Regional Cortical Thinning and Cerebrospinal Biomarkers Predict Worsening Daily Functioning Across the Alzheimer's Disease Spectrum

Abstract

Background Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver. Objective To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Methods Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimer's Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical assessments, including the Functional Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years. General linear regression and mixed effects models were employed. Results IADL impairment was associated with the interactions between lower inferior temporal cortical thickness and diagnosis (p<0.0001), greater lateral occipital cortical thickness and diagnosis (p<0.0001), and greater amyloid-beta 1-42 (Aβ1-42) and diagnosis (p=0.0002) at baseline (driven by AD dementia). Lower baseline supramarginal (p=0.02) and inferior temporal (p=0.05) cortical thickness, lower Aβ1-42 (p<0.0001), and greater total tau (t-tau) (p=0.02) were associated with greater rate of IADL impairment over time. Conclusions Temporal atrophy is associated with IADL impairment in mild AD dementia at baseline, while baseline parietal and temporal atrophy, lower CSF Aβ1-42, and greater t-tau predict worsening IADL impairment over time across the AD spectrum. These results emphasize the importance of assessing IADL at the stage of MCI and even at the transition from CN to MCI.

Decreased hippocampal metabolism in high‐amyloid mild cognitive impairment

“…As reported previously [39, 40], high-Aβ MCI have decreased ACT when compared to low-Aβ CN. However, ACT was less discriminant for high-Aβ MCI than the other biomarkers we studied.…”

Biomarkers and Functional Decline in Prodromal Alzheimer’s Disease

“…Baseline biomarker measures as a predictive factor of functional decline is a novel area of research, with very few studies having explored such relationships and of those comparable; our findings are congruent [14][15][16][41][42][43]. Two separate studies found regional cortical thinning and decreased CSF A1-42 to predict IADL decline across the AD spectrum [15,41].…”

“…Two separate studies found regional cortical thinning and decreased CSF A1-42 to predict IADL decline across the AD spectrum [15,41]. Likewise, correlations between cerebral atrophy and IADL decline in MCI individuals have been reported [14], with rate of decline found to increase three fold in APOE-4 positive individuals [42].…”

Establishing Clinical Relevance in Preclinical Alzheimer’s Disease

“…In addition, a subgroup of these subjects underwent magnetic resonance imaging (MRI), which showed that impaired performance was associated with inferior temporal cortical thinning in clinically normal subjects. This finding aligns with other studies suggesting that cortical thinning may be one of the earliest biomarker correlates of cognitive and functional decline (13, 14), and further supports the use of sensitive performance measures for the assessment of decline in the earliest stages of the disease.…”