Neural Dedifferentiation in Relation to Risk for Alzheimer\u27s Disease

Functional magnetic resonance imaging (fMRI) research indicates that as an individual\u27s age increases, the task-related spatial extent of neural activation increases. This decrease in neural specificity, or dedifferentiation, is often demonstrated by older adults during challenging cognitive tasks. Cognitively intact individuals at-risk for Alzheimer\u27s disease (AD), as deemed by having an apolipoprotein-E ε4 allele or a family history of AD, demonstrate increased fMRI activation as compared to individuals at lower risk. Using a low effort, high accuracy event-related semantic memory task involving the presentation of famous and non-famous names, we examined spatial neural specificity through a measure of dedifferentiation using fMRI. In particular, the goal was to look at degree of dedifferentiation between older healthy subjects with or without risk factors for AD. Our results indicated that while there was not a significant difference between the two groups on the total amount of neural dedifferentiation, there was a significant interaction between stimulus type and risk group. Individuals at-risk for AD displayed greater dedifferentiation for non-famous names yet greater differentiation (i.e., less dedifferentiation) for famous names as compared to the low-risk group. These findings may reflect disturbances in memory formation for individuals at-risk for AD

Predicting Cognitive Decline in Older Adults Through Multi-Voxel Pattern Analysis

Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder that is associated with cognitive and structural decline beyond what is seen in normal, healthy aging. Functional magnetic resonance imaging (fMRI) research indicates that prior to the onset of measureable cognitive impairment, individuals at-risk for AD demonstrate different patterns of neural activation than individuals at lower risk. Thus, differences in task-activated fMRI may be beneficial in predicting cognitive decline at a pre-symptomatic stage. The present study utilizes multi-voxel pattern analysis (MVPA) of baseline fMRI task-related activation to predict cognitive decline, with the hypothesis that famous and non-famous name task activation will discriminate older adults who go on to experience cognitive decline from those who do not. Ninety-nine cognitively intact older adults underwent neuropsychological testing and a semantic memory fMRI task (famous name discrimination). After follow-up neuropsychological testing 18-months later, participants were grouped as Stable (n = 65) or Declining (n = 34) based on \u3e 1.0 SD decline in performance on cognitive measures. MVPA classification accuracy was 90% for stimulus type (famous and non-famous names), thereby supporting the general approach. Mean MVPA classification accuracy for famous and non-famous names was 83% for both the Stable and Declining groups. Finally, MVPA produced greater than chance classification accuracy of participant groups for both famous name activation (56%) and non-famous name activation (55%) as determined via binomial distribution. The results of the current study suggest that MVPA possesses potential in predicting cognitive decline in older adults

Semantic Memory Functional MRI and Cognitive Function After Exercise Intervention in Mild Cognitive Impairment

Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer\u27s disease (AD) neuropathology, inefficient or ineffective neural processing, and increased risk for AD. Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging (fMRI). Seventeen MCI participants and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed an fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged 0.048 to 0.0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD

Performance Variability During a Multitrial List-Learning Task as a Predictor of Future Cognitive Decline in Healthy Elders

Introduction: In clinical settings, neuropsychological test performance is traditionally evaluated with total summary scores (TSS). However, recent studies demonstrated that indices of intraindividual variability (IIV) yielded unique information complementing TSS. This 18-month longitudinal study sought to determine whether IIV indices derived from a multitrial list-learning test (the Rey Auditory Verbal Learning Test) provided incremental utility in predicting cognitive decline in older adults compared to TSS. Method: Ninety-nine cognitively intact older adults (aged 65 to 89 years) underwent neuropsychological testing (including the Rey Auditory Verbal Learning Test) at baseline and 18-month follow-up. Participants were classified as cognitively stable (n = 65) or declining (n = 34) based on changes in their neuropsychological test performance. Logistic regression modeling tested the ability of baseline TSS indices (sum of Trials 1–5, immediate recall, and delayed recall) and IIV indices (lost access and gained access) to discriminate between stable and declining individuals. Results: Higher values of both lost access and gained access at baseline were associated with an increased risk for decline at 18-month follow-up. Further, the IIV indices provided predictive utility above and beyond the TSS indices. Conclusion: These results highlight the value of analyzing IIV in addition to TSS during neuropsychological evaluation in older adults. High levels of IIV may reflect impairment in anterograde memory systems and/or executive dysfunction that may serve as a prognostic indicator of cognitive decline

Interactive Effects of Physical Activity and APOE-ε4 on BOLD Semantic Memory Activation in Healthy Elders

Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer\u27s disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65–85) cognitively intact adults. A cross-sectional design was used with four groups (n = 17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous\u3eunfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline

FreeSurfer vs. Manual Tracing: Distinguishing Stable from Cognitively Declining Elders Using Prospectively Measured Hippocampal Volume

Objective: Alzheimer’s disease (AD) pathology is thought to begin years before symptom onset. Hippocampal volume is sensitive to age-related cognitive decline and conversion from MCI to AD. Measurement of hippocampal volumes has used either automated methods such as FreeSurfer (FS) or manual tracing (MT). We compared the ability of FS and MT in detecting baseline volume differences in cognitively intact older individuals who subsequently showed significant cognitive decline. Participants and Methods: Seventy-five cognitively intact elders underwent baseline and 18-month follow-up structural MRI scan and neuropsychological testing. Participants were classified as Declining (n=27) or Stable (n=48) based on the baseline to 18-month changes on a listlearning task and a measure of general cognitive functioning. A 2 (left, right) x 2 (anterior, posterior) x 2 (Declining, Stable) repeated measures ANOVA was conducted for both the MT and FS hippocampal volumes derived at baseline. Results: MT identified significantly smaller left and right hippocampal volumes and smaller anterior than posterior hippocampal volumes in Declining compared to Stable subjects. In contrast, no group differences in hippocampal volumes were observed using FS. Notably, MT included more subiculum and entorhinal cortex, while FS included more of the amygdala and the CA region of the hippocampus. Conclusions: MT was superior to FS for detecting prospective volumetric differences associated with cognitive decline in cognitively intact older participants. MT afforded more unique coverage of the anterior hippocampus than FS. The differences in regional coverage of the mesial temporal lobe between MT and FS may account for the different findings in discriminating Stable and Declining groups

Prediction of Longitudinal White Matter Change in Healthy Elderly Individuals

Diffusion Tensor Imaging (DTI) studies have shown that significant alteration in white matter (WM) integrity differentiates healthy older adults from persons with Mild Cognitive Impairment (MCI) and Alzheimer\u27s disease (AD). Most studies, however, have been cross-sectional and have not related longitudinal DTI changes to cognitive change. Here we report changes in WM integrity and cognition in healthy older adults over an 18-month interval. Sixty-seven cognitively intact elders underwent neuropsychological testing and DTI at baseline to follow-up on the Rey Auditory Verbal Learning Test (recall sum across trials 1-5, delayed recall) and Mattis Dementia Rating Scale-2. Declining participants (N=21) showed a minimum of 1 SD reduction on at least one cognitive measure, while Stable participants (N=46) showed comparable scores at each time point. WM regions-of-interest were derived from Freesurfer. Hierarchical linear regression was used to predict fractional anisotropy (FA) change in regions frequently identified in DTI studies of MCI and AD including transentorhinal cortex, temporal lobe, and posterior cingulate. Groups did not differ at baseline in age, cognition, FA, or WM volume. After controlling for age and baseline FA, cognitive status (Declining, Stable) predicted the baseline to 18-month reduction in FA in the right hippocampal gyrus (p=.004) and left fusi-form gyrus (p=.01) with a trend in the left middle temporal gyrus (p=.06). Future research should examine WM changes in other brain regions and determine whether DTI diffusivity measures are related to cognitive decline

Longitudinal Associations between Physical Activity, Cognitive Status, and Brain Function in Older Adults at Genetic Risk for Alzheimer’s Disease

The apolipoproteinE epsilon4 (APOE-?4) allele is associated with cognitive decline in old age and is a risk factor for Alzheimer\u27s disease (AD). Physical activity (P A) is associated with a reduced risk of incident cognitive impairment, particularly among APOE-?4 carriers. We recently reported greater semantic memory related brain activation in cognitively intact physically active (High P A) APOE-?4 carriers compared to physically inactive (Low PA) ?4 carriers and non-carriers (Smith et al., 2011). Here, we compared longitudinal changes in semantic memory-related brain activation in High PA and Low PA APOE-?4 carriers. Thirty-two older ?4 carriers completed neuropsychological testing and a fMRI semantic memory task (famous name discrimination) at baseline and after 18 months. All participants were cognitively intact at baseline and were classified as High PA (n = 16) or Low PA (n = 16) based on self-report. After 18 months, 5 of 16 High P A and 13 of 16 Low P A were classified as cognitively declining by at least 1 SD decrease in neurocognitive performance (Group difference, p = .011, Fisher\u27s exact test). A fROI analysis of the fMRI data and repeated measures ANOV As revealed significant Group by Time interactions for intensity of semantic memory-related activation. Significantly greater activation at baseline in the High PA group was attenuated over time (no change in Low P A) and resulted in no group differences at the 18-month follow-up. These findings suggest that greater P A at baseline is associated with greater cognitive stability over 18-months in APOE-?4 carriers and reduced neural activation during fame discrimination

Five-Year Changes in Brain Volume and Episodic Memory in Cognitively Intact Elders with and without an Apolipoprotein ε4 Allele

The apolipoprotein ε4 allele is a risk factor for Alzheimer\u27s disease. ε4 carriers diagnosed with AD or MCI exhibit an increased rate of atrophy on MRI relative to non-carriers. Few longitudinal studies have examined the rate of atrophy and cognitive change in older ε4 carriers who were cognitively intact at study entry. In this study, structural MRI and episodic memory testing were administered on two occasions separated by 5 years to 45 cognitively intact older adults, ages 65-90 years, divided into two groups: (1) carriers with one or both ε4 alleles (n=24) and (2) demographically-matched non-carriers (n=21). Longitudinal analysis of whole brain gray matter, whole brain white matter, and hippocampal volumes were derived from Freesurfer software. Analysis of variance indicated a significant group x time interaction for both left and right cortical gray matter (p\u27s \u3c .05; 2% decrease) and left hippocampus (p \u3c .001; 5.6% decrease); right hippocampus showed a marginal effect (p=.086; 4.9% decrease). In all instances, the ε4 group showed greater atrophy over the five-year interval than non-carriers. White matter brain volume significantly decreased over retest intervals (3.5%), but did not differ between groups. Over the same retest interval, the ε4 group also showed significantly greater decline than non-carriers on delayed word recall and percent retention on a list-learning task. These data suggest that the presence of an ε4 allele carries an increased risk for cortical gray matter and hippocampal atrophy and memory loss among older participants who were cognitively intact at study entry

Lifestyle and Genetic Contributions to Cognitive Decline and Hippocampal Structure and Function in Healthy Aging

Background: Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults. However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown. In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ?4 allele could moderate the effect of PA or CA on hippocampal structure or function. Methods: Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI. Results: After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE 4 status such that engagement in PA reduced the risk of cognitive decline in APOE 4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus. Conclusions: Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD. The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus