Clinical value of video oculomotor evaluation in the differential diagnosis of multiple system atrophy and Parkinson's disease.

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disease that progresses rapidly and has a poor prognosis. This study aimed to assess the value of video oculomotor evaluation (VOE) in the differential diagnosis of MSA and Parkinson's disease (PD). METHODS: In total, 28 patients with MSA, 31 patients with PD, and 30 age- and sex-matched healthy controls (HC) were screened and included in this study. The evaluation consisted of a gaze-holding test, smooth pursuit eye movement (SPEM), random saccade, and optokinetic nystagmus (OKN). RESULTS: The MSA and PD groups had more abnormalities and decreased SPEM gain than the HC group (64.29%, 35.48%, 10%, p < .001). The SPEM gain in the MSA group was significantly lower than that in the PD group at specific frequencies. Patients with MSA and PD showed prolonged latencies in all saccade directions compared with those with HC. However, the two diseases had no significant differences in the saccade parameters. The OKN gain gradually decreased from the HC to the PD and the MSA groups (p < .05). Compared with the PD group, the gain in the MSA group was further decreased in the OKN test at 30°/s (Left, p = .010; Right p = .016). Receiver operating characteristic curves showed that the combination of oculomotor parameters with age and course of disease could aid in the differential diagnosis of patients with MSA and PD, with a sensitivity of 89.29% and a specificity of 70.97%. CONCLUSIONS: The combination of oculomotor parameters and clinical data may aid in the differential diagnosis of MSA and PD. Furthermore, VOE is vital in the identification of neurodegenerative diseases.

[Cognitive impairment in multiple system atrophy - exclusion criteria or an integral part of the clinical picture?] / Kognitivnye narusheniya pri mul'tisistemnoi atrofii ­ kriterii isklyucheniya ili neot"emlemaya chast' klinicheskoi kartiny?

Multiple system atrophy (MSA) is a severe, orphan disease characterized by a steady increase in symptoms of parkinsonism, cerebellar disorders, and autonomic failure. In addition to autonomic failure, which is considered the defining symptom of this type of atypical parkinsonism, there are a range of other non-motor clinical manifestations, such as sleep disorders, pain syndrome, anxiety-depressive disorders, cognitive impairment (CI). CI, especially severe CI, has long been considered as a distinctive feature of MCA. Recently, there have been many clinical studies with pathomorphological or neuroimaging confirmation, indicating a high prevalence of cognitive disorders in MCA. In this article, we discuss the pathogenetic mechanisms of the development of MCA and CI in MCA, as well as the range of clinical manifestations of cognitive dysfunction.

Low and high-order topological disruption of functional networks in multiple system atrophy with freezing of gait: A resting-state study.

OBJECTIVE: Freezing of gait (FOG), a specific survival-threatening gait impairment, needs to be urgently explored in patients with multiple system atrophy (MSA), which is characterized by rapid progression and death within 10 years of symptom onset. The objective of this study was to explore the topological organisation of both low- and high-order functional networks in patients with MAS and FOG. METHOD: Low-order functional connectivity (LOFC) and high-order functional connectivity FC (HOFC) networks were calculated and further analysed using the graph theory approach in 24 patients with MSA without FOG, 20 patients with FOG, and 25 healthy controls. The relationship between brain activity and the severity of freezing symptoms was investigated in patients with FOG. RESULTS: Regarding global topological properties, patients with FOG exhibited alterations in the whole-brain network, dorsal attention network (DAN), frontoparietal network (FPN), and default network (DMN), compared with patients without FOG. At the node level, patients with FOG showed decreased nodal centralities in sensorimotor network (SMN), DAN, ventral attention network (VAN), FPN, limbic regions, hippocampal network and basal ganglia network (BG), and increased nodal centralities in the FPN, DMN, visual network (VIN) and, cerebellar network. The nodal centralities of the right inferior frontal sulcus, left lateral amygdala and left nucleus accumbens (NAC) were negatively correlated with the FOG severity. CONCLUSION: This study identified a disrupted topology of functional interactions at both low and high levels with extensive alterations in topological properties in MSA patients with FOG, especially those associated with damage to the FPN. These findings offer new insights into the dysfunctional mechanisms of complex networks and suggest potential neuroimaging biomarkers for FOG in patients with MSA.

Hypothalamic involvement in multiple system atrophy: A structural MRI study.

OBJECTIVE: To investigate hypothalamic atrophy and its clinical correlates in multiple system atrophy (MSA) in-vivo. BACKGROUND: MSA is characterized by autonomic dysfunction and parkinsonian/cerebellar manifestations. The hypothalamus regulates autonomic and homeostatic functions and is also involved in memory and learning processes. METHODS: 11 MSA, 18 Parkinson's Disease (PD) and 18 Healthy Controls (HC) were included in this study. A validated and automated hypothalamic segmentation tool was applied to 3D-T1-weighted images acquired on a 3T MRI scanner. MSA hypothalamic volumes were compared to those of PD and HC. Furthermore, the association between hypothalamic volumes and scores of autonomic, depressive, sleep and cognitive manifestations were investigated. RESULTS: Posterior hypothalamus volume was reduced in MSA compared to controls (t = 2.105, p = 0.041) and PD (t = 2.055, p = 0.046). Total hypothalamus showed a trend towards a reduction in MSA vs controls (t = 1.676, p = 0.101). Reduced posterior hypothalamus volume correlated with worse MoCA scores in the parkinsonian (MSA + PD) group and in each group separately, but not with autonomic, sleep, or depression scores. CONCLUSIONS: In-vivo structural hypothalamic involvement may be present in MSA. Reduced posterior hypothalamus volume, which includes the mammillary bodies and lateral hypothalamus, is associated with worse cognitive functioning. Larger studies on hypothalamic involvement in MSA and its clinical correlates are needed.

Comparison of autonomic dysfunction in patients with Parkinson's Disease, progressive supranuclear palsy, and multiple system atrophy.

AIM OF THE STUDY: To assess and compare autonomic nervous system (ANS) dysfunction, especially cardiovascular dysautonomia, in Parkinson's Disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and healthy controls. CLINICAL RATIONALE FOR THE STUDY: Assessment of ANS can be useful in differential diagnosis. Dysautonomia affects quality of life and can lead to potentially life-threatening complications. There is very little literature data regarding dysautonomia in PSP in relation to other parkinsonian syndromes. This study expands the knowledge about ANS dysfunction in parkinsonisms, especially PSP. MATERIAL AND METHODS: Patients with PD, MSA and PSP were prospectively recruited to our study. Demographic data and information about clinical and neuropsychological assessment, medication and comorbidities was collected. SCOPA-AUT questionnaire, 5-minute tilt test, and 5-minute heart rate variability (HRV) analysis in time and frequency domains were used to assess ANS. Analysis was also performed in patients with PSP-RS and PSP-P phenotypes, and in a subgroup with eliminated confounding factors, including age and disease duration. RESULTS: 76 PD, 25 PSP, and 12 MSA patients, and 20 controls, were included. Symptoms of dysautonomia revealed by a SCOPA-AUT questionnaire were present in all groups of patients. Urinary dysfunction was more pronounced in atypical parkinsonisms, and cardiovascular symptoms in α-synucleinopathies. HRV was disrupted in all groups of patients. However, when PSP-P and PSP-RS phenotypes were considered, HRV was diminished in PSP-RS, but there were no differences in HRV parameters between PSP-P and controls. Neurogenic orthostatic hypotension was present in 25% of PD and 58% of MSA patients, but it was absent in PSP patients and the control group. 13 PD and nine PSP patients and 16 controls were included in subanalysis. This revealed that PSP, but not PD, patients had significantly more symptoms of dysautonomia and lower HRV indices compared to controls, and that orthostatic hypotension was even more common in PD than in controls. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study suggests that dysautonomia is common in PD, MSA and PSP, even though it has different profiles in the different diseases. NOH is present in PD and MSA, but not in PSP.

A Mouse Model of Multiple System Atrophy: Bench to Bedside.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with unclear etiology, currently difficult and delayed diagnosis, and rapid progression, leading to disability and lethality within 6 to 9 years after symptom onset. The neuropathology of MSA classifies the disease in the group of a-synucleinopathies together with Parkinson's disease and other Lewy body disorders, but features specific oligodendroglial inclusions, which are pathognomonic for MSA. MSA has no efficient therapy to date. Development of experimental models is crucial to elucidate the disease mechanisms in progression and to provide a tool for preclinical screening of putative therapies for MSA. In vitro and in vivo models, based on selective neurotoxicity, a-synuclein oligodendroglial overexpression, and strain-specific propagation of a-synuclein fibrils, have been developed, reflecting various facets of MSA pathology. Over the years, the continuous exchange from bench to bedside and backward has been crucial for the advancing of MSA modelling, elucidating MSA pathogenic pathways, and understanding the existing translational gap to successful clinical trials in MSA. The review discusses specifically advantages and limitations of the PLP-a-syn mouse model of MSA, which recapitulates motor and non-motor features of the human disease with underlying striatonigral degeneration, degeneration of autonomic centers, and sensitized olivopontocerebellar system, strikingly mirroring human MSA pathology.

Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy.

Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.

Gait-Phase Modulates Alpha and Beta Oscillations in the Pedunculopontine Nucleus.

The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of the midbrain and pons, playing an important role in modulating posture and locomotion. Deep brain stimulation of the PPN has been proposed as an emerging treatment for patients with Parkinson's disease (PD) or multiple system atrophy (MSA) who have gait-related atypical parkinsonian syndromes. In this study, we investigated PPN activities during gait to better understand its functional role in locomotion. Specifically, we investigated whether PPN activity is rhythmically modulated by gait cycles during locomotion. PPN local field potential (LFP) activities were recorded from PD or MSA patients with gait difficulties during stepping in place or free walking. Simultaneous measurements from force plates or accelerometers were used to determine the phase within each gait cycle at each time point. Our results showed that activities in the alpha and beta frequency bands in the PPN LFPs were rhythmically modulated by the gait phase within gait cycles, with a higher modulation index when the stepping rhythm was more regular. Meanwhile, the PPN-cortical coherence was most prominent in the alpha band. Both gait phase-related modulation in the alpha/beta power and the PPN-cortical coherence in the alpha frequency band were spatially specific to the PPN and did not extend to surrounding regions. These results suggest that alternating PPN modulation may support gait control. Whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control remains to be tested.SIGNIFICANCE STATEMENT The therapeutic efficacy of pedunculopontine nucleus (PPN) deep brain stimulation (DBS) and the extent to which it can improve quality of life are still inconclusive. Understanding how PPN activity is modulated by stepping or walking may offer insight into how to improve the efficacy of PPN DBS in ameliorating gait difficulties. Our study shows that PPN alpha and beta activity was modulated by the gait phase, and that this was most pronounced when the stepping rhythm was regular. It remains to be tested whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control.

Nocturnal stridor in multiple system atrophy: Video-polysomnography and clinical features.

INTRODUCTION: Nocturnal stridor, a life-threatening condition linked to respiratory failure and sudden death during sleep, is a serious issue in patients with multiple system atrophy (MSA). However, little is known about polysomnographic findings and clinical features of MSA patients with nocturnal stridor. Hence, we investigated video-polysomnography (VPSG) findings and clinical features associated with nocturnal stridor in patients with MSA. METHODS: We retrospectively analyzed the clinical data of patients with MSA (n = 49) who underwent overnight VPSG for the evaluation of sleep-disordered breathing. The presence of nocturnal stridor was confirmed based on overnight VPSG findings. Clinical data, including VPSG findings and clinical features, were compared between MSA patients with and without nocturnal stridor. RESULTS: Nocturnal stridor was present in 31 (63.3%) patients with MSA. Patients with stridor showed significantly higher apnea-hypopnea, respiratory disturbance, and oxygen desaturation indices than those without stridor (P = 0.024, P = 0.049, and P = 0.006, respectively). Patients with stridor had more severe axial motor features, more impaired activities of daily living, and longer disease duration than those without stridor (P = 0.012, P = 0.036, and P = 0.003, respectively). However, there were no significant between-group differences in sex, age at disease onset, MSA subtype, parkinsonian features, cerebellar ataxia, residual urine volume, or systolic and diastolic blood pressure change. CONCLUSIONS: MSA with nocturnal stridor is related to higher apnea indices in conjunction with higher O2 desaturation index, more severe axial motor features, more impaired activities of daily living, and longer disease duration.

Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension.

[Figure: see text].

Postganglionic Sudomotor Dysfunction and Brain Glucose Hypometabolism in Patients with Multiple System Atrophy.

BACKGROUND: Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. OBJECTIVE: We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. METHODS: In this retrospective study, patients with probable MSA who underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18F-FDG-PET/CT results were collected. RESULTS: Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p = 0.037). In the regression analysis, both UMSARS Part I (ß= 1.185, p = 0.013) and Part II (ß= 1.266, p = 0.021) scores were significantly associated with the sudomotor sub-score. On 18F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. CONCLUSION: Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without.

Intraocular pressure and choroidal thickness postural changes in multiple system atrophy and Parkinson's disease.

To evaluate intraocular pressure (IOP) and choroidal thickness (ChT) postural changes in multiple system atrophy (MSA), Parkinson's disease (PD) patients and healthy controls (HC). 20 MSA patients, 21 PD patients and 14 HC, were examined. All subjects underwent a complete examination, including corneal thickness, ChT, IOP and axial length (AL) measurements. IOP measurement was performed in supine, sitting, and standing positions, whereas ChT in sitting and standing positions. Supine to standing IOP variations were significantly higher in MSA vs PD(p = 0.01) and in MSA vs HC (p < 0.0001), whereas no significant differences were observed between PD and HC (p = 0.397). Mean sub-foveal ChT in MSA was 240 ± 92 µm in sitting position, and 215 ± 94 µm in standing position with a significant reduction (p = 0.008). Mean sub-foveal ChT in PD was 258 ± 79 µm in sitting position, and 259 ± 76 µm in standing position (p = 0.887). In HC it was 244 ± 36 µm in sitting position, and 256 ± 37 µm in standing position with a significant increase (p = 0.007). The significant IOP and ChT postural changes can be considered additional hallmarks of autonomic dysfunction in MSA and further studies are needed to consider them as biomarkers in the differential diagnosis with PD.

A Life-threatening Complication of Multiple System Atrophy.

CASE PRESENTATION: A 50-year-old woman was initially seen in 2016 for sleep disorders consultation, referred by Neurology because of progressive cerebellar ataxia syndrome with possible autonomic involvement and sleep-disordered breathing described as having stridorous sounds during her sleep. She had initially presented to Neurology because of issues with balance, and she had frequent falls at home. In 2016, her speech was clear, and she was able to ambulate steadily with a cane. She underwent a diagnostic polysomnogram that did not demonstrate clinically significant sleep apnea. However, the study demonstrated rapid eye movement (REM) sleep without atonia in 62% of REM epochs (normal, up to 27%) and a soft inspiratory stridor during non-REM and REM sleep. The patient was lost to follow-up until she presented to us for reevaluation 3 years later. In the interim, she had been diagnosed with multiple system atrophy-cerebellar type (MSA-C) at another health-care institution.

A study on the characteristics of cognitive function in patients with multiple system atrophy in China.

Nonmotor symptoms in patients with multiple system atrophy (MSA) have received an increasing amount of attention in recent years, but no research on MSA patients' cognitive characteristics has been conducted in China. To evaluate the cognitive function of MSA patients in China. Using a case-control study design, 256 MSA patients and 64 controls were evaluated by the Montreal cognitive assessment (MoCA) scale to characterize their cognitive function. Like the controls, 60.5% of the patients with MSA had cognitive impairment, but the characteristics of cognitive impairment between the two groups were different. The cognitive impairment in MSA patients was prominent in the cognitive domains of visuospatial/executive functions, naming, attention, and orientation; particularly, the visuospatial/executive functions were the most significantly impaired, while impairment in language function was mainly seen in the controls. Besides, impairments in visuospatial/executive functions, attention, language, and orientation were more prominent in MSA-P (MSA with predominant Parkinsonism) patients than in MSA-C (MSA with predominant cerebellar ataxia). The cognitive impairments were more severe in patients with probable MSA than in patients with possible MSA. In addition, the results showed that the level of cognitive function was negatively correlated with the severity of MSA. This study, which characterized the cognitive function of MSA patients with the largest sample size known so far in China, found that patients with MSA do have cognitive impairment and display specific characteristics. Therefore, the cognitive impairment of MSA should be paid more attention.The study has been registered in the Chinese Clinical Trial Registry (ChiCTR) (Registration No: ChiCTR1900022462).

Pain in neurodegenerative diseases with atypical parkinsonism: a systematic review on prevalence, clinical presentation, and findings from experimental studies.

Parkinson's disease-related pain has increasingly been investigated in research studies. Still, only a few studies have addressed the prevalence and clinical characteristics of pain in neurodegenerative disorders with atypical parkinsonism. The existing evidence, although scarce, suggests that, similarly as in Parkinson's disease, individuals with neurodegenerative diseases with atypical parkinsonism might be predisposed to the development of persistent pain. Today, as the global population is aging and we face an epidemic of neurodegenerative disorders, under-treated pain is taking a great toll on an ever-rising number of people. Here, we provide an up-to-date review of the current knowledge on the prevalence of pain, its clinical features, and findings from experimental studies that might signpost altered pain processing in the most prevalent neurodegenerative disorders with atypical parkinsonism: multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, and dementia with Lewy bodies. Finally, we point out the current gaps and unmet needs that future research studies should focus on. Large-scale, high-quality clinical trials, coupled with pre-clinical research, are urgently needed to reveal the exact pathophysiological mechanisms underpinning heightened pain and pave the path for mechanistically-driven analgesic interventions to be developed, ultimately leading to an improvement in the quality of life of individuals with neurodegenerative disorders.

Broad white matter impairment in multiple system atrophy.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by the widespread aberrant accumulation of α-synuclein (α-syn). MSA differs from other synucleinopathies such as Parkinson's disease (PD) in that α-syn accumulates primarily in oligodendrocytes, the only source of white matter myelination in the brain. Previous MSA imaging studies have uncovered focal differences in white matter. Here, we sought to build on this work by taking a global perspective on whole brain white matter. In order to do this, in vivo structural imaging and diffusion magnetic resonance imaging were acquired on 26 MSA patients, 26 healthy controls, and 23 PD patients. A refined whole brain approach encompassing the major fiber tracts and the superficial white matter located at the boundary of the cortical mantle was applied. The primary observation was that MSA but not PD patients had whole brain deep and superficial white matter diffusivity abnormalities (p < .001). In addition, in MSA patients, these abnormalities were associated with motor (Unified MSA Rating Scale, Part II) and cognitive functions (Mini-Mental State Examination). The pervasive whole brain abnormalities we observe suggest that there is widespread white matter damage in MSA patients which mirrors the widespread aggregation of α-syn in oligodendrocytes. Importantly, whole brain white matter abnormalities were associated with clinical symptoms, suggesting that white matter impairment may be more central to MSA than previously thought.

Esophageal Dysmotility is Common in Patients With Multiple System Atrophy.

OBJECTIVES: Esophageal dysmotility (ED) in patients with multiple system atrophy (MSA) are poorly understood. This study aimed to investigate the prevalence of ED in patients with MSA and to assess the relationship of esophageal abnormalities with other clinical findings and characteristics in these patients. METHODS: A retrospective chart review was conducted to identify patients with MSA and to compare them to the elderly controls without MSA (65+ years) who underwent a videofluorographic esophagram from 2014 to 2019. Disease type, disease severity, vocal fold mobility impairment, abnormal deglutitive proximal esophageal contraction (ADPEC), and intra-esophageal stasis (IES) were reviewed and compared between groups. RESULTS: Thirty-seven patients with MSA were identified. The median age was 63 and 26 (70%) were male. These patients were matched to 22 elderly adults with presbylarynx but not MSA (median age 77, 68% male). In MSA patients, cerebellar variant type was predominant (59%), and ADPEC was recognized in 18 patients (49%). Disease severity level (P = 0.028) and existence of IES (P = 0.046) were associated with higher risks of developing ADPEC. The prevalence of IES was significantly higher in patients with MSA (95%) compared to controls without MSA (46%) (P < 0.001). Disease severity level and the existence of IES were significantly associated with the presence of ADPEC (p < 0.05). CONCLUSION: ADPEC and IES were significantly more common in MSA than in elderly subjects without MSA. MSA severity is associated with the development of ADPEC. The data suggest that esophageal motility is predominantly affected in MSA. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:832-838, 2021.

Signs of early cellular dysfunction in multiple system atrophy.

AIMS: Multiple system atrophy (MSA) is a fatal neurodegenerative disease that belongs to the family of α-synucleinopathies. At post mortem examination, intracellular inclusions of misfolded α-synuclein are found in neurons and oligodendrocytes and are considered to play a significant role in the pathogenesis. However, the early steps of the disease process are unknown and difficult to study in tissue derived from end-stage disease. METHODS: Induced pluripotent stem cells (iPSCs) were generated from patients' and control skin fibroblasts and differentiated into NCAM-positive neural progenitor cells (NPCs). The mitochondrial morphology and function were assessed by immunocytochemistry and high resolution respirometry. The ability to cope with exogenous oxidative stress was tested by exposure to different doses of luperox. The expression of α-synuclein was studied by immunocytochemistry. RESULTS: We identified increased tubulation of mitochondria with preserved respiration profile in MSA-derived NPCs. Exposure of these cells to exogenous oxidative stress even at low doses, triggered an excessive generation of reactive oxygen species (ROS) and cleavage of caspase-3. MSA-derived NPCs did not present changed levels of SNCA gene expression nor intracellular aggregates of α-synuclein. However, we identified disease-related translocation of α-synuclein to the nucleus. CONCLUSIONS: Our results show early cellular dysfunction in MSA-derived NPCs. We identified changes in the redox homeostasis which are functionally compensated at baseline but cause increased susceptibility to exogenous oxidative stress. In addition, nuclear translocation of α-synuclein in MSA-derived NPCs supports an early cellular stress response which may precede the neurodegenerative process in this disorder.

The Impact of Compulsivity and Impulsivity in Cerebellar Ataxia: A Case Series.

Background: The cerebellum has recently been identified to have a key role in reward processing, and individuals with ataxia have been found to be more impulsive and compulsive as part of cerebellum-related cognitive and behavioral disturbances. Case Report: We reported five individuals with cerebellar ataxia who demonstrate impulsive and compulsive behaviors, including hobbyism, gambling, and compulsive medication use, to illustrate that these symptoms can be highly disabling. Discussion: These five cases provide examples of behavioral symptoms in cerebellar ataxia. Further investigations of the pathomechanism of these symptoms will advance our understanding of the cerebellum in cognition and behavior.

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.