Evidence for alpha-synuclein aggregation in older individuals with hyposmia: a cross-sectional study

Area of Science:

• Neuroscience
• Biomarker Discovery
• Neurodegenerative Diseases

Background:

• Synuclein pathology precedes motor/cognitive symptoms in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB).
• Alpha-Synuclein seed amplification assays (α-syn SAA) show promise for detecting aggregated synuclein in pre-symptomatic stages.
• Hyposmia is an early indicator of risk for developing parkinsonism and related synucleinopathies.

Purpose of the Study:

• To investigate the prevalence of synuclein pathology in individuals with hyposmia using α-syn SAA.
• To assess the association between α-syn SAA positivity, dopamine transporter (DAT) imaging, and clinical progression in a pre-symptomatic cohort.

Main Methods:

• Utilized α-syn SAA to measure aggregated α-synuclein in cerebrospinal fluid (CSF) of 100 participants from the Parkinson Associated Risk Syndrome (PARS) study.
• Analyzed data from individuals with and without hyposmia, correlating α-syn SAA results with DAT imaging and symptom development over time.

Main Results:

• CSF α-syn SAA was positive in 48% of hyposmic participants versus 4% of normosmic participants.
• α-syn SAA positive hyposmic individuals showed a higher risk of DAT deficit (3.26-fold) compared to α-syn SAA negative hyposmics.
• Among hyposmic individuals with α-syn SAA positivity and DAT deficit, 7 out of 12 developed symptoms consistent with synucleinopathy.

Conclusions:

• Approximately 50% of individuals with hyposmia exhibit detectable synuclein pathology via α-syn SAA.
• A significant proportion (one-third) of α-syn SAA positive hyposmic individuals also show DAT deficit, indicating early neurodegeneration.
• These findings support the development of screening strategies for synuclein pathology in at-risk populations, potentially leading to preventative therapeutic studies.