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. The analysis was published online ahead of print January 26 in Brain.
Increase and Decrease in Amyloid Beta
Imaging studies demonstrated a sharp elevation in astrocyte activation, a response to neuronal insult, before amyloid-beta began to accumulate in the brain and subsequently decline. These changes eventually were followed by a steady and spreading decrease in glucose metabolism that reached the hippocampus two years before symptoms appeared, said Elena Rodriguez-Vieitez, PhD, Senior Researcher at the Karolinska Institutet in Stockholm, and her colleagues.
Elena Rodriguez-Vieitez, PhD
The findings suggest that the disease may begin with an unknown insult that, in familial forms of Alzheimer’s disease, stimulates reactive astrocytosis. The data also suggest that the cells themselves could be a legitimate therapeutic target.
The identity of the initial insult 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,” said Dr. Rodriguez-Vieitez.
The significance of the decline in astrocyte activation with disease progression also is unknown. 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 toward the late stages of Alzheimer’s disease.”
An Analysis of Three PET Tracers
The study tracked brain PET imaging changes in 52 people. Of the total population, 27 people came from families with autosomal dominant Alzheimer’s disease (ADAD) mutations, including presenilin 1 or amyloid precursor protein genes, and 25 people had sporadic Alzheimer’s disease or mild cognitive impairment (MCI). Researchers used 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 of participants had a follow-up visit after a mean of 2.8 years.
The ADAD cohort included 16 noncarriers, four symptomatic carriers, and seven presymptomatic carriers who were a mean of 10 years from symptom onset. The group of participants with sporadic Alzheimer’s disease included 13 amyloid-positive patients, four amyloid-negative patients with MCI, and eight patients with a diagnosis of Alzheimer’s disease. 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 CSF biomarker analysis and neuropsychologic assessments. Half of the subjects had additional clinical and imaging studies three years later. The investigators used historical data to estimate the age of symptom onset in the subjects with ADAD, and thus extrapolated the imaging findings to reflect the pathologic course.
Form of Disease May Affect Astrocyte Activation
At baseline, the researchers found significant between-group differences in all three imaging studies. PiB-positive patients with MCI and patients with Alzheimer’s disease from the sporadic and ADAD cohorts had the highest PiB retention. Presymptomatic carriers, however, 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 the following four of 12 brain regions surveyed: the anterior cingulate cortex, the thalamus, and the frontal and parietal regions. DED binding in the sporadic Alzheimer’s disease 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 disease, 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 disease, or ADAD groups. FDG uptake at baseline was lower in the left parietal region of presymptomatic carriers than in the healthy controls. 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 patients with MCI. This difference persisted through follow-up.