CSF α-Synuclein Decreases Early in Drug-Naive Patients With Parkinson Disease

cerebral spinal fluid, spin injection

Cerebrospinal fluid (CSF) α-synuclein decreases early in untreated Parkinson disease (PD), yet α-synuclein does not appear to correlate with disease progression. This is according to a study in Movement Disorders.

The ongoing, longitudinal study (Parkinson’s Progression Markers Initiative) included newly diagnosed, untreated patients with PD (n=423; mean age, 61.7 years) as well as age- and sex-matched healthy controls (n=196; mean age, 60.9 years). Another subset of patients categorized as prodromal hyposmic (n=16; mean age, 68.3 years) and those with prodromal isolated rapid eye movement sleep behavior disorder (n=32; mean age, 69.3 years) were also included in the analysis.

Researchers examined data from α-synuclein analyses of the CSF samples in patients with PD and healthy controls. Analyses were performed at baseline and at 6-, 12-, 24-, and 36-month visits. For patients in the prodromal categories, analyses were performed at baseline and at 6- and 12-month visits. The association between α-synuclein and International Parkinson and Movement Disorder Society (MDS-UPDRS III) motor scores, cognition, and dopamine transporter imaging were examined.

Across all visits, CSF α-synuclein was lower in patients with PD vs healthy controls (P <.0001). A significant decrease was observed in longitudinal α-synuclein from baseline to 36 months (P =.032). In patients with PD, predictors of baseline CSF α-synuclein included older age (P =.007) and height (P =.002). A significant negative correlation was found between CSF α-synuclein and MDS-UPDRS III over a 12-month period in the isolated rapid eye movement sleep behavior disorder group.

A relationship was observed between changes in CSF α-synuclein and changes in the Montreal Cognitive Assessment in healthy controls over 36 months (P =.021). While there was a longitudinal association between CSF α-synuclein and levodopa equivalent dose based on dopamine replacement (P =.016), the association dissolved when samples of hemoglobin <200 ng/mL were excluded from the analysis (P =.361 and P =.083 [dopamine agonists]).

A potential limitation of the study is its relatively short follow-up period of only 36 months.

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“CSF α-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration,” concluded the researchers. They note that “decreased CSF α-synuclein may be an indirect index of changes in the balance between α-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover.” The researchers believe future research should focus on abnormal forms of α-synuclein and the use of methods such as proteomics and metabolomics to identify novel biomarkers.

Disclosure: This clinical trial was supported by several pharmaceutical organizations. Please see the original reference for a full list of authors’ disclosures.

Mollenhauer B, Caspell-Garcia CJ, Coffey CS, et al; for the PPMI study. Longitudinal analyses of cerebrospinal fluid α-synuclein in prodromal and early Parkinson’s disease [published online July 30, 2019]. Mov Disord. doi:10.1002/mds.27806