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.

Clinical variables and biomarkers in prediction of cognitive impairment in patients with newly diagnosed Parkinson's disease: a cohort study

“…In some studies, reduced concentrations of CSF Aβ 42 without contribution of p-tau or t-tau were reported, 12,14,35,36 whereas high concentrations of CSF p-tau, but not low levels of Aβ 42 , were associated with cognitive decline in early Parkinson’s disease in the DATATOP study. 15 Some studies also reported that high concentrations of CSF α-synuclein predicted cognitive decline, 14,36 but results from the DATATOP study suggested that this association is only seen in early disease, 13 whereas in the same study high p-tau and p-tau to Aβ 42 ratio were associated with cognitive decline in patients with advanced disease, suggesting that different mechanisms are involved at different disease stages. 15 In this study, CSF α-synuclein and p-tau concentrations, which have previously been reported to be significantly lower in this Parkinson’s disease population than in controls, 11 were not helpful in predicting early cognitive deterioration.…”

Clinically meaningful parameters of progression and long-term outcome of Parkinson disease: An international consensus statement

“…Subsequent studies, however, have obtained conflicting results, with some groups showing a positive correlation between PDD and the H1 allele [56,57], while others providing negative results [58,59]. Accordingly, two recent longitudinal studies regarding the association between tau CSF levels and subsequent cognitive decline in PD patients showed conflicting results [60,61]. Studies evaluating a possible association of APOE risk alleles with PD or with cognitive decline in PD have shown conflicting results [62e65]; APOE ε4 was found not to be associated with progression of PD to cognitive decline or dementia previously [62,64], but a recent, larger study reported such an association [65].…”

Parkinson disease and cognitive impairment

“…15 Another DATATOP study found that CSF levels of phospho-tau and phospho-tau/Ab 42 ratio predicted decline in cognitive tasks over approximately 4 years. 16 Notably, this was the first study to show an association with CSF tau and progression of cognitive impairment in PD, building on previous reports documenting higher CSF tau levels in patients with PDD than in patients with PD without dementia and controls. Another smaller prospective study found that lower CSF Ab 1-42 (Ab42) and higher aSyn levels at baseline predicted cognitive decline over 2 years.…”