Multiple System Atrophy: A Comprehensive Narrative Review of Advances in Diagnosis, Treatment, and Emerging Therapies

Multiple System Atrophy: A Comprehensive Narrative Review of Advances in Diagnosis, Treatment, and Emerging Therapies | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 14 April 2025 V1 Latest version Share on Multiple System Atrophy: A Comprehensive Narrative Review of Advances in Diagnosis, Treatment, and Emerging Therapies Authors : Rasa Valiauga 0000-0002-8911-6258 [email protected] , Christian Tallo , Catriona Hong , Soumya Malhotra , Shaminy Manoranjithan , Matthew Linz , Ananya Sharma , and Wyatt Lanik Authors Info & Affiliations https://doi.org/10.22541/au.174463564.46982073/v1 712 views 238 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Multiple System Atrophy (MSA) is a rare, progressive neurodegenerative disorder characterized by a combination of autonomic dysfunction, parkinsonism, and cerebellar ataxia. Diagnostic criteria for MSA have evolved significantly, with recent updates incorporating advanced imaging techniques to enhance early and accurate detection. Pathologically, MSA is defined by the presence of α-synuclein-positive glial cytoplasmic inclusions and is increasingly associated with neuroinflammation, dysregulated iron homeostasis, and demyelination. Management of MSA remains primarily symptomatic, with treatment strategies tailored to address both motor and non-motor symptoms. The two main subtypes—MSA with predominant parkinsonism (MSA-P) and MSA with cerebellar features (MSA-C)—present distinct clinical profiles, each requiring nuanced diagnostic and therapeutic approaches. Recent advances in understanding MSA pathophysiology have driven the development of targeted treatments. These include molecular therapies aimed at reducing α-synuclein aggregation and immunotherapies directed against α-synuclein, though their clinical efficacy is still under investigation. Additionally, approaches targeting neuroinflammation and promoting neuroprotection represent promising areas of research. Despite these developments, current treatment remains largely supportive, focused on alleviating symptoms rather than halting disease progression. The underlying cause of MSA continues to be poorly understood. To improve early diagnosis, therapeutic innovation, and patient outcomes, further refinement of diagnostic criteria, broader inclusion in clinical trials, and the collection of long-term clinical data are urgently needed. This review article consolidates current knowledge on MSA, highlighting recent advancements in diagnosis, pathophysiology, and emerging therapeutic strategies to guide future research and clinical practice. Introduction Multiple system atrophy (MSA) is a progressive neurodegenerative disorder associated with autonomic failure, parkinsonism, and ataxia [1, 2]. It was first identified in the early 20th century by French neurologists J. Dejerine and A. Thomas, who described two patients with a constellation of symptoms ranging from sporadic ataxia to extrapyramidal disturbances, urinary problems, and postural hypotension [3]. By 1960, G. Shy and G. Drager from the National Institutes of Health (NIH) defined Shy-Drager syndrome as “the triad of autonomic failure, parkinsonism, and ataxia”, which would later be renamed “multiple system atrophy” [4]. However, it was not until 1998 that the American Autonomic Society and American Academy of Neurology produced the first consensus statement regarding MSA diagnostic criteria [5]. This refined the diagnostic criteria to require corticospinal dysfunction, autonomic failure/urinary dysfunction, and poor response to levodopa in parkinsonism or cerebellar ataxia for diagnosis. A decade later, a second consensus statement categorized MSA into definite MSA, probable MSA, and possible MSA according to the presence of neuropathologic findings, autonomic failure with levodopa-refractory parkinsonism or cerebellar ataxia, and parkinsonism with one hallmark of autonomic dysfunction [6]. In 2022, the diagnostic criteria was further revised to include magnetic resonance imaging (MRI) brain findings [7]. Clinical Presentation and Diagnosis MSA classically presents with progressive autonomic failure, parkinsonism, and cerebellar ataxia [8]. Notably, while dementia and cognitive impairment are associated with MSA, these findings are considered non-supportive features in the diagnosis of the disease [9]. MSA is a rare disease with an estimated crude prevalence of 7.2 cases per 100,000 people per year and an age-adjusted cumulative incidence of 14.2 per 100,000 for those thirty years or older [10]. The onset of disease is typically in the 6 th decade of life, and whether there are any sex differences in disease progression and survival is currently unclear [11-14]. The median survival time from disease onset is variable but was found to be about 9.8 years, with the parkinsonian variant predicting a shorter survival [15, 16]. Though rare and understudied, young-onset MSA is characterized by the presence of symptoms before age 40 [17, 18]. MSA is a heterogeneous disorder with two major phenotypes: cerebellar symptoms predominant type MSA (MSA-C) and parkinsonism predominant type MSA (MSA-P). In general, patients can change from MSA-C to MSA-P, but not vice versa [19]. With respect to pathophysiology, MSA-P initially affects the substantia nigra and progresses to the putamen, caudate, and globus pallidus. In contrast, MSA-C initially destroys Purkinje cells and myelin in the cerebellum followed by degeneration of the substantia nigra, pons, inferior olives, and cerebellar vermis and hemispheres [11]. Magnetic resonance imaging (MRI) reveals that fractional anisotropy, which reflects coherence of tracks in white matter, is decreased in MSA-P patients in the middle cerebellar peduncle, pontine crossing tract, and corticospinal tract compared to MSA-C patients [20]. MSA-P predominantly presents with extrapyramidal motor symptoms that mimic the hallmark signs of PD. Parkinsonism in MSA is defined as bradykinesia/akinesia, rigidity, postural instability, and tremor (i.e., postural or resting, with lower incidence of “pill-rolling” tremor characteristic of PD) [21, 22]. Unlike PD, MSA-P demonstrates poor response to levodopa therapy [6, 23]. In contrast, MSA-C is classically associated with cerebellar motor dysfunction characterized by gait and limb ataxia, oculomotor dysfunction (e.g., nystagmus), and dysarthria [21, 24]. Both subtypes of MSA present with autonomic dysfunction, their symptoms often arising early in the course of the disease and predating motor impairment [8, 13, 25]. Autonomic failure seen in MSA progresses rapidly and manifests primarily as neurogenic orthostatic hypotension, genitourinary dysfunction, and/or balance impairment. Neurogenic orthostatic hypotension is diagnosed based on a 20mmHg reduction in systolic blood pressure or 15mmHg reduction in diastolic blood pressure upon standing without appropriate reflexive tachycardia due to baroreflex failure [26]. Neurogenic orthostatic hypotension manifests with symptoms of dizziness, presyncope, and syncope, the symptom burden resulting in reduced quality of life and increased rate of falls [27]. Additionally, genitourinary impairment is characterized by bladder dysfunction (e.g., urinary incontinence, detrusor underactivity, and incomplete emptying) and erectile dysfunction [28, 29]. As the disease progresses, patients with MSA are likely to develop neuropsychiatric disorders, sleep disorders, and cognitive deficits in executive function [9, 30, 31], which all result in worsening disability. Given the heterogeneity in clinical presentation, diagnostic criteria have continuously been refined. The most recent diagnostic criteria, aimed at increasing sensitivity in early disease stages, outlines four categories of MSA: neuropathologically established MSA, clinically established MSA, clinically probable MSA, and possible prodromal MSA [7]. The specific criteria are outlined in Table 1. The diagnosis of neuropathological established MSA has the same anchors as definite MSA in the previous, second consensus criteria from 2008. Clinically established MSA is formed to ensure maximum specificity and adequate sensitivity, while clinically probable MSA balances sensitivity and specificity. Both of the clinical MSA categories are derived from the same diagnostic criteria as per previous consensus. It is important to note that the distinctions between MSA-C and MSA-P are kept. Finally, there is an introduction of a new category, possible prodromal MSA, which was created as a category to be used exclusively for research purposes and designed to potentially capture patients in the prodromal phase of the disease. While the new classification of MSA is more inclusive, the nature of the disease makes it difficult to capture all patients using the existing criteria. Additionally, MSA can resemble various other neurodegenerative diseases, thus leading to misdiagnosis and erroneous eligibility for clinical trials [32]. Furthermore, reports have revealed that only 62% of patients who are clinically diagnosed with MSA have the correct diagnosis at autopsy, which additionally demonstrates the shortcomings in current diagnostic guidelines [33]. The number of research biomarkers suggestive of MSA has been increasing and will likely continue to grow. Thus, prodromal MSA and MSA biomarkers are a potentially beneficial area to further explore [7]. Depending on the patient’s symptomatology, the following testing modalities can be utilized to assist in diagnosis or rule out alternative causes: olfactory testing, autonomic testing, urodynamic testing, swallow studies, cognitive assessments, anal sphincter EMG and manometry, gastric emptying, and polysomnography [34]. Table 1. Multiple system atrophy diagnostic criteria. Clinically probable MSA – sporadic, progressive, adult-onset (>30 years old) with: ≥2 of the following: ≥2 autonomic dysfunction features Parkinsonism Cerebellar syndrome (≥1 feature) AND ≥1 supportive clinical features AND No exclusionary features Possible prodromal MSA (for research purposes only) – sporadic, progressive, adult-onset (>30 years old) with: ≥1 clinical nonmotor features: Rapid eye movement sleep behavior disorder proven by polysomnography Neurogenic orthostatic hypotension Urogenital failure: erectile dysfunction in males with unexplained voiding difficulties and/or unexplained urinary urge incontinence ≥1 clinical motor features: Subtle parkinsonian signs Subtle cerebellar signs No exclusionary features Motor Features Autonomic Features - Parkinsonism poorly responsive to levodopa treatment - Cerebellar syndrome with ≥2 of the following: gait ataxia, limb ataxia, cerebellar dysarthria, oculomotor dysfunction - Unexplained voiding difficulties - Unexplained urinary urge incontinence - Neurogenic orthostatic hypotension Supportive Clinical Features (Motor) Supportive Clinical Features (Nonmotor) - Rapid progression within 3 years of motor onset - Moderate to severe postural instability within 3 years of motor onset - Postural deformities - Craniocervical dystonia induced or exacerbated by levodopa in the absence of limb dyskinesia - Severe dysphagia within 3 years of motor onset - Unexplained plantar reflex (Babinski sign) - Jerky myoclonic postural or kinetic tremor - Stridor - Inspiratory sighs - Cold, discolored hands and feet - Erectile dysfunction - Pathologic laughter or crying MRI Findings Exclusionary Features - Atrophy of putamen, middle cerebellar peduncle, pons, and/or cerebellum - Signal decrease of putamen on iron-sensitive sequences - “Hot cross bun” sign - Increased diffusivity of putamen and/or middle cerebellar peduncle - Substantial and persistent beneficial response to dopaminergic medications - Anosmia - Abnormal cardiac sympathetic imaging - Fluctuating cognition with early decline in visuoperceptual abilities - Recurrent visual hallucinations within 3 years of disease onset - Dementia within 3 years of disease onset - Downgaze supranuclear palsy - Brain MRI findings suggestive of an alternative diagnosis - An alternative condition known to produce autonomic failure, ataxia, or parkinsonism and plausibly connected to the patient’s symptoms Olfactory Function The presence of certain parkinsonism features can be present in various pathologies. For example, polysomnography proven rapid eye movement sleep behavior disorder (RBD) may indicate Lewy Body Dementia (LBD) or MSA [7]. Because of this, it is important to establish what symptoms are specific to MSA and which suggest another disorder. Anosmia has been deemed an exclusion criteria since olfactory function is markedly reduced in patients with PD while patients with MSA typically present with normosmia or mild hyposmia [35]. This finding has been demonstrated in both human studies and animal models [36-39]. Urinary Dysfunction Urologic dysfunction, commonly presenting with difficulty voiding, is seen in a majority of patients with MSA and can be a presenting symptom of the disease [40]. A post-void residual bladder scan can be useful to distinguish bladder abnormalities in PD versus MSA. An increased residual urinary volume >100 ml has a positive predictive value of 91.6% to distinguish MSA versus PD, making this a useful diagnostic tool [41]. Gastrointestinal and Cardiac Disorders Dysphagia is severe in 32% of patients with MSA and is associated with significant morbidity and mortality and is a supportive diagnostic feature of MSA [42]. To improve quality of life and survival, patients experiencing difficulties swallowing should be timely evaluated and treated. Conversely, abnormal 123 I-metaiodobenzylguanidine myocardial scintigraphy can be used to distinguish MSA from PD, with the latter showing innervation reduction in nearly all PD patients while abnormal findings are an exclusionary criteria for MSA [43]. However, it is important to note that approximately one-third of patients with MSA also have cardiac denervation [44]. Sleep Disorders Sleep disorders are common in patients with MSA, particularly RBD, with one multicenter meta-analysis reporting 88% of patients with MSA to have RBD [31]. RBD is one of the most effective markers for an underlying α-synucleinopathy, which is why the other exclusion factors must be used to diagnose MSA specifically. MSA has also been associated with other sleep disorders including restless legs syndrome, periodic limb movements, and sleep-related breathing disorders [45-47]. MSA is a fatal disease that progresses rapidly after the onset of symptoms and significantly impairs quality of life. The Unified Multiple System Atrophy Rating Scale (UMSARS) is used as a clinical tool to assess progression of the disease and is composed of four subscales that assess (I) functional disability in activities of daily living, (II) motor impairment, (III) orthostatic blood pressure, and (IV) disability [21, 48]. Patients diagnosed with MSA have an average life expectancy of 6-10 years following presentation of initial symptoms [8, 16, 49, 50]. While there are no significant differences in survival based on MSA subtype, evidence suggests that worsening UMSARS scores and progressive orthostatic hypotension correlate with poor survival [8, 51]. Viable prognostic predictors also include severe dysautonomia, early combined autonomic and motor symptoms, and early falls [52]. Progressive loss of motor and autonomic function in MSA results in impaired breathing and swallowing ability, and death often results from sudden respiratory compromise or infectious pneumonia [53]. Ongoing research efforts in the area aim to develop disease-modifying therapies to alter disease trajectory. Pathophysiology Postmortem neuropathologic findings of MSA include olivopontocerebellar atrophy and striatonigral degeneration. Nonspecific signs of neurodegeneration consist of changes in the central autonomic nervous system, including the hypothalamus and dorsal nucleus of the vagus nerve, as well as frontal lobe atrophy [1]. The classic histologic finding of MSA is proteinaceous glial cytoplasmic inclusions (GCIs), which are formed aggregates of α-synuclein, with their density generally reflecting severity of neurodegeneration [54, 55]. The oligodendroglial α-synucleinopathy differentiates MSA from Parkinson’s disease (PD) and LBD, which also present with histopathological α-synuclein inclusions but primarily in neurons (Fanciulli and Wenning, 2015). Similar to the aggregates in PD and LBD, GCIs in MSA are primarily made up of α-synuclein phosphorylated at serine residue 129 [56]. Other frequent pathologic signs of MSA include activated microglia and reactive astrogliosis [57]. Understanding the molecular mechanisms of MSA is a major area of research. Beyond α-synuclein misfolding and aggregation, other proposed contributors include disruption of iron homeostasis, neuroinflammation, autophagy, demyelination, and genetic contributions [11]. Iron Homeostasis MSA patients have elevated total iron content in the striatum and pons [58], as well as increased ferritin, which may lead to reduced levels of bioavailable iron [59]. Hemoglobin is also known to be elevated in the white matter of brains of MSA patients [60]. Iron has been shown to promote conversion of native α-synuclein into the β-pleated sheets that are characteristic of MSA, supporting the theory that elevated iron levels may lead to the development of MSA [61]. These findings ultimately suggest that iron chelation may have a role in MSA prevention and/or treatment [62]. Although this area is promising, it is unclear if the iron accumulation is secondary to a cascade of neuronal degeneration or the primary cause, so more research is necessary [61]. Neuroinflammation The presence of microgliosis and astrocytosis is a well-established feature of MSA brain pathology, including in close proximity to GCI-containing oligodendrocytes in rats [63-65]. This has led some to hypothesize α-synuclein elicits to an inflammatory immune response in the white matter of the brain [63, 66-70]. This idea is supported by experiments demonstrating that misfolded α-synuclein activates microglia and astrocytes, promoting further protein aggregation and apoptosis [67, 68]. Furthermore, microglial and diffuse T-cell activation was found in postmortem brain tissue of MSA patients, suggesting widespread neuroinflammation [63, 68-70]. Of note, activated microglia can differentiate into both pro-inflammatory and anti-inflammatory phenotypes, each contributing to MSA pathology in different ways via cytokine signaling [71]. There have also been reported changes in DNA methylation and the level of expression for genes that activate microglia [72]. It is hypothesized that this genetic dysregulation is stemmed from aberrant mRNA levels for intracellular inflammatory pathways [73]. Furthermore, there is evidence to support altered microRNA dysregulation, including in microRNA involved in the regulation of inflammatory pathways [74-76]. Despite this substantial evidence, a causative link between neuroinflammation and MSA has not been established, as it remains unclear whether neuroinflammation is a primary driver of protein accumulation, an aggravator, or a phenomenon secondary to neuronal degeneration [77, 78]. Autophagy Autophagy is the process by which intracellular components are degraded by lysosomes and autophagic dysfunction has been implicated in various neurodegenerative diseases [79]. While markers of autophagy are upregulated in GCIs of MSA patients, these cells display impaired autophagy maturation [80, 81]. Extracellular α-synuclein is taken up by neuronal and oligodendroglial cells, where it immediately assembles into high-molecular-weight oligomers that form the characteristic cytoplasmic inclusions [82]. With impairments in autophagy, the cell cannot degrade these proteins, leading to cellular dysfunction and death [83]. Furthermore, there is evidence to suggest that failure of intracellular clearance mechanisms lead to intracellular α-synuclein aggregation and cell-to-cell transfer of these aggregates to other neuronal cells [84, 85]. Importantly, overexpression of regulators of autophagy have been shown to be neuroprotective [86, 87]. Of note, isolated defects in autophagy do not significantly alter the level of α-synuclein uptake into cells, suggesting that multiple mechanisms likely converge to cause disease [88]. More research is necessary to elicit how autophagy interacts with other pathways involved in MSA pathogenesis. Demyelination Oligodendrocytes are the cells in the central nervous system that form myelin sheaths around nerve fibers, and MSA patients show reduction in the number of oligodendrocytes [69, 70]. α-synuclein has been associated with oligodendrocyte dysfunction, including impaired myelination and neuron support [89]. A potential mechanism behind this finding is the activity of microtubule-associated protein p25α, which has been found to relocalize from the myelin to the cell soma, where it acts as a stimulator of α-synuclein aggregation to promote formation of GCIs in vitro and in situ in postmortem brain tissue of MSA patients [90, 91]. This ultimately dysregulates the myelination process, leading to demyelination and neuronal degeneration [92]. Myelin basic protein levels have been shown to be increased in the CSF of MSA patients compared to healthy controls, which may be associated with demyelination [93]. Genetics Poewe et al. argue that, in contrast to Parkinson disease, there is relatively little evidence for a genetic etiology of MSA [11]. However, recent genome-wide association studies revealed that loss of function mutations in the COQ2 locus (part of the coenzyme Q10 synthesis pathway) were associated with parkinsonism predominant type MSA (MSA-P) and cerebellar symptoms predominant type MSA (MSA-C), respectively, in two families in Japan [94]. However, the same association was not detected among European MSA patients [94, 95]. A follow-up study found that the COQ2 V393A mutation confers high risk for susceptibility to MSA-C but not MSA-P in East Asian patients [96]. Conversely, variants of the MAPT gene, encoding microtubule-associated protein tau, were associated with MSA in European patients but not in other populations [95]. One case study found that a patient with clinically confirmed MSA-C possessed a mutation in the spinocerebellar ataxia type 3 (SCA3) gene, which is associated with a hereditary form of spinocerebellar ataxia [97]. Another study suggests an autosomal recessive inheritance pattern, describing 8 patients within 4 families in Japan with concordant phenotypes within families and lacking mutations associated with other spinocerebellar ataxias [98]. Interestingly, Hara et al. did not find any mutations in the SCNA gene encoding for ɑ-synuclein. However, other studies have identified mutations in SNCA, such as G51D, but failed to demonstrate this mutation as a cause of MSA [99]. Further studies examining genetic contributors are necessary to identify additional familial mutations in patients from various ethnic backgrounds. Advancements in Diagnostic Modalities Imaging Recent advancements in imaging techniques have significantly enhanced the ability to diagnose MSA and differentiate it from other movement disorders such as PD and spinocerebellar ataxias (SCA). Structural and diffusion MRI have proven particularly useful in identifying early disease-related changes in MSA. For instance, morphometric changes in the cerebellar white matter, brainstem, and pons were identified as key markers in distinguishing MSA-C patients from controls and for tracking longitudinal disease progression [100]. These regions also showed progressive degeneration regardless of the predominant clinical subtype of MSA, highlighting their potential as quantitative biomarkers for early diagnosis and monitoring disease progression over time. Specific imaging modalities are also useful in differentiating MSA subtypes from other disorders. For example, susceptibility-weighted imaging and quantitative susceptibility mapping have been effective in distinguishing MSA-P from PD. Narrowing of the lentiform nucleus and increased signal intensity standard deviations provided a sensitivity of 89.5% and specificity of 73.7% in identifying MSA-P [101]. Similarly, the standardized T1-weighted/T2-weighted MRI ratio in the middle cerebellar peduncle was highly accurate in distinguishing MSA-C from SCA subtypes, demonstrating superior diagnostic performance compared to visual markers like the “hot cross bun” sign [102]. Additionally, imaging of glial activation via positron emission tomography (PET) using translocator protein (TSPO)-binding radiotracers has shown promise in stratifying MSA subtypes and distinguishing them from PD, with machine learning algorithms achieving up to 96% sensitivity [103]. Techniques like diffusion MRI and neuromelanin-sensitive imaging are being investigated to further provide insights into microstructural degeneration and symptomatology, enhancing our understanding of disease pathology and its clinical correlates [104]. Additionally, it is important to consider the future role of artificial intelligence in imaging. A novel computer-based method has revealed significant variability in α-synuclein pathology, including glial cytoplasmic inclusions (GCI), across brain regions and cases, suggesting new opportunities to identify previously unrecognized MSA subtypes and refine diagnostic classifications [105]. These findings underline the importance of imaging as a tool not only for early and accurate diagnosis of MSA but also its implications for tracking the progression of MSA and tailoring interventions in clinical trials. Advanced PET imaging with α-synuclein-specific tracers, such as [18F]ACI-12589, has demonstrated strong specificity in identifying MSA-associated α-synuclein pathology in key regions, including the cerebellum and middle cerebellar peduncles [106]. Another imaging biomarker, [18F]D2-Deprenyl, targets astrogliosis and can differentiate between MSA subtypes and PD, correlating with disease progression through regional uptake patterns [107]. Biomarkers Recent advances in diagnostic methods for MSA leverage biomarkers such as neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and plasma to enhance specificity and sensitivity. NfL in CSF has demonstrated near-perfect diagnostic accuracy in distinguishing MSA from PD, with minimal overlap in levels, while NfL in plasma shows less robust diagnostic value [108]. However, like most biomarkers under study, its utility for tracking disease progression remains limited, as NfL levels remain relatively stable over time. Non-invasive blood-based biomarkers are also making strides in differentiating MSA from PD and healthy controls. Elevated phosphorylated α-synuclein in extracellular vesicles supports their diagnostic relevance, with significantly higher levels detected in MSA patients compared to PD [109]. Similarly, oxidized α-synuclein in erythrocytes effectively distinguishes both MSA and PD from controls, though its overlap between MSA and PD limits its differentiation capacity [110]. Plasma NfL shows baseline diagnostic potential and, like CSF NfL, has value in tracking progression longitudinally [111, 112]. Combining pNfL with clinical data may improve diagnostic accuracy. Additional Diagnostic Modalities Several other techniques have shown promising results in differentiating MSA from PD. Corneal confocal microscopy reveals significant reductions in corneal nerve fiber density and length in MSA compared to PD. These markers correlate with disease severity and autonomic dysfunction, making corneal confocal microscopy a sensitive and objective biomarker [113]. Additionally, video oculomotor evaluation is an effective approach that highlights distinct abnormalities in eye movements, such as reduced smooth pursuit and optokinetic nystagmus gains, which are more pronounced in MSA than in PD. Combining these parameters with clinical data enhances diagnostic accuracy and aids differentiation [114]. Similarly, electrophysiological testing using external anal sphincter electromyography and bulbocavernosus reflex offers high sensitivity and specificity for distinguishing MSA from PD by identifying autonomic dysfunction markers unique to MSA. These findings highlight the complementary roles of these diagnostic tools in improving early and precise differentiation of MSA and PD [115]. The integration of advanced PET imaging and blood-derived biomarkers represents significant progress in MSA diagnostics. Imaging modalities such as α-synuclein-specific tracers enable early differentiation from PD, while EV-based biomarkers provide promising non-invasive methods for central nervous system pathology detection, and for some diseases, drug response [106, 116-119]. Despite these advancements, the inability of many current biomarkers to track disease progression underscores the necessity for developing longitudinally dynamic markers that better capture MSA’s clinical evolution. Current Therapies Management of MSA requires an interdisciplinary team approach for optimal patient care. Depending on the symptomatic presentation of the patient, the medical team managing the patient can include specialists, physical therapists, palliative care, speech-language pathologists, and others [34]. Currently, there are no disease modifying therapies for MSA, and symptomatic management is the mainstay treatment [120]. Motor Symptoms Patients experiencing parkinsonism symptoms are recommended to take levodopa up to 1g daily for 3 months in association with physiotherapy. Though a poor response to levodopa is among the core diagnostic features of MSA, about one-third of MSA-P patients benefit from levodopa therapy [16]. Additionally, paroxetine has also been shown to improve motor symptoms in MSA [121]. A small randomized control trial also showed occupational therapy significantly reduced patients’ Unified Parkinson’s Disease Rating Scale and Parkinson’s Disease Questionnaire-39 scores, highlighting the importance of multidisciplinary care [122]. Dystonia has been reported in 12-46% of patients and botulism toxin A injections have been shown to alleviate focal dystonia [23, 123]. On the other hand, generalized dystonia may respond to clonazepam when taken at 0.5-1 mg or baclofen 5 mg up to three times a day [124]. Cardiovascular Symptoms Orthostatic hypotension should be treated with conservative measures including elastic stockings, raising the bed when sleeping, and increasing intake of fluid, salt, and small meals [125]. Midodrine (an α agonist), which was investigated in a double-blind, placebo-controlled study, is the first line therapy for orthostatic hypotension in MSA [126]. Other agents like fludrocortisone, pyridostigmine, and droxidopa have also been shown to improve orthostatic hypotension symptoms if midodrine use is unsuitable [127, 128]. Droxidopa is a new prescription drug that has shown efficacy in short-term clinical trials; it is currently in phase II trials to determine its utility [126]. In patients with supine hypertension, midodrine should be used cautiously. If needed, patients can be given low dose 5mg nifedipine/ 25mg losartan or 0.1-0.2 mg clonidine to manage supine hypertension [129]. Genitourinary Symptoms Urinary dysfunction is a primary feature in patients with MSA. Patients with urinary retention >100mL are recommended to perform clean, intermittent self-catheterization [130]. However, patients often progress to suprapubic catheters to prevent urinary tract infections [131]. Mirabegron has been shown to improve urinary urgency and incontinence in patients with PD, and it has been recommended for MSA [132]. MSA patients can also experience nocturia and are advised to empty their bladder completely before bed. They can also be prescribed low-lose desmopressin at night to manage this symptom [133]. Antimuscarinic agents can also be used, though medications with low central nervous system penetrance like solifenacin are preferred due to a safer risk profile [134]. In male MSA patients, erectile dysfunction can be a significant morbidity and is treated with phosphodiesterase 5 inhibitors [135]. Sleep and Mood Disorders Sleep disorders like RBD are also common and may be the presenting symptom of MSA. Though no therapeutic strategies have been evaluated, the first line treatment in these patients due to respiratory concerns such as stridor and sleep apnea is melatonin. Clonazepam can be used as a second line if melatonin does not provide the desired effects [136]. Depression is also more commonly reported in patients with MSA than PD [137]. Serotonin reuptake inhibitors (SSRIs) or norepinephrine reuptake inhibitors (SNRIs) are typically indicated as first line for therapy, with a lesser risk of inducing orthostatic hypotension than tricyclic antidepressants. Dextromethorphan/quinidine use along with psychological support can also provide relief in mood disorders [138]. Advances in Treatment Pharmaceuticals designed to slow disease progression are currently in preclinical and clinical trials, summarized in Table 2. A major target of these therapies is the misfolding, aggregation, and degradation of α-synuclein. Therapeutic strategies targeting α-synuclein include immunotherapy, antisense oligonucleotides, aggregation inhibitors, and degradation enhancers. In pre-clinical trials, the quinazoline inhibitor ATH434 has been used to prevent α-synuclein aggregation and has demonstrated some efficacy in reducing α-synuclein levels [139]. Further, its interim Phase II trials show decreased α-synuclein levels with only mild to moderate adverse events (NCT05109091) [140]. Immunomodulatory approaches that have recently completed Phase I trials include PD01A and PD03A, which induce an antibody response against pathogenic assemblies of α-synuclein [141]. Phase I results are encouraging as they show a temporary decrease in α-synuclein levels, but further studies are needed to evaluate full efficacy. The monoclonal antibody Lu AF82422 has shown a significant reduction of α-synuclein levels in Phase I trials; however, Phase II results failed to reach statistical significance [142, 143]. Additionally, clinical trials are underway for the monoclonal antibody TAK-341 to evaluate its effect on MSA patients through intravenous (IV) infusions, with the outcomes measured using the Unified Multiple System Atrophy Rating Scale Part I (UMSARS) (NCT05104476) [144]. BIIB101 (ION464), an antisense oligonucleotide, is also currently under investigation with ongoing recruitment to determine its long term safety and tolerability, as well as biomarker capabilities in MSA (NCT04165486) [145]. Some other α-synuclein aggregation inhibitors in development include CLR01, SynuClean-D, Kallikrein-6 serine protease, EGCG, NPT200-11A, Anle138b, NPT088, and IkT-148009 [146, 147]. Many of these drugs have progressed through preclinical trials and are currently being evaluated for next steps. Drugs aimed at increasing α-synuclein degradation include sirolimus/rapamycin, rifampicin, and lithium. Sirolimus/rapamycin, an mTOR inhibitor, failed to show any benefit on the progression of MSA and trials were terminated early when the futility criteria were met [148], On the other hand, while the pre-clinical results were hopeful, clinical trials for both rifampicin and lithium had to be terminated early due to severe adverse effects and worsening of MSA symptoms [149, 150]. Another target for disease-modifying therapy is the reduction of neuroinflammation in MSA, which may help reduce protein aggregation. A phase II RCT of minocycline, a tetracycline antibiotic, in patients with MSA failed to demonstrate motor improvement or neurologic protection [151]. Myeloperoxidase inhibition with Verdiperstat suppressed glial cell activation in a MSA mouse model; however, a phase III RCT failed to meet trial goals for MSA (NCT03952806) [152, 153]. Other drugs in the preclinical stages targeting neuroinflammation include caspase-1 inhibitor and CD5-D5/lenalidomide, which is a combination of a single-chain antibody and an anti-inflammatory agent with increased ability to penetrate the central nervous system [154, 155]. These drugs have shown a reduction of α-synuclein aggregation in MSA transgenic mice, although they require further investigation and advancement to clinical trials. Finally, treatments aimed at increasing neuroprotection are undergoing active investigation. The IGF-1 pathway has been implicated as a potential therapeutic target with exendin-4, a glucagon-like peptide agonist, demonstrating positive dopamine neuronal survival in mice [156]. A phase II clinical trial for Exenatide is in development to assess whether once weekly dosing can alter UMSARS scores in MSA patients (NCT04431713) [156, 157]. SSRI treatment using fluoxetine also gained some support due to the neurotrophic effects. However, it did not show disease score improvements in the MSA-FLOU trial [158, 159]. Moreover, a retrospective study with fluoxetine reported an increase in parkinsonian effects and falls in SSRI treated patients with MSA [160]. Active RCTs in MSA utilizing neuroprotective agents including AAV2-GDNF gene therapy to the putamen, intrathecal delivery of mesenchymal stem cells, and intranasal insulin are underway (NCT04680065, NCT05167721, NCT04876326, NCT02315027) [161-166]. These interventions have demonstrated safety and tolerability in initial trials, with the mesenchymal stem cells showing some delay in MSA progression [167]. Preclinical neuroprotective therapies tested in transgenic mice include benztropine, monophosphoryl lipid A, and sodium phenylbutyrate [168-170]. While benztropine has been used for symptomatic treatment only, monophosphoryl lipid A and sodium phenylbutyrate have shown reduced α-synuclein accumulation. Other therapies have focused on targeting the neuronal cell death that accompanies MSA. These drugs work by reducing the excitotoxicity and inflammation (riluzole, Tllsh2910, YTX-7739, fingolimod), improving mitochondrial function (CoQ10, rasagiline, safinamide) or inducing neuronal proliferation (growth hormone). While riluzole failed to show efficacy, the other pharmaceuticals listed have demonstrated safety and tolerability and are currently being evaluated for further trials (NCT03901638, NCT03753763) [171-177]. Furthermore, KM-819, a FAF1 inhibitor, has displayed neuroprotective effects and recently completed Phase I trials, reporting strong safety profiles (NCT03022799) [178]. Phase II trials are already underway to test its potential as a disease modifying therapy (NCT05670782) [179]. Lastly, the ONO-2808 sphingosine-1-phosphate receptor agonist is also being evaluated for its neuroprotective effects and is currently in active recruitment for phase 2 trials, with an estimated completion in August 2025 (NCT05923866) [180]. Although the growing number of clinical trials exploring therapies for MSA is promising, more research is necessary to identify specific targets for pharmaceutical interventions. Table 2. Novel therapeutic interventions under investigation for the treatment of multiple system atrophy. α-synuclein aggregation Inhibits α-synuclein aggregation via iron regulation ATH434/PBT434 [140] Safe and well tolerated, currently in phase II trials Inhibits α-synuclein aggregation Anle138b [181-184] Sale and well tolerated Inhibits α-synuclein aggregation SynuClean-D [147] Reduced α-synuclein aggregation and toxicity in PD C. elegans models Inhibits α-synuclein misfolding and aggregation NPT200-11 [185, 186] Safe and well tolerated in healthy subjects in phase I trial Vaccine targeting pathogenic α-synuclein PD01A/PD013A [141, 187] Safe and well tolerated Monoclonal antibody against α-synuclein Lu AF82422 [144, 188] Safe and well tolerated, did not reach statistical significance in slowing disease progression in phase II trials, phase III trials ongoing Monoclonal antibody against aggregated α-synuclein PRX002 [189-191] Safe and well tolerated in PD, no meaningful effect on global clinical or imaging measures in phase II trials but showed slower progression of motor decline Monoclonal antibody against α-synuclein MEDI1341 (Tak-341) [192-194] Safe and well tolerated, some motor improvement, phase III trials underway Antisense oligonucleotide BIIB101 (ION464) [145] Phase I trials underway Serine protease that cleaves α-synuclein Kallikrein-6 (Neurosin) [195] Reduced α-synuclein accumulation in preclinical trials Inhibits α-synuclein aggregation Epigallocatechin-3-gallate [196] No change in UMSARS compared to controls Molecular tweezer CLR01 [146] Reduced α-synuclein accumulation in preclinical trials Fusion protein that binds multiple species of amyloid NPT088 [197, 198] Reduced amyloid pathology in transgenic Alzheimer’s disease mice, no effect on brain plaques, tau aggregates, or symptoms in phase I trial of Alzheimer’s patients Tyrosine kinase inhibitor IkT-148009 (Risvodetinib) [199, 200] Safe and well tolerated in PD, currently enrolling patients with MSA Antibiotic, shown to inhibit formation of α-synuclein fibrils in mouse models Rifampicin [149, 201, 202] Did not slow or halt progression of MSA, severe adverse effects, clinical trial terminated early mTOR inhibitor Sirolimus (rapamycin) [148, 203] No UMSARS change between control and treatment, terminated in phase II trial due to futility Regulates autophagy Lithium [150] Severe adverse effects, clinical trial terminated early Neuroinflammation Anti-inflammatory, inhibits microglial activity Minocycline [151] No change in UMSARS compared to controls Reduces oxidative stress by inhibiting myeloperoxidase Verdiperstat (BHV-3241/AZD3241) [152, 153] No change in UMSARS compared to controls Caspase-1 inhibitor, reduces α-synuclein C-terminal truncation VX-765 (Belnascasan) [155] Reduced α-synuclein accumulation and improved motor performance in preclinical trials Single chain antibody targeting α-synuclein with immunomodulator Combination CD5-D5 and Lenalidomide [154] Reduced α-synuclein accumulation and reduced astroglial and microglial activation in preclinical trials Neuroprotection Glucagon-like peptide-1 receptor agonist Exenatide (exendin 4) [156, 157] Reduced α-synuclein accumulation and improved insulin resistance in preclinical trials, Phase II clinical trial in development Neurotrophic support via increase of serotonin levels in the brain Fluoxetine [158, 159] Symptomatic treatment, no UMSARS change between control and treatment Glial cell line derived neurotrophic factor delivery to promote neuronal function and survival AAV2-GDNF (AB-1005) [161] Safe and well tolerated, clinical trial underway Anticholinergic Benztropine [168] Symptomatic treatment, shown to have positive effects on myelination in preclinical trials Toll-like receptor 4 agonist Monophosphoryl lipid A [169] Reduced α-synuclein accumulation in preclinical trials Histone deacetylase inhibitor Sodium phenylbutyrate [170] Reduced α-synuclein accumulation in preclinical trials, clinical trials underway Supports energy metabolism and promotes cell survival Intranasal insulin [166, 204] Safe and well tolerated Promotes survival of neurons by secreting neurotrophic factors and modulating inflammation Mesenchymal stem cell delivery [162-165, 167] Potential for delayed progression of disease Neuronal cell death Glutamate antagonist Riluzole [171] No improvement in survival N-methyl-D-aspartic acid modulator Tllsh2910 [175] Safe and well tolerated, awaiting phase III trials undergoing replanning Antioxidant Ubiquinol [177] Safe and well tolerated, slowed disease progression, further evaluation underway Monoamine oxidase B inhibitor Rasagiline [205] No UMSARS change between control and treatment in patients with MSA-P Monoamine oxidase B inhibitor Safinamide [176, 206] Improvement in motor function in PD, no significant change in motor performance in MSA in phase II trial Neuronal proliferation Growth hormone [174] Safe and well tolerated, no significant differences in disease symptoms or progression Stearoyl-CoA desaturase inhibitor YTX-7739 [172, 207] Prevented α-synuclein toxicity in preclinical trials, well tolerated in healthy and PD patients, phase I trial on hold Fas-associated factor 1 inhibitor KM-819 [178, 179, 208] Safe and well tolerated, phase II trial underway Sphingosine-1-phosphate receptor 5 agonist ONO-2808 [180] Phase II clinical trials underway Immunomodulation FTY720-Mitoxy [209] Reduced α-synuclein accumulation and neuroinflammation, improved motor function in preclinical trials Heavy metal chelator and antioxidant Irminix/Emermaide (NBMI) [210] Safe and well tolerated, awaiting phase III clinical trials Discussion Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease marked by motor, non-motor, and autonomic dysfunctions, leading to a poor prognosis. The pathophysiology of MSA is complex and may involve dysregulations in iron homeostasis, neuroinflammation, increased autophagy, and demyelination, all leading to dense deposits of α-synuclein. The diagnosis of MSA is largely clinical, with symptomatic testing as the gold standard for determination. Given the varied presentation, testing can include olfactory, autonomic, and cognitive assessments. However, despite the advances in diagnostic modalities, current management is targeted toward symptomatic treatment and there is currently no cure. There are two subtypes of MSA, each with a different constellation of symptoms. MSA-P is the Parkinsonian type, with symptoms including bradykinesia, rigidity, and tremors [21, 22]. Despite the low efficacy, the first line treatment for this subtype of MSA is levodopa. Additionally, botulism toxin A has shown some beneficial effects in managing focal dystonia in these patients [123]. In contrast, MSA-C is the cerebellar type of MSA, in which patients present with gait and limb ataxia, oculomotor dysfunction, and dysarthria [21, 22]. These patients tend to have a poorer prognosis due to the lack of interventions, with paroxetine as the first line treatment in managing motor symptoms [121]. Both MSA-P and MSA-C share a range of autonomic symptoms, including orthostatic hypotension, genitourinary impairment, and sleep and mood disorders [9, 26-29, 31, 211]. Orthostatic hypotension is generally treated with non-pharmacological therapies such as raised beds or increased fluid and salt intake. Additionally, the α 1 agonist midodrine has shown some benefit in symptomatic neurogenic orthostatic hypotension [212, 213]. Urinary dysfunction is also a common symptom in MSA patients and is mostly treated with mirabegron; however, antimuscarinic agents like solifenacin are becoming more popular due to their superior safety profiles [132, 134]. Sleep and mood disorders are also quite prevalent in MSA patients and involve symptom-dependent treatment using pharmacotherapies like clonazepam, SSRIs, and TCAs [125, 137]. While these symptomatic treatments have managed to improve patient functional outcomes in the short term, there is a significant need for therapies to slow the progression or cure MSA. Given research supporting α-synuclein as an important driver in disease pathology, it has become a primary pharmaceutical target. Pre-clinical studies using the quinazolinone inhibitor ATH434 have demonstrated some reduced α-synuclein aggregation and improved functional outcomes, with only mild to moderate adverse events [139]. Several other aggregation inhibitors including EGCG, NPT200-11A, Anle138b, CLR01, NPT088, Synuclein-D, IkT-148009, and Kallikrein-6 have passed preclinical testing and are progressing through Phase I trials to determine their safety and tolerability, but their viability is yet to be established [120]. Another approach in treating MSA involves modulating the immune system, either by harnessing the body’s natural defenses to eliminate toxic substances or by controlling the excessive inflammation seen in the disease. Antibodies targeting α-synuclein, such as PD01A and PD03A, recently completed Phase I clinical trials, showing a temporary reduction in α-synuclein levels [141]. Similarly, the monoclonal antibody Lu AF82422 has been evaluated in Phase I clinical studies and has shown encouraging results in reducing α-synuclein aggregates, although advanced studies are needed to determine its potential clinical applications [142]. An alternative strategy for slowing MSA progression focuses on targeting the neuroinflammation, which may help reduce protein aggregation in the disease. Preclinical studies of the small molecule myeloperoxidase inhibitor verdiperstat showed a decrease in glial cells, offering some hope. However, further evaluation was halted due to significant challenges in establishing controls in the trial [152, 153]. Minocycline, an antibiotic, was also evaluated for reducing neuroinflammation but failed to show any improvements in symptoms [151]. Yet another potential target for MSA is neuroprotection. Given the involvement of the IGF-1 pathway in in the disease, GLP agonists like exendin-4 have gained attention. Early studies have shown promising results, including a reduction in α-synuclein concentrations [156]. Additionally, neuroprotective mechanisms in AAV2-GDNF, intranasal insulin, and MSCs have shown potential in slowing the progression of MSA [161-164, 166, 167]. While these clinical trials are promising, they assume that targeting α-synuclein will prevent MSA progression. However, although α-synuclein is a prominent pathological feature of MSA, further research is necessary to determine whether targeting this dysregulation is effective. While progress has been made in understanding the pathophysiology of MSA, its exact cause remains unclear. Some studies have suggested trauma or autoimmune disease as possible triggers, but evidence supporting these theories is limited. Additionally, a genetic component to MSA has been proposed, and while some Parkinsonian symptoms are genetically associated, no definitive inheritance pattern has been identified for MSA [97, 98]. Moreover, the current diagnostic criteria for MSA are limited to specialized research centers, restricting the number of professionals qualified to diagnose and study the disease [7]. Updating the Movement Disorder Society diagnostic criteria for MSA could broaden the identification and enrollment of more accurately defined MSA patients in clinical trials. Redefining the clinical criteria could also help identify patients in the earlier stages of MSA, before they meet the full diagnostic criteria. 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Abbreviations CSF Cerebrospinal fluid GCI Glial cytoplasmic inclusion LBD Lewy body dementia MRI Magnetic resonance imaging MSA Multisystem atrophy MSA-C Multisystem atrophy, cerebellar symptoms predominant type MSA-C Multisystem atrophy, parkinsonism predominant type NfL Neurofilament light chain NIH National Institutes of Health PD Parkinson’s disease PET Positron emission tomography RCT Randomized controlled trial REM Rapid eye movement sleep behavior disorder SCA Spinocerebellar ataxia SGCI α-synuclein-containing glial cytoplasmic inclusion SNRI Serotonin norepinephrine reuptake inhibitor SSRI Selective serotonin reuptake inhibitor TSPO Translocator protein UMARS Unified Multiple System Atrophy Rating Scale Information & Authors Information Version history V1 Version 1 14 April 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords atypical parkinsonism cerebellar ataxias neurodegeneration synucleinopathy Authors Affiliations Rasa Valiauga 0000-0002-8911-6258 [email protected] Loyola University Chicago Stritch School of Medicine View all articles by this author Christian Tallo University of Connecticut School of Medicine View all articles by this author Catriona Hong University of Connecticut School of Medicine View all articles by this author Soumya Malhotra Nova Southeastern University Dr Kiran C Patel College of Osteopathic Medicine View all articles by this author Shaminy Manoranjithan University of Missouri School of Medicine View all articles by this author Matthew Linz Rutgers Robert Wood Johnson Medical School View all articles by this author Ananya Sharma University of Pittsburgh Medical Center Health System View all articles by this author Wyatt Lanik The Ohio State University Wexner Medical Center View all articles by this author Metrics & Citations Metrics Article Usage 712 views 238 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Rasa Valiauga, Christian Tallo, Catriona Hong, et al. 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