Inflammatory brain changes appear to develop 20 years before the onset of symptoms in people with some familial forms of Alzheimer’s disease, according to a longitudinal analysis of PET imaging biomarkers of astrocyte activation, amyloid-beta accumulation, and glucose metabolism in the brain.
Imaging studies demonstrated a sharp elevation in astrocyte activation – a response to neuronal insult – before amyloid-beta began to accumulate in the brain, and then steadily declined. These changes were eventually followed by a steady and spreading decrease in glucose metabolism that reached the hippocampus just 2 years before symptoms appeared, first author Elena Rodriguez-Vieitez, Ph.D., of the Karolinska Institute, Stockholm, and her colleagues reported (Brain. 2016 Jan 26. doi: 10.1093/brain/awv404).
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The findings suggest that the disease may begin with an unknown insult that stimulates reactive astrocytosis – in familial forms of Alzheimer’s at least – and that the cells themselves could be a legitimate therapeutic target, wrote the investigators, led by Dr. Agneta Nordberg.
The initial astrocyte-alerting hit is still unknown, but it may be a reaction to soluble amyloid-beta. “Recent studies have supported the hypothesis that astrocytes have a beneficial role contributing to amyloid-beta clearance, but also that excess amyloid-beta can lead to oxidative stress and damage, and as a consequence to reduced astrocyte functionality, leading to reactive changes and decreased neuronal support, and thereby contributing to neurodegeneration.”
The decline in astrocyte activation with disease progression is another mystery, she said. It may be “an indication of a reduction in a certain type of astrocyte activation or functionality, a change of astrocyte activation phenotype, or possibly ‘astrodegeneration’ and astrocyte cell loss itself, as has been reported towards the late stages of Alzheimer’s disease.”
The study tracked brain PET imaging changes in 52 people: 27 from families with autosomal dominant Alzheimer’s disease (ADAD) mutations, including presenilin 1 or amyloid precursor protein genes, and 25 with sporadic Alzheimer’s disease or mild cognitive impairment (MCI). It employed three different PET tracers: Pittsburgh imaging compound B (PiB) to detect amyloid-beta; 18F-fluorodeoxyglucose (FDG) to detect glucose metabolism; and 11C-deuterium-L-deprenyl (DED) to detect astrocyte activation. Half had a follow-up visit after a mean of 2.8 years.
The ADAD cohort was divided into 16 noncarriers; 4 symptomatic carriers; and 7 presymptomatic carriers who were a mean of 10 years from symptom onset. The sporadic AD group was divided into 13 amyloid-positive and 4 amyloid-negative MCI patients, and 8 patients with an Alzheimer’s diagnosis. The 16 ADAD noncarriers served as a control group for PiB retention and FDG uptake, and 14 age-matched healthy controls served as controls for DED binding.
At baseline, all subjects underwent PET imaging with all three tracers, as well as cerebrospinal fluid biomarker analysis and neuropsychological assessments. Half of the subjects had additional clinical and imaging studies 3 years later. The investigators used historical data to estimate the age of symptom onset in the ADAD subjects, and thus extrapolated the imaging findings to reflect the pathologic course.
At baseline, there were significant between-group differences in all three imaging studies. PiB-positive MCI patients and Alzheimer’s patients from both the sporadic and ADAD cohorts had the highest PiB retention. But presymptomatic carriers had significantly higher DED binding than did any of the other groups. The increased astrocytosis that occurs with higher DED binding occurred in particular in 4 of 12 brain regions surveyed: the anterior cingulate cortex, thalamus, frontal, and parietal regions. Interestingly, the authors noted, DED binding in the sporadic Alzheimer’s and ADAD groups was not statistically different from that seen in a group of healthy control patients, except for a trend for higher binding in the frontal region.
In most brain regions at baseline, FDG uptake was greater in presymptomatic carriers and healthy controls than in either the PiB-positive MCI, sporadic Alzheimer’s, or ADAD groups, but there were no significant differences between the presymptomatic carriers and healthy controls or between the PiB-positive MCI, sporadic Alzheimer’s, or ADAD groups. FDG uptake at baseline was lower in the left parietal region of presymptomatic carriers than in the healthy controls and at follow-up this difference spread to the left posterior cingulate cortex and other parietal regions and to the left middle frontal gyrus and the bilateral cuneus. Presymptomatic carriers had significantly greater FDG uptake in the frontal and temporal regions and the right thalamus than did PiB-positive MCI patients, which persisted through follow-up.
The investigators used a linear mixed-effects model to estimate how astrocytosis, amyloid deposition, and glucose metabolism would change over time in both the ADAD and sporadic Alzheimer’s groups.