Trailblazing Research Shows the Spatial Pattern of Pathological Changes in the Brain Can Help Identify Dementia Vulnerability Decades Before It Occurs

Findings from a novel studyopens in new tab/window in Biological Psychiatry: Cognitive Neuroscience and Neuroimagingopens in new tab/window, published by Elsevier, suggest that using a specialized diffusion weighted MRI scan to monitor the spatial pattern of individual cortical microstructural change in the brain may be a promising approach to characterize individuals who may be vulnerable to developing Alzheimer's disease (AD) prior to significant cognitive decline and irreversible neuronal damage. Identifying early markers of AD-related neurodegeneration can fundamentally shift the timeline of risk identification, providing precious time for disease-modifying treatments such as those recently approved by the FDA.

First author of the study Rongxiang Tang, PhD, Postdoctoral Scholar, Department of Psychiatry and Center for Behavior Genetics of Aging University of California San Diego, explains, "Our research team previously found that a measure of cortical microstructure, an index of brain grey matter integrity, in cognitively healthy people in their mid-50s can help predict cognitive impairment a decade later. So, we were interested in examining if changes in this measure over time are linked to memory changes, and how the spatial patterns of these changes can tell us about a person’s risk of developing cognitive impairment and AD. Tracking these cortical microstructural changes early on in the aging process may be beneficial for early risk identification of cognitive impairment and AD."

The study included people in their early 60s who live in the community and did not have dementia. Investigators conducted brain assessments twice with MRI scans over a period of five to six years using an index called cortical mean diffusivity that reflects the integrity of grey matter microstructure in the brain. They then compared how similar these microstructural change brain maps are to those of typical AD pathology deposition (e.g., beta-amyloid and tau) in AD patients from a different study.

Senior author Jeremy A. Elman, PhD, Assistant Adjunct Professor, Department of Psychiatry and Center for Behavior Genetics of Aging, UC San Diego, says, "We found that the spatial pattern of microstructural change in our participants closely resembled the typical tau pathology deposition map seen in AD patients. Importantly, the participants whose change maps had greater similarity to the tau map also showed more memory decline over the same time period. Because tau is considered to be a major contributor to neurodegeneration (brain shrinkage) and cognitive decline, our results suggest that tracking these cortical microstructural changes and their spatial change patterns early on in the aging process may be beneficial for early identification of risk for cognitive impairment and AD."

The index of microstructure used comes from an MRI scan and is widely available. It may detect subtle change in the brain before substantial tissue loss has occurred, so even if a person does not yet exhibit significant cognitive problems or brain shrinkage, having a spatial change pattern that looks similar to an AD patient’s spatial pattern of tau accumulation, suggests that they may be experiencing the early stages of AD and are at risk of developing memory problems in the future. Once identified, clinicians may be able to direct these at-risk people for more in-depth screening and testing such as PET imaging, which can be used for diagnosis by more directly measuring the AD pathology in the brain.

Senior author William S. Kremen, PhD, Professor, Department of Psychiatry and Center for Behavior Genetics of Aging, UC San Diego, says, "Our work, based on the Vietnam Era Twin Study of Aging (VETSA), highlights the value of focusing on non-traditional brain structure measures and on adults as early as midlife in AD research. It is remarkable that cortical microstructural changes are earlier and more sensitive to AD-related pathological processes and memory decline than changes in cortical thickness, which are typically used for assessing neurodegeneration/brain shrinkage in AD."

Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine, comments, “This work is the first to show that it is not only whether someone is experiencing change in cortical microstructure as measured by MRI that is important, but also the spatial pattern of these changes. Paying attention to the pattern of changes may help identify people who may be at risk for memory problems and AD in their early 60s, before significant cognitive decline or visible brain shrinkage occurs."

Based on these findings, clinicians may be able to track a person’s spatial profile of cortical microstructural changes over time to identify if they are at risk of developing cognitive impairment and AD early on in the aging process. Because AD takes decades to develop, early diagnosis could improve treatment success and patient outcomes. Moreover, clinicians may recommend risk-reducing intervention or other preventive strategies for people who do not yet have significant AD pathology in the brain but are considered to be at risk based on their diffusion weighted MRI scan based spatial change profile.

Notes for editors

The article is "Early Cortical Microstructural Changes in Aging Are Linked to Vulnerability to Alzheimer’s Disease Pathology," by Rongxiang Tang, Carol E. Franz, Richard L. Hauger, Anders M. Dale, Stephen M. Dorros, Lisa T. Eyler, Christine Fennema-Notestine, Donald J. Hagler Jr, Michael J. Lyons, Matthew S. Panizzon, Olivia K. Puckett, McKenna E. Williams, Jeremy A. Elman, and William S. Kremen (https://doi.org/10.1016/j.bpsc.2024.05.012opens in new tab/window). It is published online advance of volume 9 issue 10 (October 2024) of Biological Psychiatry: Cognitive Neuroscience and Neuroimagingopens in new tab/window, published by Elsevier.

The article is openly available at https://www.biologicalpsychiatrycnni.org/article/S2451-9022(24)00158-7/fulltextopens in new tab/window.

Copies of this paper are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]opens in new tab/window. Journalists wishing to interview the study’s authors should contact Stephanie Healey at [email protected]opens in new tab/window.

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article.

Cameron S. Carter, MD, is Chair of the Department of Psychiatry & Human Behavior at the University of California, Irvine School of Medicine. His disclosures of financial and conflicts of interests are available hereopens in new tab/window.

The participants of this study are part of the VETSA program of research supported by the National Institute on Aging led by Drs. William Kremen, Michael Lyons, and Carol Franz along with a large group of co-investigators for the past 20 years. Drs. Kremen and Elman were the senior authors on this paper. Drs. Jeremy Elman, Anders Dale, Christine Fennema-Notestine, and William Kremen are now the lead investigators on the VETSA MRI study.

This work was supported by the National Institute on Aging at the National Institutes of Health grant numbers R01 AG050595, R01 AG022381, R01 AG076838, R01 AG064955, P01 AG055367, R01 AG037985, and K01 AG063805.

About Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Biological Psychiatry: Cognitive Neuroscience and Neuroimagingopens in new tab/window is an official journal of the Society of Biological Psychiatryopens in new tab/window, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal focuses on studies using the tools and constructs of cognitive neuroscience, including the full range of non-invasive neuroimaging and human extra- and intracranial physiological recording methodologies. It publishes both basic and clinical studies, including those that incorporate genetic data, pharmacological challenges, and computational modeling approaches. The 2023 Journal Impact Factor^TM score, from Clarivate, for Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is 5.7. www.sobp.org/bpcnniopens in new tab/window