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.

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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).

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.

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.

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.

Predictors of Conversion to α-Synucleinopathy Diseases in Idiopathic Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) often precedes the development of α-synucleinopathy diseases. OBJECTIVE: We aimed to assess the predictive value of clinical variables and biomarkers for the early development of α-synucleinopathy diseases in subjects with iRBD. METHODS: 56 patients with RBD Screening Questionnaire (RBDSQ) scores ≥5 at baseline and subsequent visit were enrolled as probable iRBD from the Parkinson's Progression Markers Initiative (PPMI) database. Baseline clinical data and biomarkers were analyzed. The endpoint was defined as disease progression to α-synucleinopathy diseases. Cox proportional hazard and Kaplan-Meier analyses were used to evaluate the predictive values of the indicators. RESULTS: During a mean follow-up duration of 5.1 years, 15 of 56 patients (26.8%) developed α-synucleinopathy diseases. Baseline clinical variables, including University of Pennsylvania Smell Identification Test (UPSIT, HR = 26.18, p = 0.004), 15-item Geriatric Depression Scale (GDS, HR = 14.26, p = 0.001), Montreal Cognitive Assessment (MoCA, HR = 3.56, p = 0.025), and Hopkins Verbal Learning Test Total recall (HVLT-TR, HR = 3.70, p = 0.014); genotype status of TMEM175 (HR = 3.74, p = 0.017), SCN3A (HR = 5.81, p = 0.022) and NUCKS1 (HR = 0.342, p = 0.049); ratio of phosphorylated tau to total tau (p-tau/t-tau, HR = 8.36, p = 0.001) in cerebrospinal fluid; and gray matter atrophy in inferior frontal gyrus (IFG, HR = 15.49, p = 0.001) were associated with phenoconversion to α-synucleinopathy diseases. A model combined the three independent variables (UPSIT, TMEM175 and gray matter atrophy in IFG) exhibited significantly improved predictive performance. CONCLUSION: For patients with iRBD, progression to α-synucleinopathy diseases can be predicted with good accuracy using a model combining clinical variables and biomarkers, which could form a basis for future disease prevention.

Abnormal static and dynamic functional connectivity of resting-state fMRI in multiple system atrophy.

In order to explore the topological alterations in functional brain networks between multiple system atrophy (MSA) patients and healthy controls (HC), a new joint analysis method of static and dynamic functional connectivity (FC) is proposed in this paper. Twenty-four MSA patients and twenty HCs were enrolled in this study. We constructed static and dynamic brain networks from resting-state fMRI data and calculated four graph theory attributes. Statistical comparisons and correlation analysis were carried out for static and dynamic FC separately before combining both cases. We found decreased local efficiency (LE) and weighted degree (WD) in cerebellum from both static and dynamic graph attributes. For static FC alone, we identified increased betweenness centrality (BC) at left dorsolateral prefrontal cortex, left Cerebellum_Crus9 and decreased WD at Vermis_6. For dynamic FC alone, decreased BC, clustering coefficients and LE at several cortical regions and cerebellum were identified. All the features had significant correlation with total UMSARS scores. Receiver operating characteristic analysis showed that dynamic features had the highest area under the curve value. Our work not only added new evidence for the underlying neurobiology and disrupted dynamic disconnection syndrome of MSA, but also proved the possibility of disease diagnosis and progression tracking using rs-fMRI.

Predicting phenoconversion in pure autonomic failure.

OBJECTIVE: To determine predicting factors and frequency of phenoconversion from pure autonomic failure (PAF) into a synucleinopathy with motor or cognitive involvement of multiple system atrophy (MSA), Parkinson disease (PD), or dementia with Lewy bodies (DLB). METHODS: We performed a retrospective review of all patients with PAF from 2001 to 2011 evaluated at Mayo Clinic, Rochester. Clinical follow-up and patient telephone calls were used to assess for development of symptoms and diagnosis of MSA, PD, or DLB. Clinical and laboratory variables were extracted with factors predictive of evolution assessed using group comparison, odds ratio, and logistical regression. RESULTS: Among 275 patients with PAF at presentation, 67 (24%) phenoconverted to a synucleinopathy with motor or cognitive involvement; 34 met criteria for MSA, while 33 met criteria for PD or DLB. Age at onset was younger in MSA phenoconverters. Clinical features at presentation influenced phenoconversion: severe bladder symptoms were more common in MSA phenoconverters; subtle motor signs were more frequent in MSA and PD/DLB phenoconverters. MSA phenoconverters were more likely to have higher supine norepinephrine levels and preganglionic pattern of anhidrosis. Presentation variables predicting MSA phenoconversion included subtle motor signs, supine norepinephrine levels, severe bladder symptoms, and dream enactment behavior. Presentation variables predictive of PD/DLB phenoconversion included subtle motor signs, dream enactment behavior, and constipation. CONCLUSIONS: Our findings suggest that at least a quarter of patients with PAF phenoconvert to MSA, PD, or DLB. Presentation features determine patients at risk for evolution with specific patterns indicative of phenoconversion to MSA vs PD/DLB. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that several presentation variables including subtle motor signs, severe bladder symptoms, and dream enactment behavior are associated with an increased risk of developing a synucleinopathy with motor or cognitive involvement.