CSF markers of neurodegeneration Alzheimer's and Lewy body pathology in isolated REM sleep behavior disorder

Abstract

We investigated the biomarker profile of neurodegeneration, Alzheimer's and Lewy body pathology in the CSF of 148 polysomnography-confirmed patients with isolated REM sleep behavior disorder (IRBD), a condition that precedes Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We assessed misfolded α-synuclein (AS) by RT-QuIC assay, amyloid-beta peptides (Aβ₄₂ and Aβ₄₀), phosphorylated tau (p-tau), and total tau (t-tau) by CLEIA and neurofilament light chain (NfL) by ELISA. We detected AS in 75.3% of patients, pathologically decreased Aβ₄₂/Aβ₄₀ ratio in 22.5%, increased p-tau in 15.5%, increased t-tau in 14.9%, and elevated NfL in 14.7%. After a mean follow-up of 2.48 ± 2.75 years, 47 (38.1%) patients developed PD (n = 24) or DLB (n = 23). At CSF collection, AS positivity [HR 4.05 (1.26-12.99), p = 0.019], mild cognitive impairment [3.86 (1.96-7.61), p < 0.001], and abnormal DAT-SPECT [2.31 (1.09-4.91), p < 0.030] were independent predictors of conversion to PD and DLB. Among the other CSF markers, only elevated p-tau/Aβ₄₂ was predictive of conversion, although only to DLB and not as an independent variable. In IRBD, CSF AS assessment by RT-QuIC provides an added value in defining the risk of short-term conversion to PD and DLB independent of clinical and instrumental investigations. Positive Alzheimer's disease (AD) pathology markers and elevated NfL occur in a subgroup of patients, but p-tau/Aβ₄₂ is the only marker that predicts short-term conversion to DLB. Longer follow-up is needed to assess if AD biomarkers predict the later development of PD and DLB in IRBD.

Fig. 1. Overlap and correlations between abnormal biomarker results in IRBD.

Schematic representation of concomitant pathological profiles (A) and correlations among biomarkers (B). Biomarker positivity was defined as follows: A+ = Aβ positivity (Aβ₄₂/Aβ₄₀ < 0.65), T+ = tau positivity (p-tau181 > 60 pg/ml), N+ = neurodegeneration positivity (t-tau > 450 pg/ml), AS+ = misfolded α-synuclein positivity by SAA. For correlations, t-tau, p-tau, and NfL values were log-transformed. Pearson’s r values are shown. AS misfolded α-synuclein, AS_Imax the maximum peak of SAA fluorescence curve, Aβ₄₂ 42 amino acid isoform of amyloid-beta, Aβ₄₀ 40 amino acid isoform of amyloid-beta, p-tau tau protein phosphorylated at residue 181, NfL neurofilament light chain, t-tau total tau protein, SAA seed amplification assay.

Fig. 2. Predictive value of CSF AS from the time of lumbar puncture in the conversion from IRBD to PD or DLB.

Survival curves in patients with IRBD according to the AS status (negative = blue; positive = red). CSF cerebrospinal fluid, IRBD isolated REM sleep behavior disorder, AS misfolded α-synuclein.

Fig. 3. Predictive value of CSF AD core markers and NfL in the conversion from IRBD to PD or DLB.

Survival curves in patients with IRBD according to the amyloid-beta (a), tau (b), and neurodegeneration (c) status (negative = blue; positive = red), and NfL value tertiles (d).