White Matter Hyperintensity Volume and Location: Associations with WM Microstructure, Brain Iron, and Cerebral Perfusion

Cerebral white matter hyperintensities (WMHs) represent macrostructural brain damage associated with various etiologies. However, the relative contributions of various etiologies to WMH volume, as assessed via different neuroimaging measures, is not well-understood. Here, we explored associations between three potential early markers of white matter hyperintensity volume. Specifically, the unique variance in total and regional WMH volumes accounted for by white matter microstructure, brain iron concentration and cerebral blood flow (CBF) was assessed. Regional volumes explored were periventricular and deep regions. Eighty healthy older adults (ages 60–86) were scanned at 3 Tesla MRI using fluid-attenuated inversion recovery, diffusion tensor imaging (DTI), multi-echo gradient-recalled echo and pseudo-continuous arterial spin labeling sequences. In a stepwise regression model, DTI-based radial diffusivity accounted for significant variance in total WMH volume (adjusted R2 change = 0.136). In contrast, iron concentration (adjusted R2 change = 0.043) and CBF (adjusted R2 change = 0.027) made more modest improvements to the variance accounted for in total WMH volume. However, there was an interaction between iron concentration and location on WMH volume such that iron concentration predicted deep (p = 0.034) but not periventricular (p = 0.414) WMH volume. Our results suggest that WM microstructure may be a better predictor of WMH volume than either brain iron or CBF but also draws attention to the possibility that some early WMH markers may be location-specific

Combined ERP/fMRI Evidence for Early Word Recognition Effects in the Posterior Inferior Temporal Gyrus

Two brain regions with established roles in reading are the posterior middle temporal gyrus and the posterior fusiform gyrus. Lesion studies have also suggested that the region located between them, the posterior inferior temporal gyrus (pITG), plays a central role in word recognition. However, these lesion results could reflect disconnection effects since neuroimaging studies have not reported consistent lexicality effects in pITG. Here we tested whether these reported pITG lesion effects are due to disconnection effects or not using parallel ERP/fMRI studies. We predicted that the Recognition Potential (RP), a left-lateralized ERP negativity that peaks at about 200–250 ms, might be the electrophysiological correlate of pITG activity and that conditions that evoke the RP (perceptual degradation) might therefore also evoke pITG activity. In Experiment 1, twenty-three participants performed a lexical decision task (temporally flanked by supraliminal masks) while having high-density 129-channel ERP data collected. In Experiment 2, a separate group of fifteen participants underwent the same task while having fMRI data collected in a 3T scanner. Examination of the ERP data suggested that a canonical Recognition Potential effect was produced. The strongest corresponding effect in the fMRI data was in the vicinity of the pITG. In addition, results indicated stimulus-dependent functional connectivity between pITG and a region of the posterior fusiform gyrus near the visual word form area (VWFA) during word compared to nonword processing. These results provide convergent spatiotemporal evidence that the pITG contributes to early lexical access through interaction with the VWFA

Common and Distinct Mechanisms of Cognitive Flexibility in Prefrontal Cortex

The human ability to flexibly alternate between tasks represents a central component of cognitive control. Neuroimaging studies have linked task switching with a diverse set of prefrontal cortex (PFC) regions, but the contributions of these regions to various forms of cognitive flexibility remain largely unknown. Here, subjects underwent functional brain imaging while they completed a paradigm that selectively induced stimulus, response, or cognitive set switches in the context of a single task decision performed on a common set of stimuli. Behavioral results indicated comparable reaction time costs associated with each switch type. Domain-general task-switching activation was observed in the inferior frontal junction and posterior parietal cortex, suggesting core roles for these regions in switching such as updating and representing task sets. In contrast, multiple domain-preferential PFC activations were observed across lateral and medial PFC, with progressively more rostral regions recruited as switches became increasingly abstract. Specifically, highly abstract cognitive set switches recruited anterior-PFC regions, moderately abstract response switches recruited mid-PFC regions, and highly constrained stimulus switches recruited posterior-PFC regions. These results demonstrate a functional organization across lateral and medial PFC according to the level of abstraction associated with acts of cognitive flexibility

Multimodal Imaging Evidence for Axonal and Myelin Deterioration in Amnestic Mild Cognitive Impairment

White matter (WM) microstructural declines have been demonstrated in Alzheimer\u27s disease and amnestic mild cognitive impairment (aMCI). However, the pattern of WM microstructural changes in aMCI after controlling for WM atrophy is unknown. Here, we address this issue through joint consideration of aMCI alterations in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, as well as macrostructural volume in WM and gray matter compartments. Participants were 18 individuals with aMCI and 24 healthy seniors. Voxelwise analyses of diffusion tensor imaging data was carried out using tract-based spatial statistics (TBSS) and voxelwise analyses of high-resolution structural data was conducted using voxel based morphometry. After controlling for WM atrophy, the main pattern of TBSS findings indicated reduced fractional anisotropy with only small alterations in mean diffusivity/radial diffusivity/axial diffusivity. These WM microstructural declines bordered and/or were connected to gray matter structures showing volumetric declines. However, none of the potential relationships between WM integrity and volume in connected gray matter structures was significant, and adding fractional anisotropy information improved the classificatory accuracy of aMCI compared to the use of hippocampal atrophy alone. These results suggest that WM microstructural declines provide unique information not captured by atrophy measures that may aid the magnetic resonance imaging contribution to aMCI detection

Distinct Patterns of Default Mode and Executive Control Network Circuitry Contribute to Present and Future Executive Function in Older Adults

Executive function (EF) performance in older adults has been linked with functional and structural profiles within the executive control network (ECN) and default mode network (DMN), white matter hyperintensities (WMH) burden and levels of Alzheimer\u27s disease (AD) pathology. Here, we simultaneously explored the unique contributions of these factors to baseline and longitudinal EF performance in older adults. Thirty-two cognitively normal (CN) older adults underwent neuropsychological testing at baseline and annually for three years. Neuroimaging and AD pathology measures were collected at baseline. Separate linear regression models were used to determine which of these variables predicted composite EF scores at baseline and/or average annual change in composite ΔEF scores over the three-year follow-up period. Results demonstrated that low DMN deactivation, high ECN activation and WMH burden were the main predictors of EF scores at baseline. In contrast, poor DMN and ECN WM microstructure and higher AD pathology predicted greater annual decline in EF scores. Subsequent mediation analysis demonstrated that DMN WM microstructure uniquely mediated the relationship between AD pathology and ΔEF. These results suggest that functional activation patterns within the DMN and ECN and WMHs contribute to baseline EF while structural connectivity within these networks impact longitudinal EF performance in older adults

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

Multi-compartment diffusion magnetic resonance imaging models link tract-related characteristics with working memory performance in healthy older adults

Multi-compartment diffusion MRI metrics [such as metrics from free water elimination diffusion tensor imaging (FWE-DTI) and neurite orientation dispersion and density imaging (NODDI)] may reflect more specific underlying white-matter tract characteristics than traditional, single-compartment metrics [i.e., metrics from Diffusion Tensor Imaging (DTI)]. However, it remains unclear if multi-compartment metrics are more closely associated with age and/or cognitive performance than single-compartment metrics. Here we compared the associations of single-compartment [Fractional Anisotropy (FA)] and multi-compartment diffusion MRI metrics [FWE-DTI metrics: Free Water Eliminated Fractional Anisotropy (FWE-FA) and Free Water (FW); NODDI metrics: Intracellular Volume Fraction (ICVF), Orientation Dispersion Index (ODI), and CSF-Fraction] with both age and working memory performance. A functional magnetic resonance imaging (fMRI) guided, white matter tractography approach was employed to compute diffusion metrics within a network of tracts connecting functional regions involved in working memory. Ninety-nine healthy older adults (aged 60-85) performed an in-scanner working memory task while fMRI was performed and also underwent multi-shell diffusion acquisition. The network of white matter tracts connecting functionally-activated regions was identified using probabilistic tractography. Diffusion metrics were extracted from skeletonized white matter tracts connecting fMRI activation peaks. Diffusion metrics derived from both single and multi-compartment models were associated with age (p s ≤ 0.011 for FA, FWE-FA, ICVF and ODI). However, only multi-compartment metrics, specifically FWE-FA (p = 0.045) and ICVF (p = 0.020), were associated with working memory performance. Our results suggest that while most current diffusion metrics are sensitive to age, several multi-compartment metrics (i.e., FWE-FA and ICVF) appear more sensitive to cognitive performance in healthy older adults

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

Non-fasting High-Density Lipoprotein Is Associated With White Matter Microstructure in Healthy Older Adults

A growing body of evidence indicates that biomarkers of cardiovascular risk may be related to cerebral health. However, little is known about the role that non-fasting lipoproteins play in assessing age-related declines in a cerebral biomarker sensitive to vascular compromise, white matter (WM) microstructure. High-density lipoprotein cholesterol (HDL-C) is atheroprotective and low-density lipoprotein cholesterol (LDL-C) is a major atherogenic lipoprotein. This study explored the relationships between non-fasting levels of cholesterol and WM microstructure in healthy older adults. A voxelwise and region of interest approach was used to determine the relationship between cholesterol and fractional anisotropy (FA). Participants included 87 older adults between the ages of 59 and 77 (mean age = 65.5 years, SD = 3.9). Results indicated that higher HDL-C was associated with higher FA in diffuse regions of the brain when controlling for age, sex, and body mass index (BMI). HDL-C was also positively associated with FA in the corpus callosum and fornix. No relationship was observed between LDL-C and FA. Findings suggest that a modifiable lifestyle variable associated with cardiovascular health may help to preserve cerebral WM

White Matter Microstructure Contributes to Age-Related Declines in Task-Induced Deactivation of the Default Mode Network

Task-induced deactivations within the brain’s default mode network (DMN) are thought to reflect suppression of endogenous thought processes to support exogenous goal-directed task processes. Older adults are known to show reductions in deactivation of the DMN compared to younger adults. However, little is understood about the mechanisms contributing to functional dysregulation of the DMN in aging. Here, we explored the relationships between functional modulation of the DMN and age, task performance and white matter (WM) microstructure. Participants were 117 adults ranging from 25 to 83 years old who completed an fMRI task switching paradigm, including easy (single) and difficult (mixed) conditions, and underwent diffusion tensor imaging (DTI). The fMRI results revealed an age by condition interaction (β = −0.13, t = −3.16, p = 0.002) such that increasing age affected deactivation magnitude during the mixed condition (β = −0.29, t = −3.24 p = 0.002) but not the single condition (p = 0.58). Additionally, there was a WM by condition interaction (β = 0.10, t = 2.33, p = 0.02) such that decreasing WM microstructure affected deactivation magnitude during the mixed condition (β = 0.30, t = 3.42 p = 0.001) but not the single condition (p = 0.17). Critically, mediation analyses indicated that age-related reductions in WM microstructure accounted for the relationship between age and DMN deactivation in the more difficult mixed condition. These findings suggest that age-related declines in anatomical connectivity between DMN regions contribute to functional dysregulation within the DMN in older adults