Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Wang Q
PROVIDER: S-EPMC6428957 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Surrogates of whole-brain white matter (WM) networks reconstructed using diffusion tensor imaging (DTI) are novel markers of structural brain connectivity. Global connectivity of networks has been found impaired in clinical Alzheimer's disease (AD) compared to cognitively healthy aging. We hypothesized that network alterations are detectable already in preclinical AD and investigated major global WM network properties. Other structural markers of neurodegeneration typically affected in prodromal AD but seeming largely unimpaired in preclinical AD were also examined. 12 cognitively healthy elderly with preclinical AD as classified by florbetapir-PET (mean age 73.4 ± 4.9) and 31 age-matched controls without cerebral amyloidosis (mean age 73.1 ± 6.7) from the ADNI were included. WM networks were reconstructed from DTI using tractography and graph theory. Indices of network capacity and the established imaging markers of neurodegeneration hippocampal volume, and cerebral glucose utilization as measured by fludeoxyglucose-PET were compared between the two groups. Additionally, we measured surrogates of global WM integrity (fractional anisotropy, mean diffusivity, volume). We found an increase of shortest path length and a decrease of global efficiency in preclinical AD. These results remained largely unchanged when controlling for WM integrity. In contrast, neither markers of neurodegeneration nor WM integrity were altered in preclinical AD subjects. Our results suggest an impairment of WM networks in preclinical AD that is detectable while other structural imaging markers do not yet indicate incipient neurodegeneration. Moreover, these findings are specific to WM networks and cannot be explained by other surrogates of global WM integrity.
| S-EPMC4536470 | biostudies-literature
Project description:Sleep monitoring may provide markers for future Alzheimer's disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer's disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer's disease change with age, a greater understanding of how the relationship between sleep and cognition changes over time is needed. In this study, we hypothesized that longitudinal changes in cognitive function will have a non-linear relationship with total sleep time, time spent in non-REM and REM sleep, sleep efficiency and non-REM slow wave activity. To test this hypothesis, we monitored sleep-wake activity over 4-6 nights in 100 participants who underwent standardized cognitive testing longitudinally, APOE genotyping, and measurement of Alzheimer's disease biomarkers, total tau and amyloid-β42 in the CSF. To assess cognitive function, individuals completed a neuropsychological testing battery at each clinical visit that included the Free and Cued Selective Reminding test, the Logical Memory Delayed Recall assessment, the Digit Symbol Substitution test and the Mini-Mental State Examination. Performance on each of these four tests was Z-scored within the cohort and averaged to calculate a preclinical Alzheimer cognitive composite score. We estimated the effect of cross-sectional sleep parameters on longitudinal cognitive performance using generalized additive mixed effects models. Generalized additive models allow for non-parametric and non-linear model fitting and are simply generalized linear mixed effects models; however, the linear predictors are not constant values but rather a sum of spline fits. We found that longitudinal changes in cognitive function measured by the cognitive composite decreased at low and high values of total sleep time (P < 0.001), time in non-REM (P < 0.001) and REM sleep (P < 0.001), sleep efficiency (P < 0.01) and <1 Hz and 1-4.5 Hz non-REM slow wave activity (P < 0.001) even after adjusting for age, CSF total tau/amyloid-β42 ratio, APOE ε4 carrier status, years of education and sex. Cognitive function was stable over time within a middle range of total sleep time, time in non-REM and REM sleep and <1 Hz slow wave activity, suggesting that certain levels of sleep are important for maintaining cognitive function. Although longitudinal and interventional studies are needed, diagnosing and treating sleep disturbances to optimize sleep time and slow wave activity may have a stabilizing effect on cognition in preclinical or early symptomatic Alzheimer's disease.
| S-EPMC8536939 | biostudies-literature
Project description:BACKGROUND:Narrative discourse (ND) refers to one's ability to verbally reproduce a sequence of temporally and logically-linked events. Impairments in ND may occur in subjects with Amnestic Mild Cognitive Impairment (aMCI) and Alzheimer's Disease (AD), but correlates across this function, neuroimaging and cerebrospinal fluid (CSF) AD biomarkers remain understudied. OBJECTIVES:We sought to measure correlates among ND, Diffusion Tensor Imaging (DTI) indexes and AD CSF biomarkers in patients within the AD spectrum. RESULTS:Groups differed in narrative production (NProd) and comprehension. aMCI and AD presented poorer inference abilities than controls. AD subjects were more impaired than controls and aMCI regarding WB (p<0.01). ROIs DTI assessment distinguished the three groups. Mean Diffusivity (MD) in the uncinate, bilateral parahippocampal cingulate and left inferior occipitofrontal fasciculi negatively correlated with NProd. Changes in specific tracts correlated with T-tau/A?1-42 ratio in CSF. CONCLUSIONS:AD and aMCI patients presented more ND impairments than controls. Those findings were associated with changes in ventral language-associated and in the inferior parahippocampal pathways. The latest were correlated with biomarkers' levels in the CSF. METHODS:AD (N=14), aMCI (N=31) and Control (N=39) groups were compared for whole brain (WB) and regions of interest (ROI) DTI parameters, ND and AD CSF biomarkers.
| S-EPMC6834410 | biostudies-literature
Project description:Purpose To investigate associations between neuroimaging markers of cerebrovascular disease, including lesion topography and extent and severity of strategic and global cerebral tissue injury, and cognition in carotid artery disease (CAD). Materials and Methods All participants gave written informed consent to undergo brain magnetic resonance imaging and the Addenbrooke's Cognitive Examination-Revised. One hundred eight patients with symptomatic CAD but no dementia were included, and a score less than 82 represented cognitive impairment. Group comparison and interrelations between global cognitive and fluency performance, lesion topography, and ultrastructural damage were assessed with voxel-based statistics. Associations between cognition, medial temporal lobe atrophy (MTA), lesion volumes, and global white matter ultrastructural damage indexed as increased mean diffusivity were tested with regression analysis by controlling for age. Diagnostic accuracy of imaging markers selected from a multivariate prediction model was tested with receiver operating characteristic analysis. Results Cognitively impaired patients (n = 53 [49.1%], classified as having probable vascular cognitive disorder) were older than nonimpaired patients (P = .027) and had more frequent MTA (P < .001), more cortical infarctions (P = .016), and larger volumes of acute (P = .028) and chronic (P = .009) subcortical ischemic lesions. Lesion volumes did not correlate with global cognitive performance (lacunar infarctions, P = .060; acute lesions, P = .088; chronic subcortical ischemic lesions, P = .085). In contrast, cognitive performance correlated with presence of chronic ischemic lesions within the interhemispheric tracts and thalamic radiation (P < .05, false discovery rate corrected). Skeleton mean diffusivity showed the closest correlation with cognition (R2 = 0.311, P < .001) and promising diagnostic accuracy for vascular cognitive disorder (area under the curve, 0.82 [95% confidence interval: 0.75, 0.90]). Findings were confirmed in subjects with a low risk of preclinical Alzheimer disease indexed by the absence of MTA (n = 85). Conclusion Subcortical white matter ischemic lesion locations and severity of ultrastructural tract damage contribute to cognitive impairment in symptomatic CAD, which suggests that subcortical disconnection within large-scale cognitive neural networks is a key mechanism of vascular cognitive disorder. Online supplemental material is available for this article.
| S-EPMC5283872 | biostudies-other
Project description:IntroductionDiffusion magnetic resonance imaging may allow for microscopic characterization of white matter degeneration in early stages of Alzheimer's disease.MethodsMultishell Diffusion magnetic resonance imaging data were acquired from 100 participants (40 cognitively normal, 38 with subjective cognitive decline, and 22 with mild cognitive impairment [MCI]). White matter microscopic degeneration in 27 major tracts of interest was assessed using diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging, and q-space imaging.ResultsLower DTI fractional anisotropy and higher radial diffusivity were observed in the cingulum, thalamic radiation, and forceps major of participants with MCI. These tracts of interest also had the highest predictive power to discriminate groups. Diffusion metrics were associated with cognitive performance, particularly Rey Auditory Verbal Learning Test immediate recall, with the highest association observed in participants with MCI.DiscussionWhile DTI was the most sensitive, neurite orientation dispersion and density imaging and q-space imaging complementarily characterized reduced axonal density accompanied with dispersed and less restricted white matter microstructures.
| S-EPMC6713788 | biostudies-literature
Project description:Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (A?+), amyloid indeterminate (A?i), or amyloid negative (A?-) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among A?+ compared to A?- in all three ROIs and in A?i compared to A?- in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that A? accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.
| S-EPMC4053642 | biostudies-literature
Project description:Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer's disease (AD), are believed to spread through connected regions of the brain. Combining diffusion imaging and positron emission tomography, we investigated associations between white matter microstructure specifically in bundles connecting regions where Aβ or tau accumulates and pathology. We focused on free-water-corrected diffusion measures in the anterior cingulum, posterior cingulum, and uncinate fasciculus in cognitively normal older adults at risk of sporadic AD and presymptomatic mutation carriers of autosomal dominant AD. In Aβ-positive or tau-positive groups, lower tissue fractional anisotropy and higher mean diffusivity related to greater Aβ and tau burden in both cohorts. Associations were found in the posterior cingulum and uncinate fasciculus in preclinical sporadic AD, and in the anterior and posterior cingulum in presymptomatic mutation carriers. These results suggest that microstructural alterations accompany pathological accumulation as early as the preclinical stage of both sporadic and autosomal dominant AD.
| S-EPMC8169107 | biostudies-literature
Project description:This study aims to investigate the relationship between structural changes in the retina and white matter in the brain, in early Alzheimer's disease (AD). Twenty-three healthy controls (mean age?=?63.4±7.5 years) and seventeen AD patients (mean age?=?66.5±6.6 years) were recruited for this study. By combining two imaging techniques-optical coherence tomography and diffusion tensor imaging (DTI)-the association between changes in the thickness of individual retinal layers and white matter dysfunction in early AD was assessed. Retinal layers were segmented, and thickness measurements were obtained for each layer. DTI images were analyzed with a quantitative data-driven approach to evaluating whole-brain diffusion metrics, using tract-based spatial statistics. Diffusion metrics, such as fractional anisotropy, are markers for white matter integrity. Multivariate and partial correlation analyses evaluating the association between individual retinal layers thickness and diffusion metrics were performed. We found that axial diffusivity, indexing axonal integrity, was significantly reduced in AD (p?=?0.016, Cohen's d?=?1.004) while in the retina, only a marginal trend for significance was found for the outer plexiform layer (p?=?0.084, Cohen's d?=?0.688). Furthermore, a positive association was found in the AD group between fractional anisotropy and the inner nuclear layer thickness (p?<?0.05, r?=?0.419, corrected for multiple comparisons by controlling family-wise error rate). Our findings suggest that axonal damage in the brain dominates early on in this condition and shows an association with retinal structural integrity already at initial stages of AD. These findings are consistent with an early axonal degeneration mechanism in AD.
| S-EPMC6700635 | biostudies-literature
Project description:White matter abnormalities have been shown in the large deep fibers of Alzheimer's disease patients. However, the late myelinating superficial white matter comprised of intracortical myelin and short-range association fibers has not received much attention. To investigate this area, we extracted a surface corresponding to the superficial white matter beneath the cortex and then applied a cortical pattern-matching approach which allowed us to register and subsequently sample diffusivity along thousands of points at the interface between the gray matter and white matter in 44 patients with Alzheimer's disease (Age: 71.02?±?5.84, 16M/28F) and 47 healthy controls (Age 69.23?±?4.45, 19M/28F). In patients we found an overall increase in the axial and radial diffusivity across most of the superficial white matter (P?<?0.001) with increases in diffusivity of more than 20% in the bilateral parahippocampal regions and the temporal and frontal lobes. Furthermore, diffusivity correlated with the cognitive deficits measured by the Mini-Mental State Examination scores (P?<?0.001). The superficial white matter has a unique microstructure and is critical for the integration of multimodal information during brain maturation and aging. Here we show that there are major abnormalities in patients and the deterioration of these fibers relates to clinical symptoms in Alzheimer's disease.
| S-EPMC5125444 | biostudies-literature
Project description:In comparison with late-onset Alzheimer's disease (LOAD, onset, >65 years), early-age-of-onset Alzheimer's disease (EOAD, onset, <65 years) more often presents with language, visuospatial, and/or executive impairment, often occurring earlier than a progressive memory deficit. The logopenic variant of primary progressive aphasia (lv-PPA) and posterior cortical atrophy (PCA) have recently been described as possible atypical variants of EOAD. Lv-PPA is characterized by isolated language deficit, whereas PCA is characterized by predominant visuospatial deficits. Severe hemispheric gray matter (GM) atrophy associated with EOAD, lv-PPA, and PCA has been described, but regional patterns of white matter (WM) damage are still poorly understood.Using structural magnetic resonance imaging and voxel-based morphometry, we investigated WM damage in patients with EOAD (n = 16), PCA (n = 13), lv-PPA (n = 10), and LOAD (n = 14) at presentation and 72 age-matched control subjects.In patients with EOAD, PCA, and lv-PPA, WM atrophy was centered on the lateral temporal and parietal regions, including the cingulum and posterior corpus callosum. Compared with control subjects, patients with lv-PPA showed more severe left parietal damage, and patients with PCA showed more severe occipital atrophy. Moreover, patients with EOAD had greater cingulum atrophy compared with those with LOAD. LOAD showed WM damage in the medial temporal regions and less extensive hemispheric involvement.Patterns of WM damage in EOAD, lv-PPA, and PCA are consistent with the clinical syndromes and GM atrophy patterns. WM injury in AD atypical variants may contribute to symptoms and disease pathogenesis.
| S-EPMC3717610 | biostudies-literature