Brain white matter connectivity disrupted in symptomless, early-onset Alzheimer’s

Reuters Health - 22/10/2021 - White matter structural connectivity was lower in symptomless autosomal-dominant Alzheimer's disease (AD) mutation carriers compared with noncarriers in an exploratory imaging analysis.

Lower connectivity also correlated with estimated years to dementia symptom onset in carriers, according to Dr. Jeffrey Prescott of the MetroHealth System in Cleveland and colleagues.

"Importantly, the patients involved in the study were all cognitively normal, with two cohorts consisting of carriers of an AD-related genetic mutation and those without a mutation," Dr. Prescott told Reuters Health by email. "The characterization of early structural changes in the brain that may precede clinical symptoms of cognitive impairment could help with identification of patients at increased risk of AD and guide further research into treatments."

For now, he added, "These results still need to be evaluated in a larger set of patients, and with longitudinal data."

As reported in Radiology, Dr. Prescott and colleagues analyzed data on 30 mutation carriers (mean age 34; 57% women) and 38 noncarriers (mean age, 37; 67% women) in the Dominantly Inherited Alzheimer Network between 2009-2014, all of whom had normal cognition at baseline.

The analyses included T1-weighted MRI scans, diffusion tensor imaging (DTI), and amyloid PET imaging (for mutation carriers).

Areas of the cerebral cortex were divided into three cortical networks: the default mode, frontoparietal control, and ventral attention.

The structural connectivity of the three networks was calculated using DTI. General linear models were used to examine differences in structural connectivity between mutation carriers and noncarriers and the relationship among structural connectivity, amyloid burden, and estimated year to symptom onset (EYO) in mutation carriers.

The team found that mutation carriers had lower structural connectivity in the frontoparietal control network compared to noncarriers. Mutation carriers also demonstrated a correlation between EYO and white matter structural connectivity in the frontoparietal control network. Notably, there was no significant relationship between cortical global amyloid burden and EYO.

A network measurement called global efficiency, in which decreased efficiency is considered a breakdown in the organization of the network, showed that among all participants with normal cognition, mutation status had an effect in the frontoparietal control network, with noncarrier participants having a higher global efficiency.

Dr. Linda McEvoy of the University of California San Diego, author of a related editorial, commented in an email to Reuters Health, "The authors of this study took advantage of the fact that among people who inherit a rare genetic mutation that causes AD, we can predict when symptoms will appear, and examine brain changes prior to that."

"They found that a network that connects frontal and parietal brain regions, and is important for the performance of complex tasks that require effortful sustained attention and mental flexibility, was most affected," she said. "People who were closer to the age at which their symptoms were expected to begin showed the largest changes."

"Interestingly, this article did not observe that the differences in this network were related to differences in amount of amyloid pathology, one of the defining features of AD," she noted. "This is consistent with a wide body of evidence that shows that although amyloid pathology is necessary for a diagnosis of AD, it is not sufficient to cause symptoms."

She noted, as did Dr. Prescott, "We need to do longitudinal studies to confirm that damage to the white matter tracts increases over time in the period leading up to dementia."

"Because (the authors) did not look at other biomarkers of AD, we do not know what caused the changes in the white matter they observed," she said. "One possibility is an immune reaction that may be initiated by the presence amyloid pathology."

"We are rapidly developing the capability to detect various markers of AD and central nervous system damage from blood tests, so future studies that relate changes in these blood-based biomarkers to changes in brain measures prior to the onset of dementia will help us learn more about the causes and triggers of this devastating disease, beyond amyloid pathology," Dr. McEvoy concluded.

SOURCE: https://bit.ly/3vP8Zc5 and https://bit.ly/3vBrEYw Radiology, online October 12, 2021.

By Marilynn Larkin



Posted on 22 October 20212 November 2021