Michigan Neural Distinctiveness (MiND) study II protocol: Investigating age-related neural dedifferentiation longitudinally and in Alzheimer’s pathology

Background

A growing body of research has found that neural representations of task stimuli are less distinctive in older adults relative to younger adults, a phenomenon known as age-related neural dedifferentiation. The original funding period of the Michigan Neural Distinctiveness (MiND) study aimed to investigate the scope, causes, and consequences of neural dedifferentiation. We recruited a sample of healthy older adults (aged 65+ years) and younger adults (aged 18-29) and administered fMRI (to measure neural distinctiveness), MRS (to measure GABA), and substantial behavioral testing (to measure cognitive, motor, and sensory functions). We found that neural distinctiveness was lower in older vs. younger adults, that reduced GABA was associated with this neural dedifferentiation, and that behavioral performance was associated with both neural dedifferentiation and reduced GABA. In this current paper, we describe the rationale and methods for the second phase of the MiND study, in which we: 1) investigate age-related trajectories of change in neural distinctiveness, GABA, and behavior longitudinally; and 2) explore how neural differentiation is related to Alzheimer’s disease pathology.

Methods

In the longitudinal aim, we are re-contacting participants from the original MiND funding period. We aim to test participants at two additional time points approximately 3-5 years apart using the same assessments (fMRI, MRS, and behavioral tests). We plan to have approximately 150 participants with two time points and 100 participants with three time points. We will also recruit new participants who will be tested twice, approximately 3-5 years apart in order to further increase our sample size and power. We predict to have approximately 250 new participants with one time point. We will then test whether neural distinctiveness, GABA, and behavioral performance decline longitudinally with age.

To explore neural dedifferentiation in Alzheimer’s disease pathology, we plan to recruit 100 MCI participants who are already undergoing PET imaging to determine amyloid beta and tau burden. These patients are then completing our fMRI, MRS and behavioral testing sessions so that we can examine associations between Alzheimer’s pathology and our measures of neural distinctiveness, GABA, and behavior.

Discussion

This line of research has the potential to lead to new insights into how aging affects the mind. In particular, it could shed light on the role that neural dedifferentiation, GABA, and Alzheimer’s disease pathology play in age-related behavioral declines.

Trial Registration

This study was registered with the ISRCTN registry on November 11, 2024. The registration number is <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="isrctn" xlink:href="16528440">ISRCTN16528440</ext-link> .