Early Multiple System Atrophy Research Articles

Features of lower urinary tract symptoms in patients with multiple system atrophy

Background: Multiple system atrophy (MSA) is a fatally progressive neurodegenerative disease characterized by variable combinations of parkinsonism, cerebellar ataxia and autonomic dysfunction. Lower urinary tract dysfunction, as a manifestation of autonomic failure is one of core clinical features for a diagnosis of MSA, yet it is often underrecognized especially in the early stage of the disease Objective: The study aimed to describe lower urinary tract symptoms and residual urine volume in early MSA. Subjects and methods: This was a cross-sectional study including MSA patients with disease duration of less than 5 years. Demographic and clinical characteristics were collected. All participants were assessed with UMSARS, IPSS, OABSS scores, and abdominal ultrasound was performed to measure residual urine volume. Results: 32 MSA patients were recruited, all of whom reported lower urinary tract symptoms. Urge incontinence was the most common symptom (93.8%). Symptoms related to voiding were found in 85.7% of MSA-C patients and 88.9% of MSA-P patients. Postvoid residual urine volume > 100 ml was recognized in 28% of patients. There is no statistically significant difference observed in the rate of PVR abnormalities between the MSA-C and MSA-P subgroups (p> 0.05). Conclusion: Lower urinary tract symptoms and abnormal residual urine volume are frequently present even in the early stage of MSA with no significant differences between different clinical subtypes.

White Matter Abnormalities Track Disease Progression in Multiple System Atrophy.

White matter (WM) abnormalities have been implicated in clinically relevant functional decline in multiple system atrophy (MSA). To identify the WM and gray matter (GM) abnormalities in MSA and assess the utility of longitudinal structural and diffusion changes as surrogate markers for tracking disease progression in MSA. Twenty-seven participants with early MSA [15 with clinically predominant cerebellar (MSA-C) and 12 with clinically predominant parkinsonian features (MSA-P)] and 14 controls were enrolled as a part of our prospective, longitudinal study of synucleinopathies. Using structural magnetic resonance imaging (MRI) and diffusion MRI (diffusion tensor and neurite orientation and dispersion density imaging), we analyzed whole and regional brain changes in these participants. We also evaluated temporal imaging trajectories based on up to three annual follow-up scans and assessed the impact of baseline diagnosis on these imaging biomarkers using mixed-effect models. MSA patients exhibited more widespread WM changes than GM, particularly in the cerebellum and brainstem, with greater severity in MSA-C. Structural and diffusion measures in the cerebellum WM and brainstem deteriorated with disease progression. Rates of progression of these abnormalities were similar in both MSA subtypes, reflecting increasing overlap of clinical features over time. WM abnormalities are core features of MSA disease progression and advance at similar rates in clinical MSA subtypes. Multimodal MRI imaging reveals novel insights into the distribution and pattern of brain abnormalities and their progression in MSA. Selected structural and diffusion measures may be useful for tracking disease progression in MSA clinical trials.

Neurofilament Light Chain and Clinical Progression in Early Multiple System Atrophy (P5-3.001)

Neurofilament Light Chain and Clinical Progression in Early Multiple System Atrophy (P5-3.001)

Longitudinal evolution of sleep disturbances in early multiple system atrophy: a 2‐year prospective cohort study

BackgroundThe progression of sleep disturbances remains unclear in patients with early multiple system atrophy (MSA). We aimed to explore the frequency, severity, and coexistence of 2-year longitudinal changes of sleep disturbances including REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and Parkinson’s disease-related sleep problems (PD-SP) in early MSA.MethodsMSA patients with a disease duration < 3 years were enrolled to complete a 2-year follow-up visit. Sleep disturbances including RBD, EDS, and PD-SP were assessed using the RBD Screening Questionnaire, Epworth sleepiness scale, and PD sleep scale-2, respectively.ResultsA total of 220 patients with MSA enrolled in the study and 90 patients completed the 2-year follow-up visit. The score of all three sleep disturbances significantly increased over the 2-year follow-up in MSA and MSA with the predominant parkinsonism group (all p < 0.05). The frequency of PD-SP (from 14.5 to 26.7%) and EDS (from 17.7 to 37.8%) was progressively increased (all p < 0.05) except for RBD (from 51.8 to 65.6%, p = 0.152) over the 2-year follow-up in MSA. The frequency of coexistence of two or three sleep disturbances also increased over time. The most common sleep disturbance was RBD, followed by EDS and PD-SP over the 2-year follow-up.ConclusionsThe present study demonstrated that the frequency of different types of sleep disturbances progressively increased except for RBD and the coexistence of two or three sleep disturbances became more common over time in early MSA. Our study suggested that the assessment and management of sleep disturbances should begin early in MSA.

Neurofilament light chain in spinal fluid and plasma in multiple system atrophy: a prospective, longitudinal biomarker study.

There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to cerebrospinal fluid (NfL-c) as a diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression. Well-characterized patients with early MSA (n = 32), Parkinson's disease (PD; n = 21), and matched controls (CON; n = 15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high-sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression. Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson, r = 0.99), while correlation between NfL-c and -p was only moderate (r = 0.66). NfL was significantly higher in MSA compared with CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity. These findings confirm NfL-c as a faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression.

Wearable Sensors for Quantitative Motor Assessments in Multiple System Atrophy (P8-9.002)

<h3>Objective:</h3> To determine the utility of quantitative wearable sensors in Multiple system atrophy (MSA). <h3>Background:</h3> Symptoms of MSA include parkinsonism, ataxia, and/or failure of the autonomic nervous system. Wearable sensors have potential to characterize motor impairment in an outpatient setting and to serve as clinical trial outcomes in MSA. <h3>Design/Methods:</h3> Participants enrolled in biomarkers of progression in MSA (bioMUSE) had early MSA (&lt;3 years of motor symptoms) by clinical assessment. All completed neurologic exam, neuroimaging and biofluid assessments. The Unified MSA Rating Scale motor exam (UMSARS II), Parkinson Plus Scale (PPSm), and Tandem Walk (TW), were completed every 3 months. PAMSys actigraphy sensors were worn continuously for up to 12-months to assess gait (step count, bouts of walking, steps per bout, cadence, cadence variability), postures (minutes of sitting, lying, standing, walking, sedentary [sitting + lying]) and postural transitions (sit-to-stand) by averaging data over 14-days. Pearson correlation coefficients between clinical and sensor variables were estimated at each time point and two-sided p-values were calculated. <h3>Results:</h3> 12 participants (6 Female, mean age 64.2) with motor symptoms of 2.X years were followed for ≥ 6 months (n=9), and 12 months (n=5). Significant (<i>P</i>&lt;0.05) correlations were observed between step count, bouts of walking, minutes walking and sit to stand transitions for UMSARS II, PPSm and TW. Significant correlations were most frequently observed at BL and months 3, 6 and 9. The strongest correlations (r&gt;0.8) were observed at month 6 and 9. The PPSm had more frequent and stronger correlation with sensor parameters than UMSARS II. <h3>Conclusions:</h3> In early MSA, continuous actigraphy is feasible and demonstrates significant correlation with motor exam. The PPSm appeared to have stronger correlation with sensor variables than UMSARS II. Continuous motor assessments via wearable sensors may be a suitable endpoint for clinical trials in MSA. <b>Disclosure:</b> Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Neuroscience. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark . The institution of Dr. Claassen has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Alterity. Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Neuroscience. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for HD Insights. The institution of Dr. Claassen has received research support from NIH. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from HDSA. The institution of Dr. Claassen has received research support from Department of Defense. The institution of Dr. Claassen has received research support from Griffin Family Foundation. The institution of Dr. Claassen has received research support from Neurocrine. The institution of Dr. Claassen has received research support from Vaccinex. The institution of Dr. Claassen has received research support from AbbVie. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from Genentech/ Roche. The institution of Dr. Claassen has received research support from Prilenia. The institution of Dr. Claassen has received research support from Neurocrine/ HSG. Miss Iregui has nothing to disclose. Ms. Wynn has nothing to disclose. Charles Davis has nothing to disclose. Cynthia Wong has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Stamler has received personal compensation for serving as an employee of Alterity Therapeutics.

Urinary Symptom Profile in Early Multiple System Atrophy (P9-9.002)

<h3>Objective:</h3> Evaluate the Urinary Symptom Profile (USP) in patients with multiple system atrophy (MSA). <h3>Background:</h3> MSA is a rapidly progressive neurodegenerative disease that presents with motor and autonomic symptoms. Urinary symptoms can occur at any time along the disease process; however, no study has characterized patient reported urinary symptoms in MSA. The Urinary Symptom Profile (USP) is a validated, patient-reported assessment for stress urinary incontinence (SUI), overactive bladder (OAB), and low stream (LS). We applied this scale to a cohort of early MSA patients from the bioMUSE Natural history study. <h3>Design/Methods:</h3> 16 participants, (8 females), mean age 62 (range 49–79), mean duration of motor symptoms of 3 years, completed the Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, the Natural History and Neuroprotection in Parkinson Plus Syndromes-Parkinson Plus scale (PPS), and the Urinary Symptom Profile (USP) questionnaire. The PPS and UMSARS total urinary symptom scores were correlated with the total USP score using a t-distribution and the Spearman’s rank correlation. <h3>Results:</h3> The mean USP score was 14.06, (4–30). One participant had a bladder stimulator and 3 were taking medications for urinary symptoms. Total USP scores positively correlated with total urinary symptom scores from the UMSARS (p = 0.075, r² = 0.458) and PPS (p = 0.002, r² = 0.713). Across this cohort, the most severe complaints were related to urinary urgency (OAB avg = 8.4), and reduced amount of time to hold urine (SUI avg = 2.63). Subscale analysis indicates the most common symptoms relate to OAB, and least common were SUI. <h3>Conclusions:</h3> In early MSA, urinary symptoms are greatest in relation to overactive bladder, specifically urgency and frequency. These results suggest that the USP can be used for comprehensive evaluation of urinary complaints and give important insights to the concerns of patients early in disease. <b>Disclosure:</b> Miss Iregui has nothing to disclose. Ms. Wynn has nothing to disclose. Miss Hay has nothing to disclose. Cynthia Wong has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Stamler has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Neuroscience. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark . The institution of Dr. Claassen has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Alterity. Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Neuroscience. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for HD Insights. The institution of Dr. Claassen has received research support from NIH. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from HDSA. The institution of Dr. Claassen has received research support from Department of Defense. The institution of Dr. Claassen has received research support from Griffin Family Foundation. The institution of Dr. Claassen has received research support from Neurocrine. The institution of Dr. Claassen has received research support from Vaccinex. The institution of Dr. Claassen has received research support from AbbVie. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from Genentech/ Roche. The institution of Dr. Claassen has received research support from Prilenia. The institution of Dr. Claassen has received research support from Neurocrine/ HSG.

Head-to-head comparison of 6 plasma biomarkers in early multiple system atrophy

There is a dire need for reliable biomarkers to solidify an early and accurate diagnosis of multiple system atrophy (MSA). We sought to compare the ability of emerging plasma markers in distinguishing MSA from its mimics and healthy controls in early disease stages, and to evaluate their performance in detecting disease severity and brain atrophy. Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau181, amyloid-β (Aβ)42, and Aβ40 were measured using ultrasensitive Simoa in early-stage patients with MSA (n = 73), spinocerebellar ataxia (SCA, n = 29), Parkinson’s disease (PD, n = 28), and healthy controls (n = 100). We observed that elevated NfL outperformed other biomarkers in distinguishing MSA and its subtypes (AUC = 0.9) versus controls. Intriguingly, when separating MSA from its mimics, increased GFAP (AUC = 0.717) in MSA-C and decreased Aβ40 (AUC = 0.807) in MSA-P best discriminated from SCA and PD respectively. Plasma levels were comparable between MSA-C and MSA-P and the differentiation by plasma index alone was poor. Combining plasma markers noticeably improved the discriminatory efficacy. Of note, among MSA patients, higher GFAP and NfL were correlated with the atrophy of brain regions vulnerable to MSA (e.g., cerebellum, pons, or putamen). They could also aggravate the severity of MSA, and this association was partially mediated by cerebral volumes. In contrast, no obvious associations of phosphorylated tau and Aβ with disease severity were observed. Collectively, plasma biomarkers, especially in combination, are useful to facilitate the discriminatory work-up of MSA at early stages. Moreover, NfL and GFAP may be promising biomarkers to monitor the disease severity of MSA.

Bedside Assessment of Autonomic Dysfunction in Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder of the adulthood, characterized by autonomic failure, parkinsonian and cerebellar features in various combinations. Distinguishing MSA from common clinical look-alikes such as Parkinson's disease, other atypical parkinsonian disorders or alternative causes of sporadic adult-onset cerebellar ataxia may be difficult, especially at early disease stages. Nonetheless, some simple and cost-effective screening tools help detecting important red flags guiding towards a MSA diagnosis. Here we outline which clinical pearls and bedside tests may disclose autonomic dysfunction in multiple domains, enabling an early MSA diagnosis and, even more importantly, personalized treatment.

Imaging biomarkers for early multiple system atrophy

ObjectiveTo systematically evaluate structural MRI and diffusion MRI features for cross-sectional discrimination and tracking of longitudinal disease progression in early multiple system atrophy (MSA). MethodsIn a prospective, longitudinal study of synucleinopathies with imaging on 14 controls and 29 MSA patients recruited at an early disease stage (15 predominant cerebellar ataxia subtype or MSA-C and 14 predominant parkinsonism subtype or MSA-P), we computed regional morphometric and diffusion MRI features. We identified morphometric features by ranking them based on their ability to distinguish MSA-C from controls and MSA-P from controls and evaluated diffusion changes in these regions. For the top performing regions, we evaluated their utility for tracking longitudinal disease progression using imaging from 12-month follow-up and computed sample size estimates for a hypothetical clinical trial in MSA. We also computed these selected morphometric features in an independent validation dataset. ResultsWe found that morphometric changes in the cerebellar white matter, brainstem, and pons can separate early MSA-C patients from controls both cross-sectionally and longitudinally (p < 0.01). The putamen and striatum, though useful for separating early MSA-P patients from control subjects at baseline, were not useful for tracking MSA disease progression. Cerebellum white matter diffusion changes aided in capturing early disease related degeneration in MSA. InterpretationRegardless of clinically predominant features at the time of MSA assessment, brainstem and cerebellar pathways progressively deteriorate with disease progression. Quantitative measurements of these regions are promising biomarkers for MSA diagnosis in early disease stage and potential surrogate markers for future MSA clinical trials.

Data-driven subtype classification of patients with early-stage multiple system atrophy

IntroductionPatients with multiple system atrophy (MSA) are conventionally identified as having MSA-P (prominent parkinsonism) or MSA-C (prominent cerebellar ataxia) based on their predominant motor manifestations. The objective of the present study was to conduct latent class analysis (LCA) of various motor and nonmotor symptoms in early MSA to characterize data-driven subgroups. MethodsSixty-one probable or possible MSA patients with disease durations of 3 years or less were included prospectively. LCAs were performed to identify similar clinical subgroups giving even weights to a wide range of MSA motor and nonmotor features. We ran latent models of up to 6 class solutions; the overall model fit was evaluated based on the parsimony of the derived classes, the fit indices, and clinical interpretability. ResultsThe LCA outcome supported categorization of at least three subgroups of patients with early MSA: the largest class 1, labeled “moderate parkinsonism + extensive dysautonomia”, included approximately half of our study patients and showed marked autonomic dysfunction with a burden of parkinsonism. The two other classes, class 2 “predominant parkinsonism + limited dysautonomia” and class 3 “predominant cerebellar symptoms + limited dysautonomia”, showed marked core motor features (parkinsonism or cerebellar symptoms) with generally mild dysautonomia. ConclusionsTo our knowledge, this is the first data-driven identification of disease subtypes covering various symptom constellations in early MSA (<3 years from motor symptom onset). The present LCA result did not replicate the conventional motor classification and supported the heterogeneity within MSA-P and MSA-C subtypes.

Pathological laughter and crying in multiple system atrophy with different subtypes: Frequency and related factors

Objective: The current study was aimed at examining the frequency of and potential factors related to pathological laughter and crying (PLC) in multiple system atrophy (MSA) as well as evaluating the impact of PLC on the survival of patients with early stage MSA. Methods: A total of 465 MSA patients were enrolled in the study. The binary logistic regression model was used to explore the potential factors related to PLC. Altogether, 142 patients in their early stage (disease duration ≤3 years), who were followed up for at least two years, were included in the propensity score matching (PSM) analysis. A Cox regression model was used to analyze the impact of PLC on the survival of patients with early stage MSA. Results: The frequency of PLC was 12.7%, 12.0%, and 13.2% in MSA, MSA-parkinsonian subtype (MSA-P), and MSA-cerebellar type (MSA-C), respectively. The binary logistic regression model indicated that younger age and higher total UMSARS scores were associated with PLC in MSA, MSA-P, and MSA-C patients. Additionally, for patients in the early stage, it was found that PLC was not a predictor for mortality in MSA, as indicated by the multivariate Cox regression model. Conclusion: PLC was not uncommon in patients with MSA, MSA-P, and MSA-C. Younger age and greater disease severity were associated with PLC in MSA, MSA-P, and MSA-C patients. PLC was not a predictor of mortality in patients with MSA.

Inosine 5'-Monophosphate to Raise Serum Uric Acid Level in Multiple System Atrophy (IMPROVE-MSA study).

The aim of this trial was to investigate the safety, tolerability, and capability of serum uric acid (UA) elevation of inosine 5'-monophosphate (IMP) in multiple system atrophy (MSA). The IMPROVE-MSA trial was a randomized, double-blind, placebo-controlled trial in patients with MSA with no history of hyperuricemia-related disorders. The participants were assigned to placebo (n=25) or IMP (n=30) in a 1 to 1 ratio, and then followed up for 24weeks. The primary end points included safety, tolerability, and alteration of the serum UA level during the follow-up period. The secondary end points were changes in scores of the unified MSA rating scale (UMSARS) and the Mini-Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The total number of adverse events (AEs) and serious AEs was comparable between the active and placebo groups. Serum UA level (mg/dL) was significantly increased from baseline (active vs. placebo, 4.57 vs. 4.58; P=0.98) to study end point (6.96 vs. 4.43; P<0.001) in the active group compared with the placebo group (time×group interaction; P<0.001). The change in UMSARS scores did not differ between the active and placebo groups. However, the active group showed better alterations in MoCA scores with nominal significance (P<0.001) and tendency for better alterations in MMSE scores (P=0.09) than the placebo group. Our data demonstrated that IMP treatment was generally safe and well-tolerated in patients with MSA. A further trial with a long-term follow-up is required to examine whether UA elevation will slow clinical progression in early MSA.

A Phase 1 Randomized Trial of Specific Active α‐Synuclein Immunotherapies PD01A and PD03A in Multiple System Atrophy

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease with limited symptomatic treatment options. Aggregation of α‐synuclein in oligodendrocytes is believed to be a central mechanism of the neurodegenerative process. PD01A and PD03A are 2 novel therapeutic vaccine candidates containing short peptides as antigenic moieties that are designed to induce a sustained antibody response, specifically targeting pathogenic assemblies of α‐synuclein. The objectives of the current study were to evaluate primarily the safety and tolerability of PD01A and PD03A in patients with early MSA. Thirty patients (11 women) were randomized to receive 5 subcutaneous injections of either PD01A (n = 12), PD03A (n = 12), or placebo (n = 6) in this patient‐ and examiner‐blinded, placebo‐controlled, 52‐week phase 1 clinical trial (ClinicalTrial.gov identifier: NCT02270489). Immunogenicity and clinical scores were assessed as secondary objectives. Twenty‐nine patients reported a total of 595 treatment‐emergent adverse events (mild or moderate, n = 555; severe, n = 40). Treatment‐related adverse events included 190 injection‐site reactions typically observed in vaccination trials with similar per‐subject incidence in the treatment groups over time. Sustained IgG titers were observed in the PD01A‐treated group, and 89% of treated patients developed a PD01‐specific antibody response after receiving all injections. Induced antibodies displayed clear reactivity to the α‐synuclein target epitope. Titers and antibody responder rate (58%) were lower in the PD03A‐treated group. In conclusion, both PD01A and PD03A were safe and well tolerated. PD01A triggered a rapid and long‐lasting antibody response that specifically targeted the α‐synuclein epitope. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Alpha-Synuclein Oligomers and Neurofilament Light Chain in Spinal Fluid Differentiate Multiple System Atrophy from Lewy Body Synucleinopathies.

To explore the role of alpha-synuclein (αSyn) oligomers and neurofilament light chain (NFL) in cerebrospinal fluid (CSF) as markers of early multiple system atrophy (MSA) and to contrast findings with Lewy body synucleinopathies. In a discovery cohort of well-characterized early MSA patients (n = 24) and matched healthy controls (CON, n = 14), we utilized enzyme-linked immunosorbent assay to measure NFL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF. We confirmed findings in a separate prospectively enrolled cohort of patients with early MSA (n = 38), Parkinson disease (PD, n = 16), and dementia with Lewy bodies (DLB, n = 13), and CON subjects (n = 15). In the discovery cohort, NFL was markedly elevated in MSA patients, with perfect separation from CON. αSyn-PMCA was nonreactive in all CON, whereas all MSA samples were positive. In the confirmatory cohort, NFL again perfectly separated MSA from CON, and was significantly lower in PD and DLB compared to MSA. PMCA was again nonreactive in all CON, and positive in all but 2 MSA cases. All PD and all but 2 DLB samples were also positive for αSyn aggregates but with markedly different reaction kinetics from MSA; aggregation occurred later, but maximum fluorescence was higher, allowing for perfect separation of reactive samples between MSA and Lewy body synucleinopathies. NFL and αSyn oligomers in CSF faithfully differentiate early MSA not only from CON but also from Lewy body synucleinopathies. The findings support the role of these markers as diagnostic biomarkers, and have important implications for understanding pathophysiologic mechanisms underlying the synucleinopathies. ANN NEUROL 2020;88:503-512.

Various Motor and Non-Motor Symptoms in Early Multiple System Atrophy

Background: Multiple system atrophy (MSA) patients pre­sent a variety of symptoms other than autonomic dysfunctions, parkinsonism, and cerebellar ataxia. The aim of this study was to evaluate the frequency of various motor and non-motor symptoms including so-called “red flags” in patients with early MSA and to determine whether the frequency of these symptoms was different between the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes. Methods: Sixty-one probable or possible MSA patients with disease duration of 3 years or less were included. Patients were classified into MSA-P, MSA-C, and MSA-PC. The frequency of 13 features including various motor and non-motor symptoms that commonly occur in MSA was assessed. Results: Dysarthria was the most prevalent feature (98.4%) followed by sexual dysfunction (95.1%). Probable REM sleep behavior disorder was present in 90.2%. The frequency of constipation (82.0%), dysphagia (68.9%), and snoring (70.5%) was also high. Stridor was present in 42.6% and more common in MSA-C than in MSA-P. Conclusions: Increasing awareness of various motor and non-motor symptoms may assist clinicians to make an early, accurate diagnosis and to improve management of patients with MSA. We suggest that the diagnostic accuracy can be improved if these features are appropriately reflected in the new diagnostic criteria for MSA.

MRI Morphometry in Early Multiple System Atrophy: Correlations with Indices of Disease Burden &amp; Tracking Progression (P3.6-050)

MRI Morphometry in Early Multiple System Atrophy: Correlations with Indices of Disease Burden &amp; Tracking Progression (P3.6-050)

Abnormalities on structural MRI associate with faster disease progression in multiple system atrophy

BackgroundThe rate of clinical progression in patients with multiple system atrophy (MSA) varies between individuals and predictors for disease progression remain undefined. While the MSA-rasagiline study found no difference in the rates of clinical progression for patients treated with rasagiline versus placebo, it included a large, prospective magnetic resonance imaging (MRI) substudy that can provide new information on the underlying disease progression in patients with early MSA. MethodsThis post-hoc analysis compared the rate of clinical progression in patients with MSA-specific structural changes at baseline (MRI-positive group) versus the rate of progression in patients without evidence of such changes at baseline (MRI-negative group) using a repeated measures ANCOVA. Clinical progression was assessed using the Unified MSA Rating Scale (UMSARS) and Clinical Global Impression of Improvement (CGI-I). ResultsTwenty-eight patients with early MSA of the parkinsonian subtype (MRI-positive n = 13; MRI-negative n = 15) who had complete baseline and follow-up UMSARS data were included in this analysis. Patients in the MRI-positive group had faster clinical progression from baseline to the end of the 48-week study compared with those in the MR-negative group as assessed by the UMSARS total (p = 0.028) and UMSARS motor (p = 0.008) scales. At week 48, MRI-positive patients also had a significantly worse health status vs. MRI-negative patients (p = 0.015). ConclusionsThis is the first study to demonstrate that MSA-specific abnormalities on structural MRI might represent a variant of MSA-P that is associated with more rapid progression and an overall worse prognosis.

131I-MIBG myocardial scintigraphy for differentiation of Parkinson's disease from multiple system atrophy or essential tremor in Chinese population

ObjectiveClinical distinction of Parkinson's disease (PD) from multiple system atrophy (MSA) or essential tremor (ET) is sometimes difficult. The purpose of this study was to assess changes in cardiac sympathetic nerve function in PD, MSA, and ET by 131I-MIBG myocardial scintigraphy MethodsPatients with PD (25), MSA (18), or ET (11) and 10 healthy controls (HC) were enrolled. 131I-MIBG myocardial scintigraphy was performed for each subject, and heart/mediastinum (H/M) ratios were calculated at two sample times (15min and 4h after the injection of 131I-MIBG), representing the 131I-MIBG myocardial uptake ratios. The washout ratio (WOR) of MIBG which indicates the activity tone of the presynaptic sympathetic nerves was calculated for each subject. ResultsThe H/M ratios at the two sample times (15min and 4h) were 1.65±0.36 and 1.50±0.43 in the PD group, 1.97±0.36 and 2.08±0.57 in the MSA group, 2.34±0.34 and 2.46±0.51 in the ET group, and 2.41±0.26 and 2.66±0.47 in the HC group. The H/M ratios at the two sample times were lower in the PD group than in the MSA, ET, or HC groups, with statistical significance (all P<0.05). The H/M ratios at the two sample times were significantly lower in the MSA group than in the HC group (all P<0.05). There was no significant difference in H/M ratios at either sample time between the ET and HC group (all P>0.05). The washout ratios (WORs) of MIBG were significantly increased in PD group compared with those in MSA, ET and HC groups. In subgroup analysis, The H/M ratios at the two sample times were decreased in early PD group compared with those in early MSA and early ET groups, with statistical significance (all P<0.05). ConclusionsCardiac sympathetic dysfunction can occur in both PD and MSA patients, especially in PD patients, whereas it remains normal in ET patients. 131I-MIBG myocardial scintigraphy can help distinguish patients with PD from those with MSA or ET with good sensitivity and specificity.

The value of novel MRI techniques in Parkinson-plus syndromes: Diffusion tensor imaging and anatomical connectivity studies

Conventional MRI is a well-described, highly useful tool for the differential diagnosis of degenerative parkinsonian syndromes. Nevertheless, the observed abnormalities may only appear in late-stage disease. Diffusion tensor imaging (DTI) can identify microstructural changes in brain tissue integrity and connectivity. The technique has proven value in the differential diagnosis of multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and Parkinson's disease (PD). Here, we performed a systematic review of the literature on the main corticosubcortical DTI abnormalities identified to date in the context of the diagnosis of MSA and PSP with diffusion-weighted imaging, diffusion tensor imaging and anatomical connectivity studies. In good agreement with the histological data, increased diffusivity in the putamen (in MSA and PSP), in the middle cerebellar peduncles (in MSA) and in the upper cerebellar peduncles (in PSP) has been reported. Motor pathway involvement is characterized by low fraction anisotropy (FA) in the primary motor cortex in MSA-P and PSP, a high apparent diffusion coefficient (ADC) and low FA in the supplementary motor area in PSP. We then outline the value of these techniques in differential diagnosis (especially with respect to PD). Anatomical connectivity studies have revealed a lower number of fibers in the corticospinal tract in MSA and PSP (relative to PD and controls) and fewer tracked cortical projection fibers in patients with PSP or late-stage MSA (relative to patients with early MSA or PD and controls). Lastly, we report the main literature data concerning the value of DTI parameters in monitoring disease progression. The observed correlations between DTI parameters on one hand and clinical scores and/or disease duration on the other constitute strong evidence of the value of DTI in monitoring disease progression. In MSA, the ataxia score was correlated with ADC values in the pons and the upper cerebellar peduncles, whereas both the motor score and the disease duration were correlated with putaminal ADC values. In conclusion, DTI and connectivity studies constitute promising tools for differentiating between “Parkinson-plus” syndromes.