A Decade of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Belgium.

During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer's disease (AD) CSF biomarkers: amyloid-ß peptide of 42 amino acids (Aß1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aß1-42 <638.5 pg/mL, T-tau >296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aß1-42 concentration was below the cutoff, in combination with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects.

Validation of microRNAs in Cerebrospinal Fluid as Biomarkers for Different Forms of Dementia in a Multicenter Study.

MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer's disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies.

Depression in mild cognitive impairment is associated with progression to Alzheimer's disease: a longitudinal study.

BACKGROUND: Behavioral and psychological signs and symptoms of dementia (BPSD) belong to the core symptoms of dementia and are also common in mild cognitive impairment (MCI). OBJECTIVE: This study would like to contribute to the understanding of the prognostic role of BPSD in MCI for the progression to dementia due to Alzheimer's disease (AD). METHODS: Data were generated through an ongoing prospective longitudinal study on BPSD. Assessment was performed by means of the Middelheim Frontality Score, Behave-AD, Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia (CSDD), and Geriatric Depression Scale 30-questions (GDS-30). Cox proportional hazard models were used to test the hypothesis that certain BPSD in MCI are predictors of developing AD. RESULTS: The study population consisted of 183 MCI patients at baseline. At follow-up, 74 patients were stable and 109 patients progressed to AD. The presence of significant depressive symptoms in MCI as measured by the CSDD (HR: 2.06; 95% CI: 1.23-3.44; p = 0.011) and the GDS-30 (HR: 1.77; 95% CI: 1.10-2.85; p = 0.025) were associated with progression to AD. The severity of depressive symptoms as measured by the GDS-30 was a predictor for progression too (HR: 1.06; 95% CI: 1.01-1.11; p = 0.020). Furthermore, the severity of agitated behavior, especially verbal agitation and the presence of purposeless activity, was also associated with progression, whereas diurnal rhythm disturbances were associated with no progression to AD. CONCLUSION: Depressive symptoms in MCI appear to be predictors for progression to AD.

Amyloid pathology influences aß1-42 cerebrospinal fluid levels in dementia with lewy bodies.

A significant proportion of patients with dementia with Lewy bodies (DLB) show Alzheimer's disease (AD) pathology like senile plaques and neurofibrillary tangles. Biomarkers in cerebrospinal fluid (CSF), such as amyloid-ß1-42 (Aß1-42), total tau (T-tau), and hyperphosphorylated tau (P-tau181P), are linked to the different pathological hallmarks of AD. We set up a study to investigate the influence of AD co-pathology on CSF biomarker concentrations and profiles in autopsy-confirmed DLB. DLB patients with senile plaques showed significantly lower CSF Aß1-42 concentrations than DLB patients without senile plaques, but not compared to the AD patients. There were no significant differences in CSF T-tau or P-tau181P concentrations between DLB patients with and without neurofibrillary tangles. A correlation was found between the number of APOE ε4 alleles and Aß1-42 CSF levels in DLB patients with senile plaques. Although the CSF biomarkers Aß1-42, T-tau, and P-tau181P have an added diagnostic value for the differential dementia diagnosis, concomitant amyloid pathology in DLB limits the use of CSF Aß1-42 for the differential diagnosis of AD versus DLB.