Minor neuropsychological deficits in patients with subjective cognitive decline.

OBJECTIVE: To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with CSF biomarkers of Alzheimer disease (AD). METHOD: We analyzed data from n = 449 cognitively normal participants (n = 209 healthy controls, n = 240 patients with SCD) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, 5 cognitive domain factor structure comprising learning and memory, executive functions, language abilities, working memory, and visuospatial functions. We compared groups in terms of global and domain-specific performance and correlated performance with different CSF markers of AD pathology. RESULTS: We observed worse performance (Cohen d = ≈0.25-0.5, adjusted for age, sex differences with analysis of covariance) in global performance, memory, executive functions, and language abilities for the SCD group compared to healthy controls. In addition, worse performance in these domains was moderately (r = ≈0.3) associated with lower CSF ß-amyloid42/40 and CSF ß-amyloid42/phosphorylated tau181 in the whole sample and specifically in the SCD subgroup. CONCLUSIONS: Within the spectrum of clinically unimpaired (i.e., before mild cognitive impairment) cognitive performance, SCD is associated with minor deficits in memory, executive function, and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD.

Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease.

BACKGROUND: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD). OBJECTIVE: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD. METHODS: We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors. RESULTS: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume. CONCLUSION: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.

A Reduction in Delay Discounting by Using Episodic Future Imagination and the Association with Episodic Memory Capacity.

Delay discounting (DD) refers to the phenomenon that individuals discount future consequences. Previous studies showed that future imagination reduces DD, which was mediated by functional connectivity between medial prefrontal valuation areas and a key region for episodic memory (hippocampus). Future imagination involves an initial period of construction and a later period of elaboration, with the more elaborative latter period recruiting more cortical regions. This study examined whether elaborative future imagination modulated DD, and if so, what are the underlying neural substrates. It was assumed that cortical areas contribute to the modulation effect during the later period of imagination. Since future imagination is supported by episodic memory capacity, we additionally hypothesize that the neural network underlying the modulation effect is related to individual episodic memory capacity. Twenty-two subjects received an extensive interview on personal future events, followed by an fMRI DD experiment with and without the need to perform elaborative future imagination simultaneously. Subjects' episodic memory capacity was also assessed. Behavioral results replicate previous findings of a reduced discount rate in the DD plus imagination condition compared to the DD only condition. The behavioral effect positively correlated with: (i) subjective value signal changes in midline brain structures during the initial imagination period; and (ii) signal changes in left prefrontoparietal areas during the later imagination period. Generalized psychophysiological interaction (gPPI) analyses reveal positive correlations between the behavioral effect and functional connectivity among the following areas: right anterior cingulate cortex (ACC) and left hippocampus; left inferior parietal cortex (IPC) and left hippocampus; and left IPC and bilateral occipital cortices. These changes in functional connectivity are also associated with episodic memory capacity. A hierarchical multiple regression indicates that the model with both the valuation related signal changes in the right ACC and the imagination related signal changes in the left IPC best predicts the reduction in DD. This study illustrates interactions between the left hippocampus and multiple cortical regions underlying the modulation effect of elaborative episodic future imagination, demonstrating, for the first time, empirical support for a relation to individual episodic memory capacity.