Is Pure Autonomic Failure a Warning Sign for Parkinson’s? What a New Study Shows.

People with pure autonomic failure — a disorder characterized by a severe drop in blood pressure when standing and other autonomic nervous system symptoms — developed Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy more often than those in the general population, a systematic review and meta-analysis of longitudinal studies showed.

Over 6 years, 30% of adults with pure autonomic failure converted to one of the three disorders with a pooled incidence rate of 5.09 per 100 person-years (95% CI 3.79-6.85; approximately 5% per year), reported Eduardo de Pablo-Fernández, MD, PhD, of Queen Mary University of London, and colleagues.

Overall, 12% converted to multiple system atrophy, 11% to dementia with Lewy bodies, and 7% to Parkinson’s disease, the researchers wrote in JAMA Neurology.

Conversion rates for multiple system atrophy were highest in the first years of follow-up, with a pooled incidence rate of 1.96 (95% CI 1.29-2.99). The other two disorders had more constant phenoconversion rates. For dementia with Lewy bodies, the pooled incidence rate was 1.56 (95% CI 0.94-2.61), and for Parkinson’s disease, it was 1.35 (95% CI 0.75-2.41).

The three disorders are central neurodegenerative alpha-synucleinopathies, characterized by deposits of phosphorylated alpha-synuclein within neurons and glia that lead to parkinsonism, autonomic dysfunction, ataxia, and cognitive impairment. Parkinson’s disease and dementia with Lewy bodies are classified as Lewy body disorders, while multiple system atrophy lacks Lewy body pathology.

“In this systematic review and meta-analysis of nine longitudinal cohort studies including 900 patients with pure autonomic failure during 6.4 years of follow-up, phenoconversion incidence rate to any central alpha-synucleinopathy was markedly higher than that of the general population, approximately 5% per year,” de Pablo-Fernández and colleagues wrote.

“Findings suggest that pure autonomic failure may be a prodromal presentation of central alpha-synucleinopathies, and future research should focus on the accurate identification of those at high risk of phenoconversion using a combination of clinical features and biomarkers to allow potential early interventions,” they added.

No disease-modifying agents are approved for any of the central synucleinopathies, noted Paul Beach, DO, PhD, of Emory University School of Medicine in Atlanta, and Roy Freeman, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston.

“Ongoing and prior clinical trials largely include patients in the early disease stages, before substantial neurodegeneration has occurred,” Beach and Freeman wrote in an accompanying editorial.

“A natural extension of this approach is to study individuals with prodromal — i.e., premotor and precognitive — clinical signs and symptoms associated with high risk of developing a clinically evident alpha-synucleinopathies. Well established examples of prodromal features include rapid eye movement sleep behavior disorder (RBD) and hyposmia. Pure autonomic failure, whose defining feature is neurogenic orthostatic hypotension, has been of interest in this regard for several decades,” the editorialists added.

“The results of this meta-analysis firmly establish pure autonomic failure as a prodromal disorder for central synucleinopathies,” Beach and Freeman stated. In this study, “the incidence rate for general phenoconversion, 5.1 per 100 person-years, is far greater than rates in the general population: 82-fold greater than that of Parkinson’s disease and more than 500-fold greater for multiple system atrophy,” they pointed out.

The pooled phenoconversion rates in this study — “essentially 5% per year, are also very similar to incidence estimates in RBD,” they noted.

The meta-analysis included nine longitudinal studies identified until June 2025. Studies focused on confirmed pure autonomic failure cases and excluded ones requiring RBD.

In total, 900 people with confirmed pure autonomic failure were followed for a mean of 6.4 years. The average age at pure autonomic failure onset was 63.1 years, and 63.8% of participants were men. The mean duration of pure autonomic failure was 5.3 years.

Hyposmia was the only clinical predictor with diagnostic value to distinguish those who converted to Parkinson’s disease or dementia with Lewy bodies (hyposmia pooled risk ratio 1.88, 95% CI 1.26-2.97) from those with multiple system atrophy, though RBD and subtle motor signs frequently predicted conversion to any central alpha-synucleinopathy.

The underlying studies had heterogenous methodologies, de Pablo-Fernández and colleagues acknowledged. Operational definitions of pure autonomic failure varied across cohorts, including differences in blood pressure cut-offs, autonomic testing protocols, and whether secondary causes and comorbidities were excluded. In addition, diagnoses of Parkinson’s, dementia with Lewy bodies, and multiple system atrophy disorder were based largely on clinical criteria without pathological confirmation.