Op-brai150410 1..15

Alzheimer’s disease is a multifactorial dementia disorder characterized by early amyloid-b, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer’s disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer C-deuterium-L-deprenyl), fibrillar amyloid-b plaque deposition (C-Pittsburgh compound B), and glucose metabolism (F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer’s disease mutation carriers (n = 11; 49.6 10.3 years old) and non-carriers (n = 16; 51.1 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 6.4 years old; nine male) and sporadic Alzheimer’s disease (n = 8; 63.0 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer’s disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into CPittsburgh compound B-positive (n = 13; 62.0 6.4; seven male) and C-Pittsburgh compound B-negative (n = 4; 61.8 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging followup examinations after 2.8 0.6 years. By using linear mixed-effects models, fibrillar amyloid-b plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer’s disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-b plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-b plaque deposition. Patients with sporadic mild cognitive impairment who were C-Pittsburgh compound B-positive at baseline showed increasing amyloid-b plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer’s disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer’s disease carriers, contrasting with the increasing amyloid-b plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer’s disease pathology.