Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease

Abstract

Objective We analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD. Methods Amyloid‐β 1 to 42 (Aβ42), total tau (t‐tau) and phosphorylated tau (p‐tau) at the threonine 181 position were measured using the high‐precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear‐mixed effects models. Results We found patients with PD had lower CSF t‐tau (median = 157.7 pg/mL; range = 80.9–467.0); p‐tau (median = 13.4 pg/mL; range = 8.0–40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8–3,707.0) than HCs at baseline (CSF t‐tau median = 173.5 pg/mL; range = 82.0–580.8; p‐tau median = 15.4 pg/mL; range = 8.1–73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1–3,297.0; p < 0.05–0.001) and a moderate‐to‐strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50–0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aβ42 at baseline and these patients with PD had lower p‐tau levels (median = 10.8 pg/mL; range = 8.0–32.8) compared with 27.7% of HCs with pathologically low CSF Aβ42 (CSF p‐tau median = 12.8 pg/mL; range 8.2–73.6; p < 0.03). In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aβ42 (mean difference = −41.83 pg/mL; p = 0.03) and CSF p‐tau (mean difference = −0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aβ42 values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD. Interpretation Our data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3‐year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020;88:574–587

Cerebrospinal fluid Aβ42 and fractalkine are associated with Parkinson’s disease with freezing of gait

“…However, our CSF samples were taken in much later stages of disease than are currently available in studies like PPMI; the mean duration of the disease was 10.4 (±4.8) years and the longest duration in the sample was 23 years. Commensurate with their increased disease duration, these individuals were older than those in the most recent reports from PPMI (71.6 years vs. 61.4 years in PPMI) 22 . Additionally, among the FOG group here, there was no evidence of substantial executive dysfunction – the average MoCA score was 24.1 (results published separately 12 ).…”

“…One study suggested an association of low baseline levels to worse motor scores and, in particular, postural instability gait disorder (PIGD) sub score 22 Our results suggest that the associations between lower CSF Aβ42 and incident FOG that hold in newly diagnosed PD patients 13 may not generalize to older or more advanced patients. FOG is also associated with cognitive decline, particularly executive dysfunction [7][8][9] which is associated with lower Aβ42.…”

“…Irwin et al more recently examined AD markers in PD and HC in a larger number of patients from the PPMI cohort and with a different assay from the prior assessment, this time followed up to three years. In longitudinal analysis they found that the PD cohort had a modestly greater decline in CSF Aβ42 (mean difference = −41.83 pg/mL; p = 0.03) and CSF p-tau (mean difference = −0.38 pg/mL; p = 0.03) at year 3 compared with HC 22 . These findings are consistent with our observation for PD-NoFOG.…”

“…In PD, much of the data on CSF markers comes from early-stage patients in PPMI. Aβ42 CSF levels in early PD (within 2 years of symptom onset) have been shown to be modestly lower than HC (≈9%, in baseline measures) 20,21,22 . At levels below a critical value, Aβ42 levels appear to be associated with earlier development and faster decline of cognitive function in PD patients 23 especially in those with REM sleep behavior disorder 24 or the APOE ε4 allele 25 .…”

“…The association of low baseline CSF Aβ42 with early dementia in PD has been shown by other investigators as well 27 . One study suggested an association of low baseline levels to worse motor scores and, in particular, postural instability gait disorder (PIGD) sub score 22 although such findings have not been consistently seen. The neuropathological correlates of lower CSF Aβ42 in PD also remain unclear.…”