Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

Abstract

Clinicopathologic evidence suggests the pathology of Alzheimer disease (AD) begins many years prior to cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic (“pre-clinical”) stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study comparing cerebrospinal fluid (CSF), plasma and in vivo amyloid imaging, cross-sectional data obtained at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network (DIAN) demonstrate reduced concentrations of CSF amyloid-β1-42 (Aβ1–42) associated with the presence of β-amyloid plaques, and elevated concentrations of CSF tau, ptau181 and VILIP-1, markers of neurofibrillary tangles and/or neuronal injury/death, in asymptomatic mutation carriers 10-20 years prior to their estimated age at symptom onset (EAO), and prior to detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within-individuals decrease after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

“…In both symptomatic and presymptomatic APP , PSEN1 and PSEN2 mutation carriers, the majority of the studies found a decrease in Aβ 42 and an increase in both t-tau and p-tau levels when compared with healthy control individuals, consistent with a typical AD profile [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] (table 1). In some cases, 1 or more markers were found to be unchanged compared to controls [27,28,29,30].…”

“…In individuals carrying APP or PSEN1 mutations, levels of F2-isoprostanes, which are markers of lipid peroxidation, were found to be elevated compared with controls [20]. In another study, a marker of neuronal death, VILIP-1, was found to be increased in carriers of APP , PSEN1 and PSEN2 mutations [13]. In 3 studies, mass spectrometry was used to assess Aβ isoforms and the proteome in familial AD [9,31,32].…”

Monitoring of 30 marker candidates in early Parkinson disease as progression markers

“…The stability of our markers in this early stage of motor PD could result from a slowing of the neurodegeneration process in the symptomatic phase similar to that seen in AD. 32 This underlines the need for more specific progression marker candidates for the early phase of the disease, which will emerge from this and other ongoing studies. 33 We explored many obvious candidates in a large cohort of PD participants and looked for progression markers for future use in clinical trial cohorts and tried to exclude noninformative ones.…”

Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET

“…There is an increasing number of longitudinal studies in asymptomatic subjects with or at risk for AD by virtue of a mutation (25,26), gene status (27,28), or significant amyloid burden as measured by PET (29,30) or cerebrospinal fluid analyses (31). Although highly interesting from the perspective of clinical trials, we did not include asymptomatic individuals in the present study, because their clinical fate is unclear.…”