Ceasar in the storm: A commentary on Lucan de bello civili 5.476-721

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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

Physical Activity Reduces Hippocampal Atrophy in Elders at Genetic Risk for Alzheimer\u27s Disease

We examined the impact of physical activity (PA) on longitudinal change in hippocampal volume in cognitively intact older adults at varying genetic risk for the sporadic form of Alzheimer\u27s disease (AD). Hippocampal volume was measured from structural magnetic resonance imaging (MRI) scans administered at baseline and at an 18-month follow-up in 97 healthy, cognitively intact older adults. Participants were classified as High or Low PA based on a self-report questionnaire of frequency and intensity of exercise. Risk status was defined by the presence or absence of the apolipoprotein E-epsilon 4 (APOE-ε4) allele. Four subgroups were studied: Low Risk/High PA (n = 24), Low Risk/Low PA (n = 34), High Risk/High PA (n = 22), and High Risk/Low PA (n = 17). Over the 18 month follow-up interval, hippocampal volume decreased by 3% in the High Risk/Low PA group, but remained stable in the three remaining groups. No main effects or interactions between genetic risk and PA were observed in control brain regions, including the caudate, amygdala, thalamus, pre-central gyrus, caudal middle frontal gyrus, cortical white matter (WM), and total gray matter (GM). These findings suggest that PA may help to preserve hippocampal volume in individuals at increased genetic risk for AD. The protective effects of PA on hippocampal atrophy were not observed in individuals at low risk for AD. These data suggest that individuals at genetic risk for AD should be targeted for increased levels of PA as a means of reducing atrophy in a brain region critical for the formation of episodic memories

Episodic Memory Measures Complement Structural and Functional MRI for Predicting Cognitive Decline in Apolipoprotein E ε4 Carriers

Apolipo-protein E (APOE) ?4 allele carriers demonstrate greater risk for cognitive decline and Alzheimer\u27s disease than non-carriers. However, factors associated with risk of decline among APOE ?4 carriers are not well-known. In this longitudinal study, we investigated whether discrete aspects of baseline episodic memory performance and structural (sMRI) and function (fMRI) magnetic resonance imaging were associated with cognitive decline in older APOE ?4 carriers and non-carriers. Seventy-eight healthy older adults underwent cognitive testing at baseline and after 18 months, baseline serum APOE genotyping, manually-traced hip-pocampal volume measurement from sMRI, and task-activated fMRI. Cognitive decline was defined as a one SD or greater reduction from baseline on at least one of three cognitive measures at follow-up (Rey Auditory Verbal Learning Test [AVLT] Delayed Recall and Trials 1-5 Sum, Mattis Dementia Rating Scale-2 Total Score). Declining APOE ?4 carriers (n=14) exhibited reduced hippocampal volume (

Comparison of Semantic and Episodic Memory BOLD fMRI Activation in Predicting Cognitive Decline in Older Adults

Previous studies suggest that task-activated functional magnetic resonance imaging (fMRI) can predict future cognitive decline among healthy older adults. The present fMRI study examined the relative sensitivity of semantic memory (SM) versus episodic memory (EM) activation tasks for predicting cognitive decline. Seventy-eight cognitively intact elders underwent neuropsychological testing at entry and after an 18-month interval, with participants classified as cognitively “Stable” or “Declining” based on ≥1.0 SD decline in performance. Baseline fMRI scanning involved SM (famous name discrimination) and EM (name recognition) tasks. SM and EM fMRI activation, along with Apolipoprotein E (APOE) ε4 status, served as predictors of cognitive outcome using a logistic regression analysis. Twenty-seven (34.6%) participants were classified as Declining and 51 (65.4%) as Stable. APOE ε4 status alone significantly predicted cognitive decline (R2 = .106; C index = .642). Addition of SM activation significantly improved prediction accuracy (R2 = .285; C index = .787), whereas the addition of EM did not (R2 = .212; C index = .711). In combination with APOE status, SM task activation predicts future cognitive decline better than EM activation. These results have implications for use of fMRI in prevention clinical trials involving the identification of persons at-risk for age-associated memory loss and Alzheimer\u27s disease. (JINS, 2012, 18, 1–11