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Randomized Controlled Trial
. 2014 Apr;184(4):966-975.
doi: 10.1016/j.ajpath.2013.12.007. Epub 2014 Mar 11.

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

Tessandra Stewart  1 , Changqin Liu  2 , Carmen Ginghina  1 , Kevin C Cain  3 , Peggy Auinger  4 , Brenna Cholerton  5 , Min Shi  1 , Jing Zhang  6 ; Parkinson Study Group DATATOP Investigators
Affiliations
Randomized Controlled Trial

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

Tessandra Stewart et al. Am J Pathol. 2014 Apr.

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.

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Figures

Figure 1
Figure 1
Log-transformed levels of CSF α-syn at phase 2 as a function of phase 1 level. Line represents no change from beginning of phase 1 to beginning of phase 2.
Figure 2
Figure 2
Individual slope of cognitive decline assessed by SDMT (A), SRT-Total (B), SRT-Delayed (C), or New Dot Test (D) as a function of log α-syn at the beginning of phase 2. Includes subjects meeting criteria for phase 2 analysis who had five or more test results for calculation of slope. Dotted lines show correlation. Solid lines represent a slope of 0 (no change in test score). Slopes were generated from linear regression for visualization only, and do not represent effects observed in the data in aggregate when controlling for several confounding variables.
Figure 3
Figure 3
Modeled cognitive decline over follow-up period for low (means − 1 SD; blue line), mean (black dashed line), and high (means + 1 SD; red line) CSF α-syn.
Figure 4
Figure 4
Hypothesized driving mechanisms for α-syn depletion from CSF in PD. Under normal conditions, brain mechanisms for α-syn production, release, and clearance combine to generate normal α-syn homeostatic conditions (1). In PD pathogenesis, an unknown fraction of α-syn becomes pathological (2). Cells respond to the presence of pathological α-syn by sequestering toxic species in Lewy bodies (3). Less functional α-syn is, therefore, available in the cell. The homeostatic balance is shifted toward retaining more functional protein within the cell, to maintain cellular function (4). The shift in homeostasis results in lower CSF levels of α-syn, but maintains higher (more normal) levels of functional α-syn at the synapse, resulting in improved maintenance of normal synaptic activity (5).
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