the subiculum compared to patients with normal cognition. Using patients with normal cognition (n = 18), frontal-subcortical dysfunction (n = 12) and memory impairment + frontal-subcortical dysfunction (n = 18), we further investigated whether neuronal or glial cytoplasmic inclusions in the prefrontal, temporal and cingulate cortices or the underlying white matter might affect cognitive impairment in patients with multiple system atrophy. We also examined topographic correlates of frontal-subcortical dysfunction with other clinical symptoms. Although no differences in neuronal or glial cytoplasmic inclusions were identified between the groups in the regions examined, frontal release signs were found more commonly when patients developed frontal-subcortical dysfunction, indicating the involvement of the frontal-subcortical circuit in the pathogenesis of frontal-subcortical dysfunction. Here, investigating cognitive impairment in the largest number of pathologically proven multiple system atrophy cases described to date, we provide evidence that neuronal cytoplasmic inclusion burden in the hippocampus and parahippocampus is associated with the occurrence of memory impairment in multiple system atrophy. Further investigation is necessary to identify the underlying pathological basis of frontal-subcortical dysfunction in 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.

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

Whether gray matter impairment occurs in neuromyelitis optica is a matter of ongoing debate, and the association of gray matter impairment with cognitive deficits remains largely unknown. The purpose of this study was to investigate gray matter volume reductions and their association with cognitive decline in patients with neuromyelitis optica. This study included 50 patients with neuromyelitis optica and 50 sex-, age-, handedness-, and education-matched healthy subjects who underwent high-resolution structural MR imaging examinations and a battery of cognitive assessments. Gray matter volume and cognitive differences were compared between the 2 groups. The correlations of the regional gray matter volume with cognitive scores and clinical variables were explored in the patients with neuromyelitis optica. Compared with healthy controls (635.9 ± 51.18 mL), patients with neuromyelitis optica (602.8 ± 51.03 mL) had a 5.21% decrease in the mean gray matter volume of the whole brain (P < .001). The significant gray matter volume reduction in neuromyelitis optica affected the frontal and temporal cortices and the right thalamus (false discovery rate correction, P < .05). The regional gray matter volumes in the frontal and temporal cortices were negatively correlated with disease severity in patients with neuromyelitis optica (Alphasim correction, P < .05). Patients with neuromyelitis optica had impairments in memory, information processing speed, and verbal fluency (P < .05), which were correlated with gray matter volume reductions in the medial prefrontal cortex and thalamus (Alphasim correction, P < .05). Gray matter volume reduction is present in patients with neuromyelitis optica and is associated with cognitive impairment and disease severity in this group.

The purpose of this study was to examine the relationship between signal hyperintensities--a probable marker of underlying pathology--on T2-weighted magnetic resonance brain scans and neuropsychological test findings in elderly depressed and normal subjects. Elderly subjects with a DSM-III-R diagnosis of major depression (N=41) and normal elderly comparison subjects (N=38) participated in a magnetic resonance imaging study (1.0-T) of signal hyperintensities in periventricular, deep white matter, and subcortical gray matter. Hard copies of scans were rated in random order by research psychiatrists blind to diagnosis; the modified Fazekas hyperintensity rating scale was used. Cognitive performance was independently assessed with a comprehensive neuropsychological battery. Clinical and demographic differences between groups were assessed by t tests and chi-square analysis. Relationships between neuropsychological performance and diagnosis and hyperintensities and their interaction were analyzed by using analysis of covariance, with adjustment for age and education. Elderly depressed subjects manifested poorer cognitive performance on several tests than normal comparison subjects. A significant interaction between hyperintensity location/severity and presence/absence of depression on cognitive performance was found: depressed patients with moderate-to-severe deep white matter hyperintensities demonstrated worse performance on general and delayed recall memory indices, executive functioning and language testing than depressed patients without such lesions and normal elderly subjects with or without deep white matter changes. Findings validate cognitive performance decrements in geriatric depression and suggest possible neuroanatomic vulnerabilities to developing particular neuropsychological dysfunction in depressed subjects.

Parkinson disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) share alpha-synuclein immunoreactivity. These "synucleinopathies" have overlapping signs and symptoms, but less is known about similarities and differences in their cognitive and neuropsychiatric profiles. We compared the cognitive and neuropsychiatric profiles of individuals with PD, MSA, and DLB. Overall, the DLB group showed the most cognitive impairment, the MSA group demonstrated milder impairment, and the PD group was the least cognitively impaired. The DLB and MSA groups showed worse executive function and visuospatial skills than PD, whereas DLB showed impaired memory relative to both PD and MSA. On the neuropsychiatric screening, all groups endorsed depression and anxiety; the DLB group alone endorsed delusions and disinhibition. Consistent with their greater level of cognitive and neuropsychiatric impairment, the DLB group showed the greatest amount of functional impairment on a measure of instrumental activities of daily living (Functional Activities Questionnaire). We found that MSA subjects had cognitive difficulties that fell between the mild deficits of the PD group and the more severe deficits of the DLB group. PD, MSA, and DLB groups have similar neuropsychiatric profiles of increased depression and anxiety. Similar underlying alpha-synuclein pathology may contribute to these shared features.

Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA. To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls. We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level. Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype. Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] µg/mL; P = .01) (difference between medians: -0.14; 95% CI, -0.25 to -0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) µg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02). Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

Direct and indirect effects of fetal irradiation on cortical gray and white matter volume in the macaque

Objective: We aimed to characterize the cognitive profiles in multiple system atrophy (MSA) and explore the cerebral metabolism related to the cognitive decline in MSA using 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET).Methods: In this study, 105 MSA patients were included for cognitive assessment and 84 of them were enrolled for 18F-FDG PET analysis. The comprehensive neuropsychological tests covered five main domains including execution, attention, memory, language, and visuospatial function. The cognitive statuses were classified to MSA with normal cognition (MSA-NC) and MSA with cognitive impairment (MSA-CI), including dementia (MSA-D), and mild cognitive impairment (MSA-MCI). With 18F-FDG PET imaging, the cerebral metabolism differences among different cognitive statuses were analyzed using statistical parametric mapping and post-hoc analysis.Results: Among 84 MSA patients, 52 patients were found with MSA-CI, including 36 patients as MSA-MCI and 16 patients as MSA-D. In detail, the cognitive impairments were observed in all the five domains, primarily in attention, executive function and memory. In 18F-FDG PET imaging, MSA-D and MSA-MCI patients exhibited hypometabolism in left middle and superior frontal lobe compared with MSA-NC (p < 0.001). The normalized regional cerebral metabolic rate of glucose (rCMRglc) in left middle frontal lobe showed relative accuracy in discriminating MSA-CI and MSA-NC [areas under the curve (AUC) = 0.750; 95%CI = 0.6391–0.8609].Conclusions: Cognitive impairments were not rare in MSA, and the hypometabolism in frontal lobe may contribute to such impairments.

ObjectiveReview the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these...

Multiple system atrophy (MSA) is characterized by a variable combination of cerebellar ataxia, parkinsonism and pyramidal signs associated with autonomic failure. Classically, cognitive impairment was not considered a clinical feature of MSA and dementia was pointed out as an exclusion diagnostic criteria. Based on comprehensive neuropsychological assessment, cognitive impairment was found to be a frequent feature in MSA, and clinically-defined dementia is now reported in 14-16% of cases. This article reviews the current data on cognitive impairment in MSA along with its neuropsychological profile and pathophysiology.