Roughly twenty years before the first symptoms of Alzheimer’s disease appear, inflammatory changes in the brain can be seen, according to a new study from Karolinska Institutet published in the medical scientific journal Brain. The findings of the researchers, who monitored several pathological changes in the brain, suggest that activation of astrocytes at an early stage can greatly influence the development of the disease.
Alzheimer’s disease is characterised by the atrophy of brain neurons, especially those involved in memory, and is our most common dementia disease. Exactly what causes the cells to die is not known, but many years before the first symptoms present themselves, pathological changes occur, such as the deposition of the protein amyloid in the form of amyloid plaques, the accumulation of tau proteins and inflammatory changes that eventually degrade the points of contact between neurons. Exactly when the changes take place along this chain of events remains, however, an unanswered question.
By studying families of people with known Alzheimer’s mutations and who therefore run a much higher risk of developing the disease, the researchers were able to examine changes that appear at a very early stage of the disease. The study included members of families with four different known Alzheimer’s mutations and a group of patients with non-inherited, ‘sporadic’ Alzheimer’s disease. All participants underwent memory tests and scans using PET (positron emission tomography), whereby radioactive tracer molecules with a short half-life are introduced into the brain via injection into the blood.
For this study, the team used the tracer molecules PIB, Deprenyl and FDG to study the amount of amyloid plaques, inflammatory changes in the form of astrocyte activation, astrocytes being the most common type of glial (supporting) cell in the brain. They also studied neuronal function in the brain by measuring glucose metabolism (FDG). In order to monitor the changes over time, the PET scans were repeated after three years for half of the just over fifty participants.
Amyloid plaque and inflammatory changes
The mutation carriers were found to have amyloid plaque and inflammatory changes almost twenty years before the estimated debut of memory problems. The number of astrocytes reached a peak when the amyloid plaque started to accumulate in the brain, and neuronal function, as gauged by glucose metabolism, began to decline roughly seven years before the expected disease symptoms. The individuals from families with inherited Alzheimer’s who did not carry any mutation showed no abnormal changes in their brain.
“Inflammatory changes in the form of higher levels of brain astrocytes are thought to be a very early indicator of disease onset,” explains principal investigator Professor Agneta Nordberg at the Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research at Karolinska Institutet. “Astrocyte activation peaks roughly twenty years before the expected symptoms and then goes into decline, in contrast to the accumulation of amyloid plaques, which increases constantly over time until clinical symptoms show. The accumulation of amyloid plaque and the increase in number of astrocytes therefore display opposing patterns along the timeline.”
These studies demonstrate that the pathological processes that lead ultimately to Alzheimer’s disease commence many years before symptoms start to show, and that it should be possible to provide early prophylactic or disease modifying treatment. According to the researchers behind the study, the findings indicate that astrocytes can be a possible target for new drugs.
About this Alzheimer’s disease research
First author of the study is Elena Rodriguez-Vieitez, PhD, senior scientist at Karolinska Institutet’s Department of Neurobiology, Care Sciences and Society.
Funding: The study was financed by grants from, among others, the Swedish Research Council, the Swedish Foundation for Strategic Research (SFF), the Knut and Alice Wallenberg Foundation, the Stockholm County Council/KI ALF fund, Swedish Brain Power, the Swedish Brain Fund, and a GE Healthcare unrestricted research grant.
Source: Katarina Sternudd – Karolinska Institute Image Credit: The image is credited to the researchers Original Research: Full open access research for “Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal-dominant Alzheimer’s disease” by Elena Rodriguez-Vieitez, Laure Saint-Aubert, Stephen F. Carter, Ove Almkvist, Karim Farid, Michael Schöll, Konstantinos Chiotis, Steinunn Thordardottir, Caroline Graff, Anders Wall, Bengt Långström and Agneta Nordberg in Brain. Published online January 26 2016 doi:10.1093/brain/awv404
Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal-dominant Alzheimer’s disease
Alzheimer’s disease is a multifactorial dementia disorder characterized by early amyloid-β, 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 11C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition (11C-Pittsburgh compound B), and glucose metabolism (18F-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 11C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and 11C-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 follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-β 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-β plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-β plaque deposition. Patients with sporadic mild cognitive impairment who were 11C-Pittsburgh compound B-positive at baseline showed increasing amyloid-β 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-β plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer’s disease pathology.
“Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal-dominant Alzheimer’s disease” by Elena Rodriguez-Vieitez, Laure Saint-Aubert, Stephen F. Carter, Ove Almkvist, Karim Farid, Michael Schöll, Konstantinos Chiotis, Steinunn Thordardottir, Caroline Graff, Anders Wall, Bengt Långström and Agneta Nordberg in Brain. Published online January 26 2016 doi:10.1093/brain/awv404