Abstract
ObjectiveTo assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)‐specific neurodegeneration using longitudinal multimodal neuroimaging measures.MethodsChange in verbal fluency was analyzed among 2261 non‐demented individuals with a follow‐up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non‐amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow‐up, and relations with magnetic resonance imaging (MRI; n = 1536) and 18F‐fluorodeoxyglucose brain positron emission tomography (18F‐FDG‐PET) imaging (n = 756) using linear regression models across 2 years of follow‐up.ResultsSemantic fluency declined—fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)—while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced 18F‐FDG‐PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus–posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole‐brain neurodegeneration over time was associated with faster decline in both fluencies, while AD‐specific regions were associated with a faster rate of decline in semantic but not letter fluency.InterpretationThis study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD‐specific neurodegeneration.
Highlights
The preclinical phase of Alzheimer’s disease (AD) is marked by amyloid and tau accumulation and neurodegeneration,[1] and by subtle cognitive changes years before a clinical diagnosis can be established.[2,3] A diagnostic marker of AD in clinical practice, and supported by observations in research, is a diverging performance pattern of semantic fluency versus letter fluency4,5—generating as many words within time limits that start with a specific category or letter, respectively
For aim 2, we hypothesized that baseline performance and rate of change of semantic fluency, but not letter fluency, would predict follow-up neuroimaging measures—even when semantic fluency performance is adjusted for letter fluency, which reflects the discrepancy between the two measures.[2]
Semantic fluency declined across annual assessments (B = −.044, SE = .015, P = .003; intraclass correlation coefficient (ICC) intercept = .674, ICC slope = .012, I-S corr = −.025), while letter fluency did not (B = .002, SE = .014, P = .871; ICC intercept = .689, ICC slope = .010, I-S corr = −.025)
Summary
The preclinical phase of Alzheimer’s disease (AD) is marked by amyloid and tau accumulation and neurodegeneration,[1] and by subtle cognitive changes years before a clinical diagnosis can be established.[2,3] A diagnostic marker of AD in clinical practice, and supported by observations in research, is a diverging performance pattern of semantic fluency versus letter fluency4,5—generating as many words within time limits that start with a specific category or letter, respectively. The cortical signature of neurodegeneration in early stages of AD includes medial-temporal and temporal-parietal regions.[13,14] In the left hemisphere, these regions are associated with semantic processing abilities.[15,16,17] Correspondingly, semantic fluency has been linked to temporal-parietal as well as frontal regions, while letter fluency is considered to be relatively confined to inferior frontal regions important for executive functioning.[7,18] The discrepancy between semantic and letter fluency in clinical AD has been ascribed to semantic deficits that are mediated by neurodegeneration of temporal-parietal regions.[4,19] Identifying how the discrepancy in semantic versus letter fluency develops in a preclinical phase, and how it relates to change over time in AD markers of neurodegeneration, will provide better insight into the potential predictive value of this discrepancy in the earliest stages of the AD process. For aim 2, we hypothesized that baseline performance and rate of change of semantic fluency, but not letter fluency, would predict follow-up neuroimaging measures—even when semantic fluency performance is adjusted for letter fluency, which reflects the discrepancy between the two measures.[2]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
