Semantic intrusion errors as a function of age, amyloid, and volumetric loss: a confirmatory path analysis

Abstract

Objective: To examine the direct and indirect effects of age, APOE ϵ4 genotype, amyloid positivity, and volumetric reductions in AD-prone brain regions as it relates to semantic intrusion errors reflecting proactive semantic interference (PSI) and the failure to recover from proactive semantic interference (frPSI) on the Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L), a cognitive stress test that has been consistently more predictive of preclinical and prodromal Alzheimer’s disease (AD) than traditional list-learning tests. Design: Cross-sectional study. Setting: 1Florida Alzheimer’s Disease Research Center baseline study. Participants: Two-hundred and twelve participants with Mini-Mental State Examination (MMSE) score above 16 and a broad array of cognitive diagnoses ranging from cognitively normal (CN) to dementia, of whom 58% were female, mean age of 72.1 (SD 7.9). Measures: Participants underwent extensive clinical and neuropsychological evaluations, MR and amyloid Positron Emission Tomography/Computer/Computer Tomography (PET/CT) imaging, and analyses of APOE ϵ4 genotype. Confirmatory path analyses were conducted in the structural equation modeling framework that estimated multiple equations simultaneously while controlling for important covariates such as sex, education, language of evaluation, and global cognitive impairment. Results: Both amyloid positivity and decreased brain volumes in AD-prone regions were directly related to LASSI-L Cued B1 and Cued B2 intrusions (sensitive to PSI and frPSI effects) even after controlling for covariates. APOE ϵ4 status did not evidence direct effects on these LASSI-L cognitive markers, but rather exerted their effects on amyloid positivity, which in turn related to PSI and frPSI. Similarly, age did not have a direct relationship with LASSI-L scores, but exerted its effects indirectly through amyloid positivity and volumes of AD-prone brain regions. Conclusions: Our study provides insight into the relationships among age, APOE ϵ4, amyloid, and brain volumetric reductions as it relates to semantic intrusion errors. The investigation expands our understanding of the underpinnings of PSI and frPSI intrusions in a large cohort.

Different aspects of failing to recover from proactive semantic interference predicts rate of progression from amnestic mild cognitive impairment to dementia

“…Among patients with aMCI, tests utilizing frPSI and semantic intrusions have been shown to better discriminate between those who are amyloid positive versus amyloid negative than the number of correct responses on frPSI ( Curiel et al, 2018b ; Loewenstein et al, 2018b ; Kitaigorodsky et al, 2021 ; Zheng et al, 2021 ). On the other hand, among cognitively unimpaired older adults, the number of correct responses on frPSI have been shown to be very sensitive predictors of progression to PreMCI and aMCI independent of etiology ( Curiel et al, 2018a ; Crocco et al, 2021 ).…”

A review of novel Cognitive Challenge Tests for the assessment of preclinical Alzheimer’s disease.

“…The dissociation between correct responses on LASSI-L and semantic intrusion errors caused us to reflect on how PSI and frPSI might represent different cognitive processes in AD. Using confirmatory path analysis, (Zheng et al, 2021) found that among 212 participants, semantic intrusion errors on both Cued B1 and Cued B2 of the LASSI-L were related to both amyloid positivity and decreased brain volumes on MRI using a composite of AD-prone regions (Dickerson et al, 2011). Apolipoprotein E ε4 status exerted indirect effects through its relationship with amyloid positivity while increased age also exerted its effects indirectly through both amyloid positivity and volumetric reductions.…”

A Novel Computerized Cognitive Test for the Detection of Mild Cognitive Impairment and Its Association with Neurodegeneration in Alzheimer’s Disease Prone Brain Regions

“…A growing body of evidence indicates that maximum learning of the initial targets, PSI, frPSI and semantic intrusion errors on the LASSI-L are very sensitive in discriminating between older adults who are cognitively healthy and those with PreMCI or MCI due to AD with amyloid PET biomarker positivity [ 12 ] [ 14 ] [ 15 ] [ 16 ]. Multiple studies highlighted that LASSI-L deficits, particularly frPSI, are related to volumetric reductions in AD-prone brain regions [ 12 ] [ 17 ] [ 18 ] [ 19 ]. Further, even in cognitively unimpaired older adults with otherwise normal performance on a traditional neuropsychological battery, these AD-salient cognitive deficits were also associated with increased amyloid load in AD-prone areas [ 11 ].…”