CSF tau and tau/Aβ42 predict cognitive decline in Parkinson's disease

Abstract

Introduction: A substantial proportion of patients with Parkinson's disease (PD) have concomitant cognitive dysfunction. Identification of biomarker profiles that predict which PD patients have a greater likelihood for progression of cognitive symptoms is pressingly needed for future treatment and prevention approaches.

Methods: Subjects were drawn from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, a large clinical trial that enrolled initially untreated PD patients. For the current study, Phase One encompassed trial baseline until just prior to levodopa administration (n = 403), and Phase Two spanned the initiation of levodopa treatment until the end of cognitive follow-up (n = 305). Correlations and linear mixed models were performed to determine cross-sectional and longitudinal associations between baseline amyloid β1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) and measures of memory and executive function. Analyses also considered APOE genotype and tremor- vs. rigidity-dominant phenotype.

Results: No association was found between baseline CSF biomarkers and cognitive test performance during Phase One. However, once levodopa treatment was initiated, higher p-tau and p-tau/Aβ42 predicted subsequent decline on cognitive tasks involving both memory and executive functions. The interactions between biomarkers and cognition decline did not appear to be influenced by levodopa dosage, APOE genotype or motor phenotype.

Conclusions: The current study has, for the first time, demonstrated the possible involvement of tau species, whose gene (MAPT) has been consistently linked to the risk of PD by genome-wide association studies, in the progression of cognitive symptoms in PD.

Keywords: Biomarkers; Cerebrospinal fluid; Cognition; Neuropsychological tests; Parkinson disease; tau proteins.

Figure 1. Change of predicted cognitive test scores over time in PD patients during Phase 2

Data shown are the mean cognitive scores predicted from CSF biomarkers levels (low, mean, high) at the beginning of Phase 2 based on output from a mixed linear model; sex, education, and age at the beginning of Phase 2, final Phase 1 MMSE score, average UPDRS total and cognitive scores over 6 months prior to the beginning of Phase 2 were controlled as covariates. Blue lines indicate predicted cognitive scores by the mean levels of CSF biomarkers, green lines indicate predicted scores by low levels (mean – 1 SD) of CSF biomarkers, and red lines indicate predicted scores by high levels (mean + 1 SD) of CSF biomarkers. A: CSF p-tau vs SDMT, low p-tau can predict a 0.37/year decline of SDMT, mean p-tau can predict a decline of 0.97/year, high p-tau can predict a decline of 1.58/year; B: CSF p-tau/Aβ₄₂ vs SDMT (low – 0.43/year, mean – 0.97/year, high – 1.50/year); C: CSF p-tau vs SRT-total Recall (low – 0.78/year, mean – 1.12/year, high – 1.45/year); D: CSF p-tau/Aβ₄₂ vs. SRT-total Recall (low – 0.77/year, mean –1.10/year, high –1.44/year). SRT: Selective Reminding Test; SDMT: Symbol Digit Modalities Test