July 2026 Research Update

Across these studies, the shared message was that diagnosis can be clarified by looking for specific scan patterns rather than relying on one symptom or one test. Studies using dopamine scans and MRI-based measures suggested certain brain regions are affected differently in multiple system atrophy, progressive supranuclear palsy, Parkinson's disease, and some other conditions. Several papers were single-patient reports, so their scan examples illustrate possibilities but cannot show how often a pattern appears in the wider population. [1] [2] [3] [4] [5] [6] [7] [8]

In a moderate-sized imaging study, a dopamine transporter positron emission tomography (PET) scan showed a caudate-predominant pattern in behavioral variant frontotemporal dementia with parkinsonism, while other parkinsonian syndromes (including multiple system atrophy with predominant parkinsonism) showed a more putamen-predominant pattern; a ratio comparing these regions helped separate groups and was replicated in another cohort. This matters because symptoms can overlap, but the pattern of dopamine changes may point toward a different underlying disease. [1]

In a large cross-sectional study using a dopamine transporter single-photon scan (SPECT), certain uptake ratios between brain regions separated Parkinson's disease from atypical parkinsonism with high overall discrimination, and a machine-learning model showed different decision pathways that tended to group multiple system atrophy with predominant parkinsonism closer to Parkinson's disease than to some other atypical syndromes. The practical meaning is that quantitative scan readouts, not only visual interpretation, may add extra information when diagnoses are difficult early on. [2]

Two MRI-based diagnostic studies focused mainly on distinguishing progressive supranuclear palsy from other conditions that can resemble multiple system atrophy or Parkinson's disease. One retrospective study reported that an automated MRI volumetry index separated progressive supranuclear palsy from Parkinson's disease, multiple system atrophy (both cerebellar and parkinsonism-predominant forms), and healthy controls with performance similar to a manual index, though with lower sensitivity. Another retrospective MRI study using a susceptibility-based measure of the substantia nigra also separated progressive supranuclear palsy from multiple system atrophy and Parkinson's disease, with external validation reported for progressive supranuclear palsy versus healthy controls and Parkinson's disease. [3] [4]

Several case reports showed how diagnosis can shift when typical signs are absent or when earlier tests are inconclusive. One person with suspected cerebellar-predominant multiple system atrophy had an inconclusive MRI, but a brain metabolism PET scan showed low activity in the brainstem and cerebellum consistent with that diagnosis. Other single-patient reports emphasized structural MRI signs such as the hot cross bun sign (seen with cerebellar and brainstem changes) or a putaminal rim pattern that supported multiple system atrophy in the right clinical context. [5] [7] [8] [6]

One case report also highlighted that some tests can be harder to interpret if medications influence results: cardiac imaging uptake improved after stopping selegiline in a man later reclassified from Parkinson's disease to multiple system atrophy with predominant parkinsonism, suggesting caution when using that heart test alone to separate diagnoses. The broader point is that diagnosis often depends on the combination of symptom evolution and multiple test results over time, not a single snapshot. [6]

For patients and caregivers, these papers mainly provide background on why clinicians may order different types of brain imaging and why results can sometimes seem mixed early in the disease. Some tools (quantitative dopamine scans and automated MRI measurements) are being studied to make distinctions between look-alike conditions more consistent, while individual case reports show how advanced imaging can support a diagnosis when standard tests do not. What remains uncertain is how well any single imaging pattern applies across all real-world patients, especially outside specialized centers and outside research settings. [1] [2] [3] [4] [5] [6] [7] [8]

These papers focused on two practical diagnostic challenges: how to identify who with early autonomic problems is more likely to later develop multiple system atrophy, and how to recognize less common diseases that can mimic multiple system atrophy. The evidence included one moderate-sized, long follow-up cohort validation study, one protocol describing a large future cohort, and a small case series describing a rare mimic. Together they suggest that better prediction may require combining clinical features with selected tests, and that some look-alike conditions may require different types of testing (including genetics). [9] [10] [11]

In a prospective cohort of 76 people with pure autonomic failure followed for at least 6 years, the Movement Disorder Society prodromal multiple system atrophy criteria identified most people who later developed multiple system atrophy (high sensitivity), but also labeled many people who did not (limited specificity). When a stricter smell test cutoff was added as an exclusion, specificity and the chance that a positive result truly predicted multiple system atrophy increased, while sensitivity decreased. This pattern suggests a tradeoff between catching nearly everyone who may convert versus reducing false positives. [9]

A separate paper described the ExPRESS study plan: a UK prospective cohort aiming to enroll 500 people with new-onset parkinsonism and collect clinical data plus blood and other biomarkers, with some participants getting more detailed testing and follow-up to 4 years for a final diagnosis. Because this was a protocol, it did not report results yet, but it signals a move toward large, well-tracked groups to improve early distinction between Parkinson's disease and Parkinson-plus syndromes such as multiple system atrophy. [10]

A small case series described four adults with adult-onset Alexander disease, a rare condition that can present with parkinsonism-plus features and autonomic symptoms that resemble multiple system atrophy. In these cases, MRI showed cervicomedullary atrophy with a tadpole sign, and gene testing found changes in the GFAP gene (including variants of uncertain significance), underscoring that imaging plus genetics may be needed when the presentation does not fit neatly. This series is descriptive, so it cannot show how often this mimic occurs among people evaluated for multiple system atrophy. [11]

For patients, this theme is most relevant to two situations: (1) people whose earliest problems are mainly autonomic (for example, bladder and blood pressure symptoms) and (2) people whose symptoms do not align well with typical patterns over time. The cohort validation study suggests that prodromal criteria may be good at flagging possible future multiple system atrophy but can also over-identify people unless additional filters (such as stricter smell testing) are used; how these tools will be used outside research remains uncertain. The protocol and the rare-disease case series mainly provide context on why larger long-term studies and occasional genetic evaluation may be part of future efforts to reduce misdiagnosis. [9] [10] [11]

Across these papers, researchers tested several kinds of blood markers to help with diagnosis in people with multiple system atrophy (MSA) and to better understand differences from Parkinsons disease (PD) and other similar conditions. The overall pattern was that some markers clearly separated MSA from healthy controls, while separating MSA from PD was harder and often only modest. [12] [13] [14] [15]

In a large multicenter clinical biomarker study, plasma total alpha-synuclein and phosphorylated alpha-synuclein were higher in MSA than in healthy controls, and this distinction stayed strong in an independent validation group. However, these alpha-synuclein measures were not different between MSA and PD in this dataset, meaning they may not help as much when the main question is MSA versus PD. [12]

A separate biomarker study measured methylation (a chemical tag on DNA) in cell-free DNA in blood, focusing on the SNCA gene region. People with MSA showed higher methylation at several sites and a higher overall average methylation than controls, and the highest methylation group had higher odds of having MSA than the lowest group. [14]

Another cross-sectional study looked at plasma ceramide ratios (fat-like molecules in the blood) along with inflammation markers and a nerve-injury marker called neurofilament light chain. It reported higher ceramide ratios in MSA than in PD, suggesting these ratios could help tell these conditions apart in that sample. [13]

Two exploratory studies tested broader molecular patterns that might separate MSA from related disorders, but with only moderate success for MSA versus PD. One study measured circular RNAs in blood immune cells and found that multi-marker panels had only modest accuracy for MSA versus PD. Another compared laboratory workflows for untargeted metabolomics and found that PD versus a different parkinsonian condition (PSP-P) showed the clearest signal, while MSA-P comparisons produced few clear differences. [15] [16]

For patients and caregivers, these studies mainly show where blood-based testing for MSA is strongest and where it is still uncertain. Measuring alpha-synuclein in plasma looked reliable for distinguishing MSA from healthy people and also changed over time in MSA in one study, but it did not clearly separate MSA from Parkinsons disease there. Other approaches (DNA methylation, ceramide ratios, and broader RNA or metabolomics panels) add background knowledge and may contribute to future multi-test strategies, but many results are still exploratory and need confirmation before they can be considered dependable tools across clinics and patient groups. [12] [14] [13] [15] [16]

Across these studies, different symptoms in multiple system atrophy (MSA) lined up with changes in specific brain areas rather than a single whole-brain pattern. Freezing of gait related most strongly to shrinkage in a particular cerebellar region together with attention and planning problems, while an involuntary sighing breathing pattern lined up with lower activity in a motor-planning area on brain blood-flow scans. Over about one year, brain shrinkage progressed in several regions, but the amount of cortex thinning did not track with typical measures of disease severity or duration. [17] [18] [19]

In a cross-sectional study of 106 people with probable MSA, smaller volume in cerebellar Crus II was linked to more severe freezing of gait. Problems with executive function (planning, switching tasks) and attention explained part of this link, meaning cerebellar shrinkage and cognitive changes appeared to work together in freezing of gait in this group. [17]

A smaller retrospective case-control MRI study (27 people with MSA and 19 controls) also reported widespread cerebellar and brainstem changes in MSA, and suggested that larger volumes in some posterior cerebellar areas tended to go with better executive function. These executive-function links were exploratory and did not hold up after strict statistical correction, so they need confirmation. [20]

In a retrospective study of 90 people with probable or established MSA, about 23% had an involuntary inspiratory sigh identified by interview and/or exam, and it was more often noticed in interviews than during the examination. People with this sigh pattern had a higher burden of day-to-day symptoms and more autonomic problems, and their brain blood-flow scans showed lower perfusion in both supplementary motor areas, a region involved in starting and sequencing movements. [18]

In a longitudinal MRI study of 36 people with clinically diagnosed MSA followed for about a year, the cortex gradually thinned in motor, frontal, cingulate, and insular areas, spanning several functional networks. At the same time, volume loss was more pronounced in deeper and lower brain regions including the pons, putamen, and cerebellum, and the amount of thinning did not show a clear relationship with disease severity or duration in this dataset. [19]

For patients and caregivers, this set of papers mainly adds background about why symptoms can look different from person to person in MSA: gait freezing and an involuntary sighing pattern may reflect changes in different brain circuits (cerebellum and motor-planning regions), and cognitive symptoms may be part of the gait-freezing picture for some people. These studies do not show that a single scan can predict an individuals symptoms or track day-to-day changes, and several results (especially cerebellum-to-thinking links) are still uncertain and need larger, confirmatory studies.

This set of papers looked at treatment and symptom management in multiple system atrophy (MSA) from three angles: noninvasive brain stimulation, a drug approach for neurogenic orthostatic hypotension (blood pressure drops on standing), and an early-stage lab strategy targeting the alpha-synuclein protein. Overall, clinical evidence suggested symptom improvements in certain areas, but results were not consistently strong across primary trial endpoints, and the protein-targeting approach is not yet tested in people. [21] [22] [23]

A systematic review pooling six randomized controlled trials (140 people with MSA) reported that repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique, improved ataxia (coordination problems) and also improved measures of motor function. The same analysis reported improvements in anxiety, depression, and fatigue scores, suggesting rTMS may affect both movement and non-motor symptoms, while the authors noted that more randomized trials are still needed. [21]

In adults with MSA and symptomatic neurogenic orthostatic hypotension, an exploratory two-phase study tested ampreloxetine (a norepinephrine reuptake inhibitor) using an open-label period followed by a randomized withdrawal to either continue the drug or switch to placebo. The study did not meet its primary endpoints, but symptoms stayed stable for people who continued ampreloxetine and worsened for people withdrawn to placebo on several measures, and standing blood pressure fell after placebo withdrawal. The report also noted no observed increases in supine (lying down) blood pressure in this study. [22]

A preclinical study developed an RNA aptamer (a short RNA molecule) called 1R6 that binds to alpha-synuclein regions involved in aggregation (clumping). In test tubes and cells, 1R6 reduced alpha-synuclein assembly and seeding and could disassemble pre-formed fibrils, and in a fruit fly model expressing human alpha-synuclein it improved movement-related tests and other disease-like features. The authors emphasized that delivery, stability, immune effects, and testing in mammals are important next steps before this kind of approach could be considered for people. [23]

For patients and caregivers, these papers mainly add context about what kinds of symptoms researchers are trying to treat in MSA and how strong the evidence is so far. rTMS has the most direct clinical evidence here, with pooled results across small randomized trials suggesting improvements in coordination, mood, and fatigue, but larger trials would be needed to know how reliable and long-lasting benefits are. The orthostatic hypotension study suggests some symptom measures worsened when participants were switched to placebo after time on ampreloxetine, but the trial also highlights uncertainty because the primary endpoints were not met. The RNA aptamer work is background research only for now, because it was not tested in humans and key questions (such as safe delivery into the nervous system) remain open. [21] [22] [23]

This month, studies looking at what comes before a multiple system atrophy (MSA) diagnosis suggested a mixed picture: some factors seemed linked to later MSA, but several links became weaker when researchers required a longer time gap between the factor and the MSA diagnosis. That pattern raises the possibility that some "risk factors" could actually be early changes of the disease (for example, reduced activity) rather than true causes. [24]

In a UK Biobank study using medical coding to identify incident MSA, antihistamine use, alcohol use, and reduced physical activity showed associations at baseline that weakened when the analysis used longer latency windows, which the authors noted could suggest reverse causation. In the same study, rural living was the one exposure whose association strengthened at longer latency windows (for example, at 5 years). [24]

In a hospital-based case-control study from Sichuan, China, having ever smoked was linked to higher odds of MSA compared with never smoking, and the higher odds were most apparent among former smokers and among people who had quit within the last few years. The study did not find a clear exposure-response pattern for MSA (unlike the pattern seen for Parkinson's disease in the same analysis), and the authors cautioned that recall and reverse-causality biases can affect case-control studies. [25]

The UK Biobank analysis also reported that statin use was linked to lower odds of being diagnosed with MSA at baseline and at a 5-year latency window, but this link weakened at 10 years. The authors also noted an apparently discordant pattern where moderately elevated cholesterol was linked to lower MSA odds, highlighting uncertainty about what these medication and cholesterol signals mean. [24]

These studies add background information about possible factors seen more often in people who later receive an MSA diagnosis, but they do not show that any single factor causes or prevents MSA. The fact that several associations weakened when researchers looked further back in time suggests some may be related to early, unnoticed disease changes rather than true risk factors. Larger studies with careful diagnosis confirmation and long follow-up are still needed to clarify which signals are meaningful.

Across studies of patient perspectives and day-to-day body changes in MSA, a common message was that lived experience matters: people with MSA expressed more concern about the psychological impact of learning future risk, and clinical research continued to refine how often orthostatic hypotension (blood pressure drops on standing) is identified in MSA and what body features may relate to it. Evidence here is mainly survey-based or observational, so it can describe patterns but cannot prove cause and effect. [26] [27] [28]

In a nationwide survey from Turkiye that included people with isolated REM sleep behavior disorder, Parkinson's disease, and MSA, support for disclosing future synucleinopathy risk was lowest in the MSA group. People with MSA also reported the greatest concern about psychological impact, and willingness for additional testing and clinical trial participation differed by group and by factors like sex, age, and education. [26]

In a retrospective comparison across synucleinopathies, orthostatic hypotension in probable MSA was detected more often when using the Movement Disorder Society (MDS) criteria than with older Gilman criteria. The study also found that patterns seen during tilt testing (including systolic blood pressure "overshoot") differed across MSA, Parkinson's disease, dementia with Lewy bodies, and pure autonomic failure. [27]

In a small, exploratory clinic-based study of people with different neurodegenerative parkinsonism conditions, orthostatic hypotension was common overall and more frequent in MSA than in progressive supranuclear palsy. Measures related to limb muscle mass and lower-limb water indices were among the strongest predictors of orthostatic hypotension status, and higher limb muscle index related to a smaller drop in systolic blood pressure after standing. [28]

A separate biology-focused study examined neutrophil extracellular traps (NETs), a type of immune structure, using blood markers and postmortem brain tissue from Parkinson's disease and MSA. It reported that NET structures were increased in both Parkinson's disease and MSA brains compared with controls, while blood NET complexes were reduced in Parkinson's disease and tracked with disease severity in that group. [29]

For patients and caregivers, this set of studies is most relevant as context for understanding two areas: (1) how different people feel about receiving information on future disease risk and the potential emotional burden of that information, and (2) how frequently orthostatic hypotension may be identified in MSA depending on the criteria used, and what body-composition measures might relate to blood pressure drops. The immune-marker work is early-stage and mainly helps researchers explore disease mechanisms; it does not yet translate into changes in routine care, and it is still uncertain how these brain and blood NET signals relate to symptoms or progression in MSA.