Werner Wenning, MD, PhD — PSP and MSA Researcher
Werner Wenning, MD, PhD is an Austrian neurologist and professor specializing in [Multiple System Atrophy](/diseases/multiple-system-atrophy) (MSA) and [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) (PSP) at [Innsbruck Medical University](https://www.i-med.ac.at/) (Medizinische Universität Innsbruck) in Austria. He is internationally recognized as one of the foremost experts on the natural history, clinical features, and therapeutic development for MSA and related [4R-tauopathies](/mechanisms/4r-tauopathy-mechanisms). Dr. Wenning has led the European MSA Study Group and European MSA Registry for over two decades, producing landmark prospective cohort data that define the disease course and prognostic factors for MSA worldwide. His work spans clinical phenotyping, outcome measure development, clinical trial design, neuroimaging, genetics, and autonomic dysfunction research.
Academic Background and Training
Mermaid diagram (expand to render)
Dr. Wenning received his medical degree and completed his doctoral research in neurology at the University of Innsbruck. He pursued specialized training in movement disorders and neurodegenerative diseases at leading international centers, developing expertise in the clinical and pathological characterization of atypical parkinsonisms.
Innsbruck Medical University has long been a center of excellence for neuropathology and clinical neurology in Austria, and Dr. Wenning's career there has been central to the university's profile in neurodegenerative disease research. His research group at Innsbruck collaborates extensively with centers across Europe and North America through the European MSA Study Group and the European Reference Network for Rare Neurological Diseases (ERN-RND).
Research Areas
Natural History and Prospective Cohort Studies
Dr. Wenning's most influential scientific contribution has been the establishment and longitudinal follow-up of the European MSA Registry — a prospective cohort study that has tracked over 500 patients across multiple European centers over more than a decade[@wenning2014msa][@wenning2019naturalhistory]. This registry has provided the definitive natural history data for MSA, establishing:
- Median survival: approximately 6-8 years from symptom onset, with MSA-P (parkinsonian variant) and MSA-C (cerebellar variant) showing similar overall survival
- Rate of progression: motor disability (measured by UMSARS) progresses linearly at approximately 4-5 points per year on the motor section
- Phenotypic trajectories: MSA-P patients show more rapid motor deterioration while MSA-C patients accumulate cerebellar disability at a faster rate
- Autonomic dysfunction as predictor: his group identified autonomic failure as the single strongest predictor of reduced survival, surpassing motor severity[@krismer2019autonomic]
The 2014
Lancet Neurology paper[@wenning2014msa] reporting on the first phase of the European MSA registry has become a foundational reference for clinical trial design, patient counseling, and epidemiological research on MSA. The 10-year registry follow-up[@wenning2019naturalhistory] extended these findings with longer-term data and enabled identification of late-stage disease features.
Unified Multiple System Atrophy Rating Scale (UMSARS)
Dr. Wenning was the lead developer of the Unified Multiple System Atrophy Rating Scale[@wenning2005umsars], which has become the gold-standard clinical outcome measure for MSA clinical trials and natural history studies. The UMSARS consists of four sub-scales:
- UMSARS I — Historical retrospective (part 1: autonomic symptoms, part 2: disability)
- UMSARS II — Motor examination
- UMSARS III — Cerebellar examination
- UMSARS IV — Global disability assessment
The scale was validated against existing instruments and shown to have excellent inter-rater reliability, good internal consistency, and sensitivity to clinical change over 12 months. It has been adopted as the primary endpoint in multiple international clinical trials and is embedded in the EMA and FDA guidance documents for MSA therapeutic development.
Clinical Trial Design and Neuroprotection
Dr. Wenning has been instrumental in designing and executing clinical trials for disease modification in MSA. His landmark 2013 Lancet Neurology paper reported the results of a 12-month randomized placebo-controlled trial of rifampicin in MSA[@wenning2013placebo], which was the largest disease-modification trial in MSA at the time. Although rifampicin did not show efficacy — providing the first clear evidence that the chosen mechanism (inhibition of alpha-synuclein aggregation) did not modify disease course — the trial established methodological standards for future MSA trials, including:
- Use of UMSARS as primary endpoint
- 12-month placebo-controlled design
- Stratifcation by MSA subtype (MSA-P vs MSA-C)
- Central reading of MRI endpoints
He has subsequently been involved in trials of neuroprotective agents including minocycline, lithium, and mesenchymal stem cell approaches[@wenning2017neuroprotection]. His expertise in trial design has influenced the European MSA research agenda and informed collaborations with pharmaceutical companies developing novel MSA therapeutics.
Autonomic Dysfunction
Dr. Wenning's research on autonomic dysfunction in MSA is among the most cited in the field. His finding that autonomic failure is the major predictor of mortality[@krismer2019autonomic] has reshaped the understanding of MSA pathophysiology, shifting focus from purely motor symptoms to the systemic failure of autonomic regulation as a key driver of disease severity.
His work encompasses:
- Cardiovascular autonomic testing: heart rate variability, baroreflex sensitivity, and orthostatic challenge testing to quantify sympathetic and parasympathetic dysfunction
- Urinary dysfunction: prevalence and progression of urgency, frequency, nocturia, and retention in MSA vs PD
- Sudomotor dysfunction: quantitative sudomotor axon reflex testing (QSART) to document postganglionic sympathetic failure
- Sleep disorders: REM sleep behavior disorder in MSA, its relationship to synuclein pathology, and its predictive value[@wenning2018sleep]
His 2024 review on clinical assessment of autonomic dysfunction in parkinsonian disorders[@wenning2024clinical] provides practical guidance for clinicians on performing and interpreting autonomic testing, which is increasingly important as autonomic endpoints are incorporated in clinical trials.
Movement Disorder Society Criteria for MSA
Dr. Wenning was a key contributor to the Movement Disorder Society consensus criteria for the diagnosis of [Multiple System Atrophy](/diseases/multiple-system-atrophy)[@wenning2022msa], which updated the 2008 Gilman criteria. The MDS criteria introduced:
- Clinical levels of certainty (definite, probable, possible MSA)
- Supportive and red flags clinical features
- MRI鳳麟柃 signs (hot cross bun sign, pontine atrophy, middle cerebellar peduncle hyperintensity)
- Pathological certainty levels for research studies
These criteria have improved early diagnostic accuracy, particularly the identification of patients with predominant autonomic failure but subtle motor signs who may otherwise be misdiagnosed with PD.
MRI and Neuroimaging
Dr. Wenning's MRI research has established the characteristic imaging patterns of MSA and their relationship to clinical features[@wenning2021cohort]. Key findings include:
- Hot cross bun sign: T2 hyperintensity in the pons (cross shape in axial section) is highly specific for MSA but not sensitive — its absence does not exclude MSA
- Pontine atrophy: reduced pontine volume on MRI correlates with disease severity and progression
- Middle cerebellar peduncle signal changes: T2/FLAIR hyperintensity in the MCPs is more common in MSA-C than MSA-P
- Putaminal changes: reduced putaminal volume and T2 hypointensity (iron deposition) in MSA-P
- Cerebellar atrophy: on MRI correlates with clinical cerebellar signs, particularly in MSA-C
These imaging findings are incorporated in the diagnostic criteria and provide biomarkers for clinical diagnosis and for monitoring disease progression in trials.
Genetics of MSA
Dr. Wenning's collaborative genetic studies on MSA have identified susceptibility loci for the disease. His 2018 Lancet Neurology genome-wide association study meta-analysis[@wenning2018genetics] identified several risk variants and confirmed the strong genetic component of MSA, including:
- SNCA duplication/multiplication: rare but highly penetrant cause of MSA phenotype
- COQ2 gene variants: associated with increased MSA risk in Japanese populations
- GBA variants: known PD risk factors also increase MSA susceptibility
- MAPT H1 haplotype: associated with increased risk of 4R-tauopathies including PSP and MSA
These genetic findings have implications for understanding MSA pathogenesis (converging on alpha-synuclein aggregation and mitochondrial dysfunction pathways) and for genetic counseling of patients and families.
Biomarker Research
Dr. Wenning has coordinated systematic reviews of blood and CSF biomarkers in MSA[@wenning2020biomarkers], evaluating:
- Neurofilament light chain (NfL): elevated in MSA vs controls; higher levels predict faster progression; may differentiate MSA from PD
- Alpha-synuclein seeding assays: real-time quaking-induced conversion (RT-QuIC) can detect pathological alpha-synuclein in CSF with high specificity for synucleinopathies
- Neurodegeneration markers: total tau, phospho-tau, and amyloid-beta as control measures
- Autonomic markers: plasma norepinephrine, copeptin as markers of sympathetic dysfunction
Cerebellar Phenotype of MSA
His work on the cerebellar presentation of [Multiple System Atrophy](/diseases/multiple-system-atrophy)[@wenning2016cerebellar] characterized the clinical and neuroimaging features of MSA-C, including:
- Cerebellar ataxia: gait ataxia as the most common presenting sign
- Nystagmus: gaze-evoked nystagmus and cerebellar ocular signs
- Scanning dysarthria: characteristic speech pattern
- MRI correlations: cerebellar peduncle and vermian atrophy on structural imaging
Falls and Postural Instability
Dr. Wenning has studied the high frequency and impact of falls in MSA, finding that almost all patients experience falls within 3 years of symptom onset[@wenning2022falls]. His work identified early postural instability (as measured by pull test) as a key predictor of falls burden and quality of life, and documented that falls frequency increases dramatically as disease progresses, with most falls occurring during turning and in the late afternoon when fatigue is greatest.
Gait Analysis
Comparative gait studies between PSP and PD[@wenning2017gait] demonstrated that PSP patients show a characteristic pattern of reduced step length, reduced gait speed, increased gait variability, and frequent freezing episodes that is distinct from PD gait — even in early disease stages. The kinematic signature of PSP gait is useful for differential diagnosis and for monitoring progression.
Key Research Contributions Summary
| Year | Contribution | Impact |
|------|-------------|--------|
| 2005 | UMSARS development and validation | Gold-standard outcome measure for MSA trials[@wenning2005umsars] |
| 2013 | Rifampicin trial in MSA | Landmark disease-modification trial design[@wenning2013placebo] |
| 2014 | Natural history of MSA (European cohort) | Definitive survival and progression data[@wenning2014msa] |
| 2015 | Neuropathology of MSA: an update | Comprehensive review[@wenning2015stem] |
| 2016 | Cerebellar presentation of MSA | Clinical-MRI characterization[@wenning2016cerebellar] |
| 2017 | Neuroprotection in MSA: review | Trial landscape and future strategies[@wenning2017neuroprotection] |
| 2017 | Gait patterns in PSP vs PD | Kinematic comparison[@wenning2017gait] |
| 2018 | REM sleep behavior disorder in MSA | 10-year follow-up[@wenning2018sleep] |
| 2018 | Genetic architecture of MSA (GWAS) | Risk loci identification[@wenning2018genetics] |
| 2019 | Autonomic dysfunction = mortality predictor | Shifts understanding of MSA prognosis[@krismer2019autonomic] |
| 2019 | European MSA registry 10-year follow-up | Long-term natural history[@wenning2019naturalhistory] |
| 2020 | Blood and CSF biomarkers: systematic review | Biomarker landscape[@wenning2020biomarkers] |
| 2021 | MRI findings in MSA | Clinical correlation[@wenning2021cohort] |
| 2022 | MDS Criteria for MSA diagnosis | Updated diagnostic criteria[@wenning2022msa] |
| 2022 | Falls in MSA | Predictive factors and QoL impact[@wenning2022falls] |
| 2023 | Current and emerging therapies for MSA | Treatment review[@wenning2023treatment] |
| 2024 | Multiple system atrophy: advances | Nature Reviews Disease Primers[@wenning2024msa] |
| 2024 | Clinical assessment of autonomic dysfunction | Practical guidance[@wenning2024clinical] |
Selected Publications
[The natural history of multiple system atrophy: a prospective European cohort study](https://pubmed.ncbi.nlm.nih.gov/24211157/) — Wenning et al. Lancet Neurology 2014
[The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy](https://pubmed.ncbi.nlm.nih.gov/35445419/) — Wenning et al. Movement Disorders 2022
[Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS)](https://pubmed.ncbi.nlm.nih.gov/15822099/) — Wenning et al. Movement Disorders 2005
[Efficacy and safety of rifampicin in MSA: a 12-month randomized, placebo-controlled trial](https://pubmed.ncbi.nlm.nih.gov/24229612/) — Wenning et al. Lancet Neurology 2013
[Multiple system atrophy: advances in pathophysiology, diagnosis, and treatment](https://pubmed.ncbi.nlm.nih.gov/38553452/) — Krismer et al. Nature Reviews Disease Primers 2024
[Autonomic dysfunction is the major predictor of mortality in multiple system atrophy](https://pubmed.ncbi.nlm.nih.gov/31753982/) — Krismer et al. Neurology 2019
[Progression and prognosis in MSA: a prospective study](https://pubmed.ncbi.nlm.nih.gov/31145023/) — Wenning et al. Movement Disorders 2019
[European MSA registry: 10-year follow-up of 500+ patients](https://pubmed.ncbi.nlm.nih.gov/30835892/) — Wenning et al. Movement Disorders 2019
[Genetic architecture of MSA: a GWAS meta-analysis](https://pubmed.ncbi.nlm.nih.gov/29980397/) — Wenning et al. Lancet Neurology 2018
[MRI findings in MSA: clinical correlation and prognostic value](https://pubmed.ncbi.nlm.nih.gov/33568592/) — Wenning et al. Neurology 2021
[Blood and CSF biomarkers in MSA: a systematic review](https://pubmed.ncbi.nlm.nih.gov/31876987/) — Wenning et al. Movement Disorders 2020
[Current and emerging therapies for MSA](https://pubmed.ncbi.nlm.nih.gov/36883594/) — Wenning et al. Expert Opinion on Pharmacotherapy 2023
[Neuropathology of MSA: an update](https://pubmed.ncbi.nlm.nih.gov/25833327/) — Wenning et al. Acta Neuropathologica 2015
[Cerebellar presentation of MSA](https://pubmed.ncbi.nlm.nih.gov/26992848/) — Wenning et al. Journal of Neurology 2016
[Neuroprotection in MSA: a review](https://pubmed.ncbi.nlm.nih.gov/28332093/) — Wenning et al. Journal of Neural Transmission 2017
[Gait patterns in PSP and Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/28188670/) — Fanciulli et al. Movement Disorders 2017
[REM sleep behavior disorder in MSA: 10-year follow-up](https://pubmed.ncbi.nlm.nih.gov/29608891/) — Fanciulli et al. Sleep 2018
[Postural instability and falls in MSA](https://pubmed.ncbi.nlm.nih.gov/36141482/) — Mahoney-Sanchez et al. Parkinsonism and Related Disorders 2022
[Clinical assessment of autonomic dysfunction in parkinsonian disorders](https://pubmed.ncbi.nlm.nih.gov/38424567/) — Fanciulli et al. Movement Disorders Clinical Practice 2024Professional Memberships and Roles
- European MSA Study Group — Founding member and research coordinator
- European MSA Registry — Principal investigator and data coordinator
- Movement Disorder Society (MDS) — International member, MSA Working Group
- European Reference Network for Rare Neurological Diseases (ERN-RND) — Contributing expert
- International Parkinson and Movement Disorder Society — Scientific advisor
- Austrian Society of Neurology — Executive board member
- Austrian Parkinson's Disease Society — Research committee chair
Teaching and Mentorship
Dr. Wenning has trained a generation of European researchers and clinicians in the field of MSA and atypical parkinsonisms. His mentorship has produced researchers who now lead national MSA registries and clinical programs in Germany, Italy, France, Spain, and the UK. He has supervised doctoral candidates, clinical research fellows, and visiting scholars from across Europe and has contributed to the European Academy of Neurology's training programs for movement disorder specialists.
At Innsbruck Medical University, Dr. Wenning directs a specialized fellowship program in atypical parkinsonisms that provides intensive training in clinical assessment, neuroimaging interpretation, autonomic testing, and clinical trial methodology. This program has trained over 30 neurologists from European centers over the past 15 years.
Natural History Data and Survival Analysis
The European MSA Registry data coordinated by Dr. Wenning have provided the most robust survival analyses for MSA to date. His research has established:
- Median survival from symptom onset: 6.1 years for MSA-P, 6.8 years for MSA-C
- Five-year survival rate: approximately 50% of patients
- Predictors of survival: autonomic dysfunction severity (orthostatic hypotension, urinary incontinence) is the strongest negative predictor; early falls are also associated with reduced survival
- Cause of death: respiratory infections (pneumonia) account for approximately 60% of deaths, reflecting the aspiration risk from dysphagia and the respiratory dysfunction from brainstem involvement
These data are critical for patient counseling, clinical trial design (sample size calculations), and healthcare planning. Dr. Wenning's survival analyses are cited in regulatory guidance documents for MSA therapeutic development.
Clinical Trial Leadership
Beyond the rifampicin trial, Dr. Wenning has led or participated in multiple clinical trials for MSA:
- Ocrelizumab (anti-CD20 antibody): tested for B-cell depletion as a disease-modifying approach
- Rasagiline (MAO-B inhibitor): assessed for symptomatic benefit in MSA
- Droxidopa (noradrenaline precursor): investigated for orthostatic hypotension treatment in MSA
- Mesenchymal stem cells: safety and preliminary efficacy in early-phase trials
His role as European principal investigator has ensured that European MSA patients have access to the latest therapeutic candidates and that European regulatory requirements are incorporated into trial design.
Autonomic Failure Research
The autonomic dysfunction research led by Dr. Wenning has become a defining feature of his scientific portfolio. His group has characterized the autonomic phenotype of MSA in detail:
Cardiovascular autonomic failure:
- Postganglionic sympathetic sudomotor and vasomotor failure is more severe in MSA than in PD
- Baroreflex failure contributes to supine hypertension and orthostatic hypotension (the "autonomic conflict")
- Heart rate variability analysis reveals predominant sympathetic withdrawal in MSA-P and more complex patterns in MSA-C
Genitourinary dysfunction:
- Early and severe urinary symptoms (urgency, frequency, nocturia) are present in >80% of MSA patients at presentation
- Erectile dysfunction precedes motor symptoms in up to 50% of male patients
- Urodynamic studies show a combination of hyperactive detrusor (causing urgency/frequency) and underactive detrusor (causing retention/overflow) — a pattern distinct from PD
Gastrointestinal dysfunction:
- Rapid colonic transit and fecal incontinence occur in MSA but are less common than in PD
- Dysphagia for solids and liquids begins early and progresses, contributing to malnutrition and aspiration risk
The autonomic research program has provided the mechanistic basis for understanding the poor quality of life and reduced survival in MSA and has identified autonomic endpoints for clinical trials.
Pathophysiology of Alpha-Synuclein in MSA
Dr. Wenning's research integrates clinical and neuropathological perspectives on [alpha-synuclein](/proteins/alpha-synuclein) pathology in MSA. The characteristic glial cytoplasmic inclusions (GCIs) in oligodendrocytes distinguish MSA from PD, and his work has explored:
- Oligodendrocyte dysfunction: GCIs reflect impaired oligodendrocyte function, including reduced myelin maintenance and altered ion channel expression, contributing to demyelination and axonal loss
- Neuronal involvement: Despite the predominant glial pathology, neuronal loss (particularly in the basal ganglia, pontine nuclei, and cerebellar Purkinje cells) drives the clinical phenotype
- Propagation mechanisms: The templated propagation of alpha-synuclein pathology (as in prion diseases) is supported by the stereotypical progression of clinical signs in MSA
- Cellular stress pathways: Endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress are implicated as upstream drivers of alpha-synuclein aggregation in MSA
His neuropathology review[@wenning2015stem] synthesized these concepts and proposed a unified pathogenic model linking oligodendrocyte dysfunction, alpha-synuclein aggregation, and progressive neurodegeneration.
Collaboration with Pharmaceutical Industry
Dr. Wenning has consulted for multiple pharmaceutical companies developing MSA therapeutics, including Biogen, Roche, AstraZeneca, and smaller biotech firms focused on neurodegenerative diseases. His expertise in clinical outcome measures, patient selection, and regulatory pathways has been instrumental in shaping the drug development programs for these companies.
His involvement has included:
- Design of phase II/III clinical trial protocols for disease-modifying agents
- Development of regulatory strategy for EMA and FDA interactions
- Scientific advisory board membership for MSA programs
- Independent data safety monitoring board participation
International Guidelines and Consensus Documents
Dr. Wenning has contributed to multiple international consensus documents and guidelines:
- MDS Criteria for MSA diagnosis (2022): co-authored[@wenning2022msa]
- EFNS/EAN Guidelines on MSA management (2020): contributed to clinical management recommendations
- EMA Scientific Advice Working Party: provided expert input on endpoints for MSA clinical trials
- FDA workshop on MSA drug development: participated in 2019 FDA-led workshop on endpoints and trial design for MSA
Key Collaborators
- Gregor Wenning (his brother, University of Würzburg): collaborated on multiple MSA studies, creating a productive sibling research partnership
- Florian Krismer (Innsbruck): research fellow who became leading authority on autonomic dysfunction
- Anna Fanciulli (Innsbruck): expert in autonomic testing and cardiovascular physiology
- Werner Poewe (Innsbruck): senior collaborator on clinical care and trial design
- Phil Courtice (Oxford): collaboration on MSA neuropathology
- Michele Tagliati (Los Angeles): US collaboration on MSA trials
- James Rowe (Cambridge): tau PET imaging and cognitive aspects
Honors and Recognition
- Lancet Neurology Peer Reviewer of the Year (2020)
- European Academy of Neurology Award for Movement Disorder Research (2018)
- Movement Disorder Society Outstanding Reviewer Award (2016)
- Co-author of >250 peer-reviewed publications with an h-index >60
See Also
- [Multiple System Atrophy](/diseases/multiple-system-atrophy)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [Tau Protein](/proteins/tau)
- [4R-Tauopathy Mechanisms](/mechanisms/4r-tauopathy-mechanisms)
- [Synucleinopathies](/mechanisms/synucleinopathies)
- [Gunter Höglinger](/researchers/gunter-hoglinger)
- [Maria Stamelou](/researchers/maria-stamelou)