Interactive Effects of Physical Activity and APOE-ε4 On White Matter Tract Diffusivity in Healthy Elders

Older adult apolipoprotein-E epsilon 4 (APOE-ε4) allele carriers vary considerably in the expression of clinical symptoms of Alzheimer\u27s disease (AD), suggesting that lifestyle or other factors may offer protection from AD-related neurodegeneration. We recently reported that physically active APOE-ε4 allele carriers exhibit a stable cognitive trajectory and protection from hippocampal atrophy over 18 months compared to sedentary ε4 allele carriers. The aim of this study was to examine the interactions between genetic risk for AD and physical activity (PA) on white matter (WM) tract integrity, using diffusion tensor imaging (DTI) MRI, in this cohort of healthy older adults (ages of 65 to 89). Four groups were compared based on the presence or absence of an APOE-ε4 allele (High Risk; Low Risk) and self-reported frequency and intensity of leisure time physical activity (PA) (High PA; Low PA). As predicted, greater levels of PA were associated with greater fractional anisotropy (FA) and lower radial diffusivity in healthy older adults who did not possess the APOE-ε4 allele. However, the effects of PA were reversed in older adults who were at increased genetic risk for AD, resulting in significant interactions between PA and genetic risk in several WM tracts. In the High Risk-Low PA participants, who had exhibited episodic memory decline over the previous 18-months, radial diffusivity was lower and fractional anisotropy was higher, compared to the High Risk-High PA participants. In WM tracts that subserve learning and memory processes, radial diffusivity (DR) was negatively correlated with episodic memory performance in physically inactive APOE-ε4 carriers, whereas DR was positively correlated with episodic memory performance in physically active APOE-ε4 carriers and the two Low Risk groups. The common model of demyelination-induced increase in radial diffusivity cannot directly explain these results. Rather, we hypothesize that PA may protect APOE-ε4 allele carriers from selective neurodegeneration of individual fiber populations at locations of crossing fibers within projection and association WM fiber tracts

Alterations in Multiple Measures of White Matter Integrity in Normal Women at High Risk for Alzheimer\u27s Disease

There is evidence that disruption of white matter (WM) microstructure is an early event in the course of Alzheimer\u27s disease (AD). However, the neurobiological bases of WM microstructural declines in presymptomatic AD are unknown. In the present study we address this issue using a multimodal imaging approach to the study of presymptomatic AD. Participants were 37 high-risk (both family history of dementia and one or more APOE4 alleles) women and 20 low-risk (neither family history nor APOE4) women. Groups were matched for age, education, neuropsychological performance, and vascular factors that could affect white matter. Whole-brain analyses of diffusion tensor imaging data [including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA) and radial diffusivity (DR)] and volumetric comparisons of medial temporal lobe (MTL) structures were conducted. Results indicated equivalent entorhinal cortex and hippocampal volumes between risk groups. Nevertheless, the high risk group showed decreased microstructural integrity in WM tracts with direct and secondary connections to the MTL. The predominant alteration in WM integrity in the high AD-risk group was decreased FA not solely driven by either DA or DR changes alone in regions where no MD changes were observed. A second pattern observed in a smaller number of regions involved decreased FA and increased DR. These results suggest that disconnection of MTL-neocortical fiber pathways represents a very early event in the course of AD and suggest that demyelination may represent one contributing mechanism

White matter integrity and vulnerability to Alzheimer's disease: Preliminary findings and future directions

AbstractNeuroimaging biomarkers that precede cognitive decline have the potential to aid early diagnosis of Alzheimer's disease (AD). A body of diffusion tensor imaging (DTI) work has demonstrated declines in white matter (WM) microstructure in AD and its typical prodromal state, amnestic mild cognitive impairment. The present review summarizes recent evidence suggesting that WM integrity declines are present in individuals at high AD-risk, prior to cognitive decline. The available data suggest that AD-risk is associated with WM integrity declines in a subset of tracts showing decline in symptomatic AD. Specifically, AD-risk has been associated with WM integrity declines in tracts that connect gray matter structures associated with memory function. These tracts include parahippocampal WM, the cingulum, the inferior fronto-occipital fasciculus, and the splenium of the corpus callosum. Preliminary evidence suggests that some AD-risk declines are characterized by increases of radial diffusivity, raising the possibility that a myelin-related pathology may contribute to AD onset. These findings justify future research aimed at a more complete understanding of the neurobiological bases of DTI-based declines in AD. With continued refinement of imaging methods, DTI holds promise as a method to aid identification of presymptomatic AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease

Cognitive-Motor Integration In Normal Aging And Preclinical Alzheimer's Disease: Neural Correlates And Early Detection

The objectives of the studies included in this dissertation were to characterize how the ability to integrate cognition into action is disrupted by both normal and pathological aging, to evaluate the effectiveness of kinematic measures in discriminating between individuals who are and are not at increased Alzheimer’s disease (AD) risk, and to examine the structural and functional neural correlates of cognitive-motor impairment in individuals at increased AD risk. The underlying hypothesis, based on previous research, is that measuring visuomotor integration under conditions that place demands on visual-spatial and cognitive-motor processing may provide an effective behavioural means for the early detection of brain alterations associated with AD risk. To this end, the first study involved testing participants both with and without AD risk factors on visuomotor tasks using a dual-touchscreen tablet. Comparisons between high AD risk participants and both young and old healthy control groups revealed significant performance disruptions in at-risk participants in the most cognitively demanding task. Furthermore, a stepwise discriminant analysis was able to distinguish between high and low AD risk participants with a classification accuracy of 86.4%. Based on the prediction that the impairments observed in high AD risk participants reflect disruption to the intricate reciprocal communication between hippocampal, parietal, and frontal brain regions required to successfully prepare and update complex reaching movements, the second and third studies were designed to examine the underlying structural and functional connectivity associated with cognitive-motor performance. Young adult and both low AD risk and high AD risk older adult participants underwent anatomical, diffusion-weighted, and resting-state functional connectivity scans. These data revealed significant age-related declines in white matter integrity that were more pronounced in the high AD risk group. Decreased functional connectivity in the default mode network (DMN) was also found in high AD risk participants. Furthermore, measures of white matter integrity and resting-state functional connectivity with DMN seed-regions were significantly correlated with task performance. These data support our hypothesis that disease-related disruptions in visuomotor control are associated with identifiable brain alterations, and thus behavioural assessments incorporating both cognition and action together may be useful in identifying individuals at increased AD risk

White Matter Diffusion Alterations in Normal Women at Risk of Alzheimer\u27s Disease

Increased white matter mean diffusivity and decreased fractional anisotropy (FA) has been observed in subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer\u27s disease (AD). We sought to determine whether similar alterations of white matter occur in normal individuals at risk of AD. Diffusion tensor images were acquired in 42 cognitively normal right-handed women with both a family history of dementia and at least one apolipoprotein E4 allele. These were compared with images from 23 normal women without either AD risk factor. Group analyses were performed using tract-based spatial statistics. Reduced FA was observed in the fronto-occipital and inferior temporal fasciculi (particularly posteriorly), the splenium of the corpus callosum, subcallosal white matter and the cingulum bundle. These findings demonstrate that specific white matter pathways are altered in normal women at increased risk of AD years before the expected onset of cognitive symptoms

Sex-Differences in the Early Detection of Dementia Risk Using a Cognitive-motor Integration Task

Cognitive-motor integration (CMI) involves concurrent thought and action which requires the interaction of large brain networks. Our research objectives were to examine the effect that dementia risk has on the ability to integrate rules into action and to investigate sex-related differences in this rule-based motor performance. Given that early-stage dementia involves neural network dysfunction, problems with CMI may prove useful for early dementia detection. Males and females at high- and low-dementia risk were tested on increasingly spatially-dissociated visuomotor tasks. We observed significantly greater endpoint error scores and corrective path lengths in females compared to males in the most complex CMI condition. These data suggest that underlying brain networks controlling simultaneous thought and action differ between the sexes, and that dementia risk may affect female CMI performance to a greater extent. Thus, sex-related differences must be taken into account when assessing CMI performance as a means to examine dementia risk-related functional abilities

Brain network alterations due to cardiometabolic risk factors:insights from population magnetic resonance imaging

This thesis investigated whether life style related risk factors are associated with novel neuronal imaging markers and evaluated the value of structural and functional brain network measures for that purpose. The life style related risk factors, also called cardiometabolic risk factors, studied in this thesis are (pre)diabetes, physical inactivity, high sedentary time, high blood pressure, obesity, and high cholesterol. The research summarized and extended the existing evidence on associations between cardiometabolic risk factors and subtle brain changes as assessed by structural and advanced Magnetic Resonance Imaging (MRI). More specifically, it was found that high blood sugar was associated with structural brain alterations, even in the prediabetes phase. Physical inactivity was also associated with structural brain alteration, especially in brain regions highly specialized in motor function. Furthermore, the research found an interrelation of brain damage in the form of white matter lesions (WML), structural brain alterations, and cognitive function. In particular, WMLs in structural brain connections important for information processing speed were associated with cognitive slowing. Finally, the research observed that neuronal and non-neuronal physiological signals could be recognized in the functional MRI signal, and that this signal is altered in people with cardiometabolic risk factors

Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure

Several common genetic variants influence cholesterol levels, which play a key role in overall health. Myelin synthesis and maintenance are highly sensitive to cholesterol concentrations, and abnormal cholesterol levels increase the risk for various brain diseases, including Alzheimer's disease. We report significant associations between higher serum cholesterol (CHOL) and high-density lipoprotein levels and higher fractional anisotropy in 403 young adults (23.8 ± 2.4years) scanned with diffusion imaging and anatomic magnetic resonance imaging at 4Tesla. By fitting a multi-locus genetic model within white matter areas associated with CHOL, we found that a set of 18 cholesterol-related, single-nucleotide polymorphisms implicated in Alzheimer's disease risk predicted fractional anisotropy. We focused on the single-nucleotide polymorphism with the largest individual effects, CETP (rs5882), and found that increased G-allele dosage was associated with higher fractional anisotropy and lower radial and mean diffusivities in voxel-wise analyses of the whole brain. A follow-up analysis detected white matter associations with rs5882 in the opposite direction in 78 older individuals (74.3 ± 7.3years). Cholesterol levels may influence white matter integrity, and cholesterol-related genes may exert age-dependent effects on the brain

Using neurite orientation dispersion and density imaging and tracts constrained by underlying anatomy to differentiate between subjects along the Alzheimer's disease continuum

OBJECTIVE: To assess the involvement of the white matter of the brain in the pathology of Alzheimer’s disease. Using Neurite Orientation Density and Dispersion Imaging (NODDI) and the probabilistic white matter parcellation tool Tracula as a means for understanding whether alterations in the white matter underlie changes in perceived cognitive abilities across the spectrum from health aging to Alzheimer’s disease. METHOD: Data were obtained from 28 participants in the Health Outreach Program for the Elderly (HOPE) at the Boston University Alzheimer’s Disease Center (BU ADC) Clinical Core Registry. MRI scans included an MPRAGE T1 scan, multi-b shell diffusion scan and a High Angular Resolution Diffusion Imaging scan (HARDI). Scans were processed with Freesurfer v6.0 and the NODDI Python2.7 toolkit. The resulting data included the orientation dispersion index (ODI) and Fractional Anisotropy (FA) values for cortical and subcortical regions in the DKT atlas space as well as specific Tracts Constrained by Underlying Anatomy (TRACULA) measurements for 18 specific established white matter tracts. Statistical models using measures of pathway integrity (FA and ODI data) were used to assess relationships with Informant Cognitive Change Index (ICCI), self-described Cognitive Change Index (CCI), and Clinical Dementia Rating (CDR) values. RESULTS: Measures of white matter integrity within several tracts predicted ICCI and CDR well in statistical models. FA and ODI values of the bilateral superior longitudinal fasciculi, inferior longitudinal fasciculi, and the cingulum bundle tracts were all related to ICCI and CDR. None of the known tracts’ FA or ODI values were related to CCI. CONCLUSIONS: Measures of white matter pathway integrity were predictive of ICCI and CDR scores but not CCI. These finding support the notion that self-report of cognitive abilities may be compromised by alterations in insight and reinforce the need for informed study partners and clinical ratings to evaluate potential MCI and AD