Features Of Multiple System Atrophy Research Articles

The Vocal Flutter of Multiple System Atrophy: A Parkinsonian-Type Phenomenon?

Early features of multiple system atrophy (MSA) are similar to those in Parkinson's disease (PD), which can challenge differential diagnosis. Identifying clinical markers that help distinguish MSA from forms of parkinsonism is essential to promptly implement the most appropriate management plan. In the context of a thorough neurological evaluation, the presence of a vocal flutter might be considered a potential feature of MSA-parkinsonian type (MSA-P). This case series describes clinical histories of 3 individuals with MSA-P. In each case, vocal flutter was detected during neurological and motor speech evaluations. It seemed to be a concomitant feature with the constellation of other signs and symptoms that led to the clinical diagnosis. The vocal flutter may be described as pitch and loudness fluctuations during phonation. Different from a vocal tremor, the flutter phenomenon has higher oscillation frequencies. The neuropathological underpinnings of vocal flutter may be related to generalized laryngeal dysfunction that is commonly described in MSA-P. Vocal flutter may be a unique speech feature in some individuals who have MSA-P. Future studies using perceptual and acoustic measures of speech are warranted to quantify these observations and directly compare to other MSA variants, PD, and a control group.

Understanding the Role of CDH4 in Multiple System Atrophy Brain.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. A major pathological feature of MSA is the presence of α-synuclein aggregates in oligodendrocytes, the myelinating cells of the central nervous system. A genome-wide association study revealed that the CDH4 gene is associated with MSA. However, virtually nothing is known about the role of CDH4 in the context of MSA. Our aim was to compare the expression of CDH4 between MSA and control brains, and to investigate its relationship with α-synuclein in oligodendrocytes. RNA and protein were prepared from putamen, motor cortex white matter, cerebellum, and superior occipital cortex tissues collected from MSA (N = 11) and control (N = 13) brains. The expression of CDH4 was measured at mRNA and protein levels by qPCR and western blotting. Oligodendrocyte cells were cultured on plates and transfected with CDH4 cDNA and its impact on α-synuclein was analyzed. Firstly, we found that CDH4 in MSA brain was significantly elevated in the disease-affected motor cortex white matter in MSA (N = 11) compared to controls (N = 13) and unaltered in the disease-unaffected superior occipital cortex. Secondly, we determined that increases in CDH4 expression caused changes in the cellular levels of α-synuclein in oligodendrocytes. When put together, these results provide evidence that support the GWAS association of CDH4 with MSA.

Pain in Multiple System Atrophy a Systematic Review and Meta‐Analysis

AbstractBackgroundIndividuals with multiple system atrophy (MSA) often complain about pain, nonetheless this remains a poorly investigated non‐motor feature of MSA.ObjectivesHere, we aimed at assessing the prevalence, characteristics, and risk factors for pain in individuals with MSA.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta‐Analyzes (PRISMA) guidelines, we systematically screened the PubMED, Cochrane, and Web of Science databases for papers published in English until September 30, 2022, combining the following keywords: “pain,” “multiple system atrophy,” “MSA,” “olivopontocerebellar atrophy,” “OPCA,” “striatonigral degeneration,” “SND,” “Shy Drager,” and “atypical parkinsonism.”ResultsThe search identified 700 records. Sixteen studies provided information on pain prevalence in cohorts of MSA individuals and were included in a qualitative assessment based on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Thirteen studies (11 cross‐sectional, two longitudinal) scored ≥14 points on QUADAS assessment and were included in a quantitative analysis, pooling data from 1236 MSA individuals. The resulting pooled prevalence of pain in MSA was 67% (95% confidence intervals [CI] = 57%–75%), and significantly higher in individuals with MSA of parkinsonian rather than cerebellar type (76% [95% CI = 63%–87%] vs. 45% [95% CI = 33%–57%], P = 0.001). Pain assessment tools and collected information were highly heterogeneous across studies. Two studies reported pain treatment strategies and found that only every second person with MSA complaining about pain had received targeted treatment.ConclusionsWe found that pain is a frequent, but still under‐recognized and undertreated feature of MSA. Further research is needed to improve pain detection and treatment in MSA.

Rapidly progressive multiple system atrophy in a patient carrying LRRK2 G2019S mutation.

Multiple system atrophy (MSA) is considered a primarily sporadic neurodegenerative disease, but the role of genetic is poorly understood. We present a female patient of Moroccan origin who developed a rapidly progressive non-levodopa responsive parkinsonism, gait and balance problems, and dysautonomia including severe bulbar symptoms. She was diagnosed with MSA Parkinsonian-type (MSA-P) and suddenly died at night at 58 years of age. Reduced striatal DAT-SPECT, putaminal hyperintensity on T2-MRI, and hypometabolism with FDG-PET were present. Genetic testing documented a G2019S mutation in the LRRK2 gene. A skin biopsy was obtained and used to perform alpha-synuclein RT-QuIC, which was negative, and immunohistochemical analysis, which demonstrated abnormal alpha-synuclein deposits in cutaneous nerves. Elevated blood neurofilament light chain levels were also documented. LRRK2 mutations are the most common cause of monogenic Parkinson's disease (PD) and G2019S is the most frequent variant. Our patient presented with biological, clinical, and radiological features of MSA, but genetic testing revealed a G2019S LRRK2 mutation, which has been previously reported only in one other case of pathologically proven MSA but with mild progression. In our patient, post-mortem confirmation could not be performed, but RT-QuIC and immunohistochemical findings on skin biopsy support the diagnosis of MSA. G2019S LRRK2 may be linked to an increased risk of MSA. Cases of atypical parkinsonism with rapid disease course should be screened for PD-related genes especially in populations with a high prevalence of mutations in known genes.

Mild cognitive impairment in multiple system atrophy: a brain network disorder.

Cognitive impairment (CI), previously considered as a non-supporting feature of multiple system atrophy (MSA), according to the second consensus criteria, is not uncommon in this neurodegenerative disorder that is clinically characterized by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, motor and cerebellar signs. Mild cognitive impairment (MCI), a risk factor for dementia, has been reported in up to 44% of MSA patients, with predominant impairment of executive functions/attention, visuospatial and verbal deficits, and a variety of non-cognitive and neuropsychiatric symptoms. Despite changing concept of CI in this synucleinopathy, the underlying pathophysiological mechanisms remain controversial. Recent neuroimaging studies revealed volume reduction in the left temporal gyrus, and in the dopaminergic nucleus accumbens, while other morphometric studies did not find any gray matter atrophy, in particular in the frontal cortex. Functional analyses detected decreased functional connectivity in the left parietal lobe, bilateral cuneus, left precuneus, limbic structures, and cerebello-cerebral circuit, suggesting that structural and functional changes in the subcortical limbic structures and disrupted cerebello-cerebral networks may be associated with early cognitive decline in MSA. Whereas moderate to severe CI in MSA in addition to prefrontal-striatal degeneration is frequently associated with cortical Alzheimer and Lewy co-pathologies, neuropathological studies of the MCI stage of MSA are unfortunately not available. In view of the limited structural and functional findings in MSA cases with MCI, further neuroimaging and neuropathological studies are warranted in order to better elucidate its pathophysiological mechanisms and to develop validated biomarkers as basis for early diagnosis and future adequate treatment modalities in order to prevent progression of this debilitating disorder.

Serum lipid levels are associated with orthostatic hypotension in multiple system atrophy patients

ObjectivesOrthostatic hypotension (OH) is one of the most important autonomic features of multiple system atrophy (MSA). This study was established to confirm the correlation between lipid levels and OH in MSA. MethodsA total of 580 patients with probable or possible MSA from neurological wards in six hospitals in Tianjin, Beijing, Hebei Province, and Henan Province, China, were included in this study. The tilt test or stand test was used to assess the severity of OH. Lipid contents, including total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), and triglyceride were evaluated. ResultsSerum levels of total cholesterol, LDL-C, and triglyceride in MSA-OH patients were significantly lower than those in MSA without OH. The risks of OH were significantly higher in the lowest quartiles of triglyceride and LDL-C than in the highest quartiles, after adjusting for confounders (OR = 2.17, 95% CI: 1.23–3.82, P = 0.008 and OR = 2.02, 95% CI: 1.16–3.47, P = 0.012). The risk of severe OH was significantly higher in the lowest quartile and the second quartile of triglyceride than in the highest quartile after adjusting for confounders (OR = 2.16, 95% CI: 1.20–3.87, P = 0.010 and OR = 2.25, 95% CI: 1.24–4.07, P = 0.007). Moreover, the risk of OH was significantly higher in the lowest quartile, and the third quartile of TC than in the highest quartile after adjusting for confounders (OR = 2.04, 95% CI: 1.18–3.52, P = 0.010 and OR = 2.06, 95% CI: 1.19–3.56, P = 0.010). ConclusionLow levels of TC, LDL-C, and triglyceride increased the risk of OH in MSA. A low level of triglyceride predicted severe OH in MSA.

Non-pharmacological and drug treatment of autonomic dysfunction in multiple system atrophy: current status and future directions.

Multiple system atrophy (MSA) is a sporadic, fatal, and rapidly progressive neurodegenerative disease of unknown etiology that is clinically characterized by autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. Early onset and extensive autonomic dysfunction, including cardiovascular dysfunction characterized by orthostatic hypotension (OH) and supine hypertension, urinary dysfunction characterized by overactive bladder and incomplete bladder emptying, sexual dysfunction characterized by sexual desire deficiency and erectile dysfunction, and gastrointestinal dysfunction characterized by delayed gastric emptying and constipation, are the main features of MSA. Autonomic dysfunction greatly reduces quality of life and increases mortality. Therefore, early diagnosis and intervention are urgently needed to benefit MSA patients. In this review, we aim to discuss the systematic treatment of autonomic dysfunction in MSA, and focus on the current methods, starting from non-pharmacological methods, such as patient education, psychotherapy, diet change, surgery, and neuromodulation, to various drug treatments targeting autonomic nerve and its projection fibers. In addition, we also draw attention to the interactions among various treatments, and introduce novel methods proposed in recent years, such as gene therapy, stem cell therapy, and neural prosthesis implantation. Furthermore, we elaborate on the specific targets and mechanisms of action of various drugs. We would like to call for large-scale research to determine the efficacy of these methods in the future. Finally, we point out that studies on the pathogenesis of MSA and pathophysiological mechanisms of various autonomic dysfunction would also contribute to the development of new promising treatments and concepts.

Altered network of limbic system in multiple system atrophy with mild cognitive impairment (P8-11.008)

<h3>Objective:</h3> The purpose of this study is to investigate the structural network of limbic system in Multiple system atrophy with mild cognitive impairment (MCI). <h3>Background:</h3> Cognitive impairment (CI) is considered as a non-supporting feature of multiple system atrophy (MSA). However, CI has been frequently observed in MSA. Despite changing concept of CI in MSA, exact characteristics and pathophysiology are still uncertain. We would investigate structural and functional change in limbic system in MSA with CI. <h3>Design/Methods:</h3> 15 MSA patients with normal cognition and 11 MSA patients with MCI were enrolled in this study. All participants underwent brain MRI with 3D T1 imaging and Seoul Neuropsychological Screening Battery which is widely used neuropsychological test in Korea. Volumetric analysis of the limbic structures was carried out using the FreeSurfer program. We applied Graph Theory program (BRAPH; http://braph.org) to calculate network measures such as characteristic path length, global efficiency, local efficiency, mean clustering coefficient, and small-worldness index to determine the limbic covariance network. <h3>Results:</h3> In neuropsychological test, MCI patients showed decreased memory and executive function, however attention, visuospatial and language function was relatively preserved. In volumetric analysis, there was significant decreased volume of nucleus accumbens in MSA with MCI than MSA with normal cognition (0.026±0.005 vs 0.021±0.00, p=0.03). Among network measures for covariance network, the small-worldness index in the MSA with MCI was lower than that in the MSA with normal cognition (0.973 vs. 0.849, <i>p</i>=0.008). <h3>Conclusions:</h3> This study is the first report to investigate the limbic system in MSA with CI. We found that volumetric difference and the altered functional network connectivity of the limbic system in MSA with MCI compared to MSA with normal cognition. Our findings suggest that structural and functional changes in subcortical limbic structure may be associated with CI in MSA. <b>Disclosure:</b> The institution of Dr. Park has received research support from Korean ministry of SMEs and Startups. Prof. Cha has nothing to disclose. Dr. Seo has nothing to disclose.

Serotonin in synucleinopathies

Dysfunction of the serotonergic system represents an important feature in synucleinopathies like Parkinson disease (PD), dementia with Lewy bodies (DLB) and Multiple system atrophy (MSA). Serotonergic fibers from the raphe nuclei (RN) extend broadly throughout the central nervous system, innervating several brain areas affected in synucleinopathies. Alterations of the serotonergic system are associated with non-motor symptoms or motor complications in PD as well as with autonomic features of MSA. Postmortem studies, data from transgenic animal models and imaging techniques greatly contributed to the understanding of this serotonergic pathophysiology in the past, even leading to preclinical and clinical candidate drug tests targeting different parts of the serotonergic system. In this article, we review most recent work extending the knowledge of the serotonergic system and highlighting its relevance for the pathophysiology of synucleinopathies.

New MDS Criteria for the Diagnosis of Multiple System Atrophy: Overview and Genetic Viewpoint

A new diagnostic criteria for multiple system atrophy, "The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy (MSA)", has been proposed. Under the new criteria, new categories of "clinically established MSA," "clinically probable MSA," and "possible prodromal MSA" have been introduced. The new diagnostic criteria is expected to facilitate early and accurate diagnosis of MSA in clinical practice for MSA patients and clinical trials for MSA. In the diagnostic criteria, "A sporadic, progressive adult (>30 years) onset disease" is described as an "essential feature of MSA," and thus attention to familial occurrence of MSA is not included. Familial occurrence of MSA, however, was recognized first in Japan, and later in the world. We have witnessed discoveries of numerous genes underlying other neurodegenerative diseases, including Parkinson disease, and therefore application of molecular genetics research for MSA is highly expected to contribute to elucidating the molecular basis of MSA. Although the new diagnostic criteria is designed to facilitate early and accurate diagnosis of sporadic MSA, we simultaneously need to pay attention to familial occurrence of MSA and promotion of molecular genetics research of MSA.

Prevalence and Clinical Characteristics of Dementia and Cognitive Impairment in Multiple System Atrophy: A Systematic Review and Meta-Analysis.

Cognitive impairment is a clinical feature of multiple system atrophy (MSA). However, the prevalence and factors influencing the prevalence of cognitive impairment and dementia in MSA patients remain unclear. We aim to provide an estimate of the prevalence of cognitive impairment and dementia in patients with MSA and to evaluate the possible effect of demographic, clinical and methodological factors on the prevalence. We systematically searched the PubMed, Embase, and Web of science databases to identify studies that report the prevalence of cognitive impairment or dementia in MSA published up to February 2022. We computed the estimates of the pooled prevalence using random-effects models. Heterogeneity was investigated by subgroup analyses and meta-regression. Differences between MSA patients with and without cognitive impairment in demographic and clinical features were explored. A total of 23 studies comprising 2064 MSA patients were included in meta-analysis. The pooled prevalence of cognitive impairment in MSA patients was 37% (95% CI: 29% -45%), the prevalence of dementia was 11% (95% CI: 7% -15%). The subgroup analyses showed the prevalence of dementia in pathologically-confirmed MSA was 7% (95% CI: 0% -12%), in clinically diagnosed MSA was 14% (95% CI: 10% -18%). Cognitive impairment in MSA patients was associated with older age, lower education, longer disease duration and more severe motor symptoms. Cognitive impairment is a common non-motor symptom in MSA. Dementia can develop in a few patients with MSA as well, but usually in the late stage.

Determinants of cognitive impairment in multiple system atrophy: Clinical and genetic study.

Classically, cognitive impairment (CI) was not considered as a paramount feature of multiple system atrophy(MSA) in both parkinsonian(MSA-P) and cerebellar(MSA-C) motor-subtypes. Yet, growing evidence indicates currently the commonness of such deficits among MSA patients in different populations. Our aim was to evaluate the cognitive profile of MSA Tunisian patients and to analyze the underlying clinical and genetic determinants. In a retrospective cross-sectional study, clinically-diagnosed MSA patients were included. All subjects underwent clinical and neuropsychological assessments to characterize their cognitive profile. The associations with their APOE genotype status were analyzed. Determinant of CI were specified. We included 71 MSA patients. Female gender(sex-ratio = 0.65) and MSA-P subtype(73%) were predominant. Mean age of disease onset was 59.1years. CI was found in 85.7% of patients(dementia in 12.7% and Mild cognitive impairment(MCI) in 73% of patients mainly of multiple-domain amnestic type(37.3%)). Mean MMSE score was lower among MSA-P compared to MSA-C(23.52 vs. 26.47;p = 0.027). Higher postural instability gait disorder(PIGD) and MDS-UPDRS-III scores were noted in demented MSA patients(p = 0.019;p = 0.015 respectively). The main altered cognitive domain was attention(64.8%). Executive functions and mood disorders were more affected in MSA-P(p = 0.029,p = 0.035 respectively). Clinical and neurophysiological study of dysautonomia revealed no differences across cognitive subtypes. APOE genotyping was performed in 51 MSA patients with available blood samples. Those carrying APOEε4 had 1.32 fold higher risk to develop CI, with lower MMSE score(p = 0.0001). Attention and language were significantly altered by adjusting the p value to APOEɛ4 carriers(p = 0.046 and p = 0.044 respectively). Executive dysfunction was more pronounced among MSA-PAPOEε4 carriers(p = 0.010). In this study, the main determinants of CI in Tunisian MSA patients were MSA-P motor-subtype, mainly of PIGD-phenotype, disease duration and APOEε4 carrying status, defining a more altered cognitive phenotype. This effect mainly concerned executive, attention and language functions, all found to be more impaired in APOEε4 carriers with variable degrees across MSA motor-subtypes.

Alterations of voxel-wise spontaneous activity and corresponding brain functional networks in multiple system atrophy patients with mild cognitive impairment.

Emerging evidence has indicated that cognitive impairment is an underrecognized feature of multiple system atrophy (MSA). Mild cognitive impairment (MCI) is related to a high risk of dementia. However, the mechanism underlying MCI in MSA remains controversial. In this study, we conducted the amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) analyses to detect the characteristics of local neural activity and corresponding network alterations in MSA patients with MCI (MSA-MCI). We enrolled 80 probable MSA patients classified as cognitively normal (MSA-NC, n=36) and MSA-MCI (n=44) and 40 healthy controls. Compared with MSA-NC, MSA-MCI exhibited decreased ALFF in the right dorsal lateral prefrontal cortex (RDLPFC) and increased ALFF in the right cerebellar lobule IX and lobule IV-V. In the secondary FC analyses, decreased FC in the left inferior parietal lobe (IPL) was observed when we set the RDLPFC as the seed region. Decreased FC in the bilateral cuneus, left precuneus, and left IPL and increased FC in the right middle temporal gyrus were shown when we set the right cerebellar lobule IX as the seed region. Furthermore, FC of DLPFC-IPL and cerebello-cerebral circuit, as well as ALFF alterations, were significantly correlated with Montreal Cognitive Assessment scores in MSA patients. We also employed whole-brain voxel-based morphometry analysis, but no gray matter atrophy was detected between the patient subgroups. Our findings indicate that altered spontaneous activity in the DLPFC and the cerebellum and disrupted DLPFC-IPL, cerebello-cerebral networks are possible biomarkers of early cognitive decline in MSA patients.

Host oligodendrogliopathy and α-synuclein strains dictate disease severity in multiple system atrophy.

Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages, different subtypes of the disease are distinguished by their predominant parkinsonian or cerebellar symptoms, reflecting its heterogeneous nature. The pathognomonic feature of multiple system atrophy is the presence of α-synuclein (αSyn) protein deposits in oligodendroglial cells. αSyn can assemble in specific cellular or disease environments and form αSyn strains with unique structural features, but the ability of αSyn strains to propagate in oligodendrocytes remains elusive. Recently, it was shown that αSyn strains with related conformations exist in the brains of patients. Here, we investigated whether different αSyn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant αSyn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that they determined disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. αSyn strains significantly impact disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagated oligodendroglial inclusions that were structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions, in the brains of patients with multiple system atrophy. This study, therefore, shows that the multiple system atrophy phenotype is governed by both the nature of the αSyn strain and the host environment and that by injecting αSyn strains into an animal model of the disease, a more comprehensive phenotype can be established.

Role of fatty acid-binding protein 7 and novel therapeutic approach in synucleinopathies

The synucleinopathies are neurodegenerative disease caused by abnormal accumulation of the 140-amino acid-containing protein α-synuclein (αSyn), including Parkinson's disease (PD), diffuse Lewy body dementia (DLBD), and multiple system atrophy (MSA). In patients with PD and DLBD, αSyn is misfolded in neurons, and its aggregation forms Lewy bodies (LB) and Lewy neurites (LN). On the other hand, in patients with MSA, αSyn accumulates primarily in oligodendrocytes (OLGs) and forms glial inclusion bodies (GCIs), a typical pathological feature of MSA. We recently demonstrated a making complex between αSyn and fatty acid-binding proteins (FABPs) in synucleinopathies and received wide attention. Fatty acid-binding protein 3 (FABP3) in dopamine nerves, and fatty acid-binding protein 7 (FABP7) in glial cells promoted αSyn accumulation and aggregation, respectively and caused cell death. Here, we introduced the current studies about the role of αSyn and FABP7 in MSA and novel therapeutic approach targeting for FABP7.

ATH434 Reduces α-Synuclein-Related Neurodegeneration in a Murine Model of Multiple System Atrophy.

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by aggregated α-synuclein (α-syn) in oligodendrocytes and accompanied by striatonigral and olivopontocerebellar degeneration and motor symptoms. Key features of MSA are replicated in the PLP-α-syn transgenic mouse, including progressive striatonigral degeneration and motor deterioration. There are currently no approved treatments for MSA. ATH434 is a novel, orally bioavailable brain penetrant small molecule inhibitor of α-syn aggregation. To characterize ATH434 for disease modification in a mouse model of MSA. Six-month-old PLP-α-syn mice (MSA mice) were ATH434-treated (ATH434 in food) or untreated (normal food) for 6 months. Motor behavior and numbers of nigral and striatal neurons were evaluated. α-syn aggregates and oligomers were quantified by immunohistochemical and western blot analyses. Microglial activation and neuroinflammation were assessed by histological and molecular analyses. Ferric iron in the Substantia nigra was evaluated with the Perls method. ATH434-treated mice demonstrated preservation of motor performance in MSA mice that was associated with neuroprotection of nigral and striatal neurons. The rescue of the phenotype correlated with the reduction of α-syn inclusions and oligomers in animals receiving ATH434. ATH434-treated mice exhibited significantly increased lysosomal activity of microglia without increased pro-inflammatory markers, suggesting a role in α-syn clearing. ATH434-treatment was associated with lower intracellular nigral iron levels. Our findings demonstrate the beneficial disease-modifying effect of ATH434 in oligodendroglial α-synucleinopathy on both the motor phenotype and neurodegenerative pathology in the PLP-α-syn transgenic mouse and support the development of ATH434 for MSA. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

REM Sleep Behaviour Disorder in Multiple System Atrophy: From Prodromal to Progression of Disease.

A higher frequency of motor and breathing sleep-related disorders in multiple system atrophy (MSA) populations is reported. REM sleep behaviour disorder (RBD) is one of the most robust markers of an underlying alpha-synucleinopathy. Although a large corpus of literature documented the higher prevalence of RBD in MSA, few studies have systematically investigated the prevalence of RBD as mode of disease onset and its role in disease progression. Moreover, there has been increasing interest in phenoconversion into synucleinopathies of cohorts of patients with isolated RBD (iRBD). Finally, some studies investigated RBD as predictive factor of conversion in isolated autonomic failure, a synucleinopathy presenting with autonomic failure as the sole clinical manifestation that could convert to a manifest central nervous system synucleinopathy. As the field of neurodegenerative disorders moves increasingly towards developing disease-modifying therapies, detecting individuals in the prodromal stage of these synucleinopathies becomes crucial. The aims of this review are to summarise (1) the prevalence of RBD during the course of MSA and as presenting feature of MSA (iRBD), (2) the RBD features in MSA, (3) MSA progression and prognosis in the subgroup of patients with RBD predating disease onset, and (4) the prevalence of MSA conversion in iRBD cohorts. Moreover, we summarise previous results on the role of RBD in the context of isolated autonomic failure as marker of phenoconversion to other synucleinopathies and, in particular, to MSA.

Variability of FP-CIT PET Patterns Associated With Clinical Features of Multiple System Atrophy.

To validate the role of the dopamine transporter (DAT) imaging as a biomarker in multiple system atrophy (MSA), we analyzed the association between spatial patterns of [18F]fluoro-propyl-carbomethoxy-iodophenyl-tropane ([18F]FP-CIT) PET and the clinical characteristics of MSA. Sixty-five patients with MSA who underwent [18F]FP-CIT PET between 2009 and 2018 were retrospectively enrolled. To identify spatial patterns of [18F]FP-CIT PET, principal component (PC) analysis was used and correlated with the clinical presentation. Of the 65 patients, 42 presented with parkinsonian subtype of MSA, and 23 presented with cerebellar subtype of MSA (mean age 63.7 ± 9.3 years; disease duration, 1.8 ± 1.8 years). Each PC represents a specific pattern of degeneration: PC1 and PC2 were associated with the DAT binding of the entire putamen and the posterior putamen, respectively. PC3 was associated with increased [18F]FP-CIT uptake of the caudate and decreased uptake of the dorsal pons. PC2 was significantly correlated with the presence of parkinsonism (p = 5.34 × 10-5) and a positive levodopa response (p = 0.044), with age as a cofactor. PC3 was correlated with the presence of urinary incontinence (p = 0.036). Onset age was significantly correlated with both PC2 (R = 0.48, p = 5.0 × 10-5) and PC3 (R = -0.39, p = 0.0013). The spatial pattern of DAT binding can reflect distinct clinical features of MSA and provides insight into the underlying pathophysiology of a broad spectrum of clinical features in MSA.

Cognitive Profile and Its Evolution in a Cohort of Multiple System Atrophy Patients

Introduction: Cognitive decline is not a characteristic feature of multiple system atrophy (MSA), but recent evidence suggests cognitive impairment as an integral part of the disease. We aim to describe the cognitive profile and its progression in a cohort of patients with MSA.Methods: We retrospectively selected patients referred to our department with a clinical diagnosis of MSA who were evaluated at least once a year during the course of the disease and underwent a comprehensive neuropsychological evaluation.Results: At the first evaluation (T0), 37 out of 60 patients (62%) were cognitively impaired, mainly (76%) in attention and executive functioning. Thirteen patients were impaired in one cognitive domain and 24 in more than one cognitive domain. Six out of the 24 had dementia. Twenty patients underwent a follow-up evaluation (T1) after a mean of 16.6 ± 9.3 months from the first evaluation (T0). Eight out of 20 patients were cognitively normal at both T0 and T1. Seven out of 12 patients presented with stable cognitive impairment at T1, while cognitive decline progressed in five patients. Patients with progression in cognitive decline performed significantly worse at T0 than cognitively stable patients. Education was significantly different between patients with and without cognitive impairment. No other differences in demographic and clinical variables and autonomic or sleep disturbances were found. Patients with dementia were older at disease onset and at T0 and had lower education and disease duration at T0 compared to those in other groups.Conclusions: In patients with MSA, we observed three different cognitive profiles: normal cognition, stable selective attention-executive deficits, and progressive cognitive deficits evolving to dementia. The detection of cognitive impairment in patients with suspected MSA suggests the need for comprehensive and longitudinal neuropsychological evaluation.

An update on MSA: premotor and non-motor features open a window of opportunities for early diagnosis and intervention

In this review, we describe the wide clinical spectrum of features that can be seen in multiple system atrophy (MSA) with a focus on the premotor phase and the non-motor symptoms providing an up-to-date overview of the current understanding in this fast-growing field. First, we highlight the non-motor features at disease onset when MSA can be indistinguishable from pure autonomic failure or other chronic neurodegenerative conditions. We describe the progression of clinical features to aid the diagnosis of MSA early in the disease course. We go on to describe the levels of diagnostic certainty and we discuss MSA subtypes that do not fit into the current diagnostic criteria, highlighting the complexity of the disease as well as the need for revised diagnostic tools. Second, we describe the pathology, clinical description, and investigations of cardiovascular autonomic failure, urogenital and sexual dysfunction, orthostatic hypotension, and respiratory and REM-sleep behavior disorders, which may precede the motor presentation by months or years. Their presence at presentation, even in the absence of ataxia and parkinsonism, should be regarded as highly suggestive of the premotor phase of MSA. Finally, we discuss how the recognition of the broader spectrum of clinical features of MSA and especially the non-motor features at disease onset represent a window of opportunity for disease-modifying interventions.