Cerebrospinal fluid α-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort

Am J Pathol. 2014 Apr;184(4):966-975. doi: 10.1016/j.ajpath.2013.12.007. Epub 2014 Mar 11.

Abstract

Most patients with Parkinson disease (PD) develop both cognitive and motor impairment, and biomarkers for progression are urgently needed. Although α-synuclein is altered in cerebrospinal fluid of patients with PD, it is not known whether it predicts motor or cognitive deterioration. We examined clinical data and α-synuclein in >300 unmedicated patients with PD who participated in the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study, with up to 8 years of follow-up. Longitudinal measures of motor and cognitive function were studied before (phase 1) and during (phase 2) levodopa therapy; cerebrospinal fluid was collected at the beginning of each phase. Correlations and linear mixed models were used to assess α-synuclein association with disease severity and prediction of progression in the subsequent follow-up period. Despite decreasing α-synuclein (phase 1 to phase 2 change of -0.05 ± 0.21 log-transformed values, P < 0.001), no correlations were observed between α-synuclein and motor symptoms. Longitudinally, lower α-synuclein predicted better preservation of cognitive function by several measures [Selective Reminding Test total recall α-synuclein × time interaction effect coefficient, -0.12 (P = 0.037); delayed recall, -0.05 (P = 0.002); New Dot Test, -0.03 (P = 0.002)]. Thus, α-synuclein, although not clinically useful for motor progression, might predict cognitive decline, and future longitudinal studies should include this outcome for further validation.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antiparkinson Agents / therapeutic use
  • Cognition Disorders / cerebrospinal fluid*
  • Cognition Disorders / etiology*
  • Cohort Studies
  • Disease Progression
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Parkinson Disease / cerebrospinal fluid*
  • Parkinson Disease / complications*
  • Parkinson Disease / drug therapy
  • Selegiline / therapeutic use
  • alpha-Synuclein / cerebrospinal fluid*
  • alpha-Tocopherol / therapeutic use

Substances

  • Antiparkinson Agents
  • alpha-Synuclein
  • Selegiline
  • alpha-Tocopherol