Age-Associated Cortical Thinning in Speech Motor Regions Precedes Hippocampal Decline: Implications for Alzheimer's Disease

Abstract

Speech-motor and cognitive impairments are commonly observed in age-related neurodegenerative diseases, including mild cognitive impairment (MCI) and Alzheimer's Disease (AD). Although there is a strong interaction between motor and cognitive functions, intact speech motor control is a crucial yet often-overlooked component of cognitive functioning. Additionally, motor decline can occur independently and may precede the onset of cognitive impairment in neurodegenerative conditions. These impairments can confound measures of higher-order cognition, typically assessed through behavioral performance. Notably, the associations between cognitive performance and biological indices of speech motor production have been largely unexplored. This study is the first to examine cognitive associations of cortical thickness in brain regions implicated in speech motor performance across the adult lifespan, and to investigate whether age-related structural changes in speech motor regions precede those seen in the hippocampus. Our sample included 699 cognitively healthy adults (56% female) spanning 35-90 years from the Human Connectome Project (HCP)-Aging dataset. Cognition was estimated using standard neuropsychological assessments including: the Trail Making Task A/B (TMT), the Rey Auditory Verbal Learning Test (RAVLT), and a cognitive composite score (summating cognitive performance across multiple tasks). Whole-brain T1- and T2-weighted MRI images were acquired using 3-Tesla scanners across multiple study sites. Structural images were preprocessed using the HCP minimal preprocessed pipelines to reconstruct cortical surfaces. Volume-based estimates including hippocampal volume and total gray matter volume were adjusted for head size using an adjusted measure of estimated Total Intracranial Volume (eTIV). Speech motor regions were investigated relative to well-characterized relationships with hippocampal volume (a hallmark region for memory and cognition and AD-related atrophy). Estimates of cortical thickness were extracted from 14 bilateral speech motor control regions spanning premotor, motor, somatosensory, insular, and prefrontal cortices. Performance across all cognitive tasks and estimates of brain structure were all highly correlated with age. After controlling for the effects of age, greater hippocampal volume remained correlated with better cognitive performance across all cognitive tasks. However, only cognitive associations with greater total gray matter volume survived correction for multiple comparisons. As expected, age associations with hippocampal volume differed between early (-0.191%/year) and late adulthood (-0.714%/year) (T = 6.179, p = 0.0002). Age associations with speech motor control regions significantly differed from the associations seen in GMV, mCT, and/or hippocampal volume across the lifespan (Pcor < 0.0001) and during late adulthood when compared separately. Half the speech motor control regions explored showed decelerated estimated percent difference per year from early and late adulthood. Our results suggest that neurocognitive relationships are highly impacted and often confounded by age. The thickness of several speech motor regions was not associated with cognitive performance and can therefore provide a more intrinsic measure of aging. Additionally, speech motor control regions decline earlier in adulthood than hippocampal volume and may therefore serve as a target and early indicator of AD-related neurodegeneration. This nuanced understanding is critical for refining early diagnostic criteria for neurodegenerative diseases, including AD, and sheds light on the complex interplay between age-related changes, disease pathology, and cognitive decline.

FIGURE 1

This theoretical model depicts how normative age curves may provide insight into which regions age first. Using this method, a region that ages earlier should show an accelerated decline earlier and show a slower decline later in adulthood. Whereas a region that is more resilient to age would show a reduced rate of decline earlier and a more accelerated decline later in adulthood. Color depicts the strength of the age‐association or rate of change. Maximal rate of change (or rate of decline) may be a different age for different regions of the brain.

FIGURE 2

Better performance across cognitive tasks was associated with larger hippocampal volume and greater thickness in speech motor control regions. Cognitive performance across tasks is organized by row, in order: (A) Trail Making Task A, (B) Trail Making Task B, (C) Rey Auditory Verbal Learning Task (RAVLT) and (D) Cognitive Composite Score. Structural brain estimates include hippocampal volume and cortical thickness of premotor, motor, somato‐motor, insular, and inferior frontal cortices. Each plot displays the cognitive score on the y‐axis, while hippocampal volume or cortical thickness of speech motor control regions is found on the x‐axis; the beta and R‐squared are provided for each brain‐cognitive association.

FIGURE 3

Age associations with speech motor control regional thickness was significantly different than associations seen with hippocampal volume during adulthood. (A) Individual estimates of hippocampal volume are plotted against age. The line represents the mean and standard error of estimates grouped into 5‐year age bins. (B) Age associations in 14 speech motor control regions as well as mean cortical thickness are displayed across the adult lifespan. Each line connects the mean and standard error of region is grouped into 5‐year age bins. (C) Normalized age‐curves for hippocampal volume are plotted alongside total gray matter volume (GMV) and estimated total intracranial volume (eTIV) across the full adult lifespan. (D) Similarly, normalized age‐curves for speech‐motor regions were plotted alongside mean cortical thickness across the adult lifespan. Finally, age associations were further displayed as (E) early and (F) late adulthood for hippocampal volume. and for (G) early and (H) late adulthood for speech motor control regions.