Loss Of White Matter Integrity Research Articles

Loss of white matter integrity mediates the association between cortical cerebral microinfarcts and cognitive dysfunction: A longitudinal study.

Cortical cerebral microinfarcts (CMIs) are associated with loss of white matter (WM) integrity and cognitive impairment in cross-sectional studies, while further investigation using longitudinal datasets is required. This study aims to establish the association between cortical CMIs and WM integrity assessed by diffusion-tensor imaging (DTI) measures and to investigate whether DTI measures mediate the relationship between cortical CMIs and cognitive decline. Cortical CMIs were graded on 3T MRI. DTI measures were derived from histogram analysis of mean diffusivity (MD) and fractional anisotropy (FA). Cognitive function was assessed using a neuropsychological test battery. Linear mixed-effect models were employed to examine associations of cortical CMIs with longitudinal changes in DTI measures and cognitive function. Final analysis included 231 patients (71.14 ± 7.60 years). Presence of cortical CMIs at baseline was associated with longitudinal changes in MD median and peak height and FA median and peak height, as well as global cognition (β = -0.50, 95%CI: -0.91, -0.09) and executive function (β = -0.77, 95%CI: -1.25, -0.28). MD median mediated the cross-sectional association between cortical CMIs and global cognition. Further studies are required to investigate whether cortical CMIs and loss of WM integrity are causally related or if they are parallel mechanisms that contribute to cognitive decline.

The volume and the distribution of premorbid white matter hyperintensities: Impact on post-stroke aphasia.

White matter hyperintensities (WMH) are a radiological manifestation of progressive white matter integrity loss. The total volume and distribution of WMH within the corpus callosum have been associated with pathological cognitive ageing processes but have not been considered in relation to post-stroke aphasia outcomes. We investigated the contribution of both the total volume of WMH, and the extent of WMH lesion load in the corpus callosum to the recovery of language after first-ever stroke. Behavioural and neuroimaging data from individuals (N = 37) with a left-hemisphere stroke were included at the early subacute stage of recovery. Spoken language comprehension and production abilities were assessed using word and sentence-level tasks. Neuroimaging data was used to derive stroke lesion variables (volume and lesion load to language critical regions) and WMH variables (WMH volume and lesion load to three callosal segments). WMH volume did not predict variance in language measures, when considered together with stroke lesion and demographic variables. However, WMH lesion load in the forceps minor segment of the corpus callosum explained variance in early subacute comprehension abilities (t = -2.59, p = .01) together with corrected stroke lesion volume and socio-demographic variables. Premorbid WMH lesions in the forceps minor were negatively associated with early subacute language comprehension after aphasic stroke. This negative impact of callosal WMH on language is consistent with converging evidence from pathological ageing suggesting that callosal WMH disrupt the neural networks supporting a range of cognitive functions.

Baseline Amyloid and Tau Deposition Predict Distinct Patterns of Longitudinal White Matter Degeneration: A Diffusion MRI Investigation

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aβ) peptides and tau‐protein neurofibrillary tangles are hallmark features of Alzheimer’s disease (AD) pathology. While concomitant differences in white matter (WM) integrity were found in association with Aβ deposition or tau pathology, a unique effect of each pathology on WM integrity remains unknown. In this study, we examined the unique effects of AD pathologies on WM integrity both cross‐sectionally and longitudinally.MethodA total of 334 participants (188 cognitively normal (CN), 114 mild cognitive impairment, and 32 AD) was selected from the ADNI database, based on the availability of two timepoints of diffusion MRI (dMRI) data, and baseline amyloid and tau PET data. The dMRI data were processed using FSL’s TBSS pipeline to quantify the degree of fractional anisotropy (FA) and annualized FA change maps were created to measure voxel‐wise WM change over time. Baseline global amyloid SUVR values were converted to a centiloid scale. Baseline tau SUVRs were evaluated by Braak staging (I‐entorhinal, II‐hippocampal, III/IV‐limbic, V/VI‐neocortex). The associations between AD pathologies and cross‐sectional and longitudinal WM integrity were assessed by FSL’s randomise and cluster‐level correction, controlling for age and sex.ResultCross‐sectionally, baseline tau burden in Braak stages I, III/IV, and V/VI related to lower WM integrity, independent of Aβ, while there was no association between baseline Aβ and WM integrity, independent of tau. Longitudinally, limbic and neocortical tau at baseline uniquely predicted WM integrity loss across widespread regions, including left superior longitudinal fasciculus and the body and splenium of corpus callosum. Moreover, baseline Aβ burden significantly related to WM integrity loss across widespread regions, only when entorhinal and hippocampal tau was controlled for. Similar, but weaker, patterns of the associations between baseline AD pathology and longitudinal WM integrity loss were also found only within CN group.ConclusionThese findings suggest distinctive associations between AD pathology and WM degeneration such that Aß exerts widespread deleterious effects on WM integrity primarily early in AD pathophysiology, whereas, once spreading to the neocortex, tau burden drives WM neurodegeneration. The distinctive downstream pathways associated with each AD pathology may underlie differential cognitive profiles across the disease stages.

Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐ß plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐ß deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐β plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐β deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

A new insight into the role of pericytes in ischemic stroke.

The functional structure of the blood-brain barrier (BBB) deteriorates after stroke by developing diffuse microvascular and neurovascular dysfunction and loss of white matter integrity. This causes nervous tissue injury and causes sensory and motor disabilities in stroke patients. Improving the integrity of the BBB and neurovascular remodeling after stroke can promote post-stroke injury conditions. Pericytes are contractile cells abundant in the BBB and sandwiched between astrocytes and endothelial cells of the microvessels. Stroke could lead to the degeneration of pericytes in the BBB. However, recent evidence shows that promoting pericytes enhances BBB integrity and neurovascular remodeling. Furthermore, pericytes achieve multipotent properties under hypoxic conditions, allowing them to transdifferentiate into the brain resident cells such as microglia. Microglia regulate immunity and inflammatory response after stroke. The current review studies recent findings in the intervening mechanisms underlying the regulatory effect of pericytes in BBB recovery after stroke.

The T1-weighted/T2-weighted ratio as a biomarker of anti-NMDA receptor encephalitis

BackgroundAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To improve prognostic capabilities, we evaluate the T1-weighted/T2-weighted (T1w/T2w) ratio, a...

Multimodal MRI study on the relation between WM integrity and connected GM atrophy and its effect on disability in early multiple sclerosis

BackgroundMultiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence clinical progression.ObjectiveTo study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing–remitting (RR) MS in relation to clinical progression.MethodsHealthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM z-scores and changes in connected GM z-scores, and between baseline GM z-scores and changes in connected WM z-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners.ResultsWe included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM z-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups.DiscussionLower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely.

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters – amplitude, time-to-peak (TTP), and time-to-baseline (TTB) – and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10−6, 95%CI [1.84 × 10−6, 1.48 × 10−5], p = 0.02, Adj. R2 = 0.25) and TTB (β = 6.57 × 10−6, 95%CI [1.92 × 10−6, 1.12 × 10−5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.

Assessing traffic-related air pollution-induced fiber-specific white matter degradation associated with motor performance declines in aged rats

Fine particulate matter (PM2.5) is thought to exacerbate Parkinson's disease (PD) in the elderly, and early detection of PD progression may prevent further irreversible damage. Therefore, we used diffusion tensor imaging (DTI) for probing microstructural changes after late-life chronic traffic-related PM2.5 exposure. Herein, 1.5-year-old Fischer 344 rats were exposed to clean air (control), high-efficiency particulate air (HEPA)-filtered ambient air (HEPA group), and ambient traffic-related PM2.5 (PM2.5 group, 9.933 ± 1.021 µg/m3) for 3 months. Rotarod test, DTI tractographic analysis, and immunohistochemistry were performed in the end of study period. Aged rats exposed to PM2.5 exhibited motor impairment with decreased fractional anisotropy and tyrosine hydroxylase expression in olfactory and nigrostriatal circuits, indicating disrupted white matter integrity and dopaminergic (DA) neuronal loss. Additionally, increased radial diffusivity and lower expression of myelin basic protein in PM2.5 group suggested ageing progression of demyelination exacerbated by PM2.5 exposure. Significant production of tumor necrosis factor-α was also observed after PM2.5 exposure, revealing potential inflammation of injury to multiple fiber tracts of DA pathways. Microstructural changes demonstrated potential links between PM2.5-induced inflammatory white matter demyelination and behavioral performance, with indication of pre-manifestation of DTI-based biomarkers for early detection of PD progression in the elderly.

Cortico-Subcortical White Matter Bundle Changes in Cervical Dystonia and Blepharospasm

Dystonia is thought to be a network disorder due to abnormalities in the basal ganglia-thalamo-cortical circuit. We aimed to investigate the white matter (WM) microstructural damage of bundles connecting pre-defined subcortical and cortical regions in cervical dystonia (CD) and blepharospasm (BSP). Thirty-five patients (17 with CD and 18 with BSP) and 17 healthy subjects underwent MRI, including diffusion tensor imaging (DTI). Probabilistic tractography (BedpostX) was performed to reconstruct WM tracts connecting the globus pallidus, putamen and thalamus with the primary motor, primary sensory and supplementary motor cortices. WM tract integrity was evaluated by deriving their DTI metrics. Significant differences in mean, radial and axial diffusivity between CD and HS and between BSP and HS were found in the majority of the reconstructed WM tracts, while no differences were found between the two groups of patients. The observation of abnormalities in DTI metrics of specific WM tracts suggests a diffuse and extensive loss of WM integrity as a common feature of CD and BSP, aligning with the increasing evidence of microstructural damage of several brain regions belonging to specific circuits, such as the basal ganglia-thalamo-cortical circuit, which likely reflects a common pathophysiological mechanism of focal dystonia.

Gait decline while dual-tasking is an early sign of white matter deterioration in middle-aged and older adults.

Loss of white matter integrity (WMI) is associated with gait deficits in middle-aged and older adults. However, these deficits are often only apparent under cognitively demanding situations, such as walking and simultaneously performing a secondary cognitive task. Moreover, evidence suggests that declining executive functions (EF) are linked to gait decline, and their co-occurrence may point to a common underlying pathology, i.e., degeneration of shared brain regions. In this study, we applied diffusion tensor imaging (DTI) and a standardized gait assessment under single- and dual-tasking (DT) conditions (walking and subtracting) in 74 middle-aged and older adults without any significant gait or cognitive impairments to detect subtle WM alterations associated with gait decline under DT conditions. Additionally, the Trail Making Test (TMT) was used to assess EF, classify participants into three groups based on their performance, and examine a possible interaction between gait, EF, and WMI. Gait speed and subtracting speed while dual-tasking correlated significantly with the fractional anisotropy (FA) in the bilateral anterior corona radiata (highest r = 0.51/p < 0.0125 FWE-corrected). Dual-task costs (DTC) of gait speed correlated significantly with FA in widespread pathways, including the corpus callosum, bilateral anterior and superior corona radiata, as well as the left superior longitudinal fasciculus (highest r = −0.47/p < 0.0125 FWE-corrected). EF performance was associated with FA in the left anterior corona radiata (p < 0.05); however, EF did not significantly mediate the effects of WMI on DTC of gait speed. There were no significant correlations between TMT and DTC of gait and subtracting speed, respectively. Our findings indicate that gait decline under DT conditions is associated with widespread WM deterioration even in middle-aged and older adults without any significant gait or cognitive impairments. However, this relationship was not mediated by EF.

Does Loss of Integrity of the Cingulum Bundle Link Amyloid-β Accumulation and Neurodegeneration in Alzheimer's Disease?

Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration. Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. We found at most a weak association between cingulate Aβ and MTL volume (added R2 &lt;0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 &lt;0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy.

CSF Tau phosphorylation at Thr205 is associated with loss of white matter integrity in autosomal dominant Alzheimer disease

BackgroundHyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s). MethodsIn autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD. ResultsThe WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss. ConclusionsWe identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline.

White matter integrity changes and neurocognitive functioning in adult-late onset DM1: a follow-up DTI study

Myotonic Dystrophy Type 1 (DM1) is a multisystemic disease that affects gray and white matter (WM) tissues. WM changes in DM1 include increased hyperintensities and altered tract integrity distributed in a widespread manner. However, the precise temporal and spatial progression of the changes are yet undetermined. MRI data were acquired from 8 adult- and late-onset DM1 patients and 10 healthy controls (HC) at two different timepoints over 9.06 years. Fractional anisotropy (FA) and mean diffusivity (MD) variations were assessed with Tract-Based Spatial Statistics. Transversal and longitudinal intra- and intergroup analyses were conducted, along with correlation analyses with clinical and neuropsychological data. At baseline, reduced FA and increased MD values were found in patients in the uncinate, anterior-thalamic, fronto-occipital, and longitudinal tracts. At follow-up, the WM disconnection was shown to have spread from the frontal part to the rest of the tracts in the brain. Furthermore, WM lesion burden was negatively correlated with FA values, while visuo-construction and intellectual functioning were positively correlated with global and regional FA values at follow-up. DM1 patients showed a pronounced WM integrity loss over time compared to HC, with a neurodegeneration pattern that suggests a progressive anterior–posterior disconnection. The visuo-construction domain stands out as the most sensitive neuropsychological measure for WM microstructural impairment.

Gut Microbiome, Inflammation, and Cerebrovascular Function: Link Between Obesity and Cognition.

Obesity affects 13% of the adult population worldwide and this number is only expected to increase. Obesity is known to have a negative impact on cardiovascular and metabolic health, but it also impacts brain structure and function; it is associated with both gray and white matter integrity loss, as well as decreased cognitive function, including the domains of executive function, memory, inhibition, and language. Especially midlife obesity is associated with both cognitive impairment and an increased risk of developing dementia at later age. However, underlying mechanisms are not yet fully revealed. Here, we review recent literature (published between 2010 and March 2021) and discuss the effects of obesity on brain structure and cognition, with a main focus on the contributions of the gut microbiome, white adipose tissue (WAT), inflammation, and cerebrovascular function. Obesity-associated changes in gut microbiota composition may cause increased gut permeability and inflammation, therewith affecting cognitive function. Moreover, excess of WAT in obesity produces pro-inflammatory adipokines, leading to a low grade systemic peripheral inflammation, which is associated with decreased cognition. The blood-brain barrier also shows increased permeability, allowing among others, peripheral pro-inflammatory markers to access the brain, leading to neuroinflammation, especially in the hypothalamus, hippocampus and amygdala. Altogether, the interaction between the gut microbiota, WAT inflammation, and cerebrovascular integrity plays a significant role in the link between obesity and cognition. Future research should focus more on the interplay between gut microbiota, WAT, inflammation and cerebrovascular function to obtain a better understanding about the complex link between obesity and cognitive function in order to develop preventatives and personalized treatments.

The association of blood pressure variability with white matter integrity and cognitive impairment in cerebral amyloid angiopathy

AbstractBackgroundEmerging evidence suggests that blood pressure variability (BPV) may contribute to small vessel disease (SVD) progression and cognitive impairment beyond the deleterious effects of elevated blood pressure, but the mechanisms remain largely unknown. This study investigates if BPV is associated with white matter (WM) microstructural integrity and the slope of cognitive decline in elderly individuals with cerebral amyloid angiopathy (CAA), a well characterized type of SVD.MethodWe recruited 94 non‐demented individuals (73.3 ± 7.0 y, 40 F, MMSE 27.7 ± 1.5) from a memory‐clinic cohort with and without possible/probable CAA with available neuropsychological evaluation and 3.0 T research MRI. Visit‐to‐visit BPV was assessed using the coefficient of variation derived from the serial outpatient BP measures during a 5‐year interval. A novel diffusion tensor imaging marker – peak width of skeletonized mean diffusivity (PSMD) – was used to evaluate the WM integrity. Using linear regression models, we evaluated the association of PSMD with BPV, adjusted for standard cardiovascular risk factors.ResultWe found a significant association between loss of WM integrity and high systolic BPV (β = 0.37, P &lt; 0.001), but not mean BP. The association remained significant after adjusting for age, antihypertensive medication usage, diabetes, smoking, and body mass index. Furthermore, the association of BPV with WM integrity was stronger when CAA was present (P for interaction = 0.018). Higher BPV at baseline was associated with worse executive function in CAA patients at 2‐year follow‐up (β = ‐0.53, P = 0.003), adjusted for baseline function.ConclusionOur findings show that visit‐to‐visit BP fluctuations are associated with loss of WM microstructural integrity and cognitive decline. The association between BP variability and WM integrity might in part be driven by CAA pathology. Further studies are warranted to disentangle the relationship between BP fluctuations, microvascular injury, and cognitive impairment in older adults.

Higher systolic and diastolic blood pressures are associated with loss of white matter integrity in postmenopausal women of the KEEPS Continuation Study

AbstractBackgroundElevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) are risk factors for white matter (WM) injury associated with cognitive decline and dementia. White matter hyperintensities (WMH) on MRI, markers of WM injury, increase with aging and are more common in women than in men after the age of 60. We examined SBP and DBP in relation to WMH volume and diffusion MRI measures of WM integrity in postmenopausal women.MethodWomen (n=144) with median age of 67 (range 58‐72) and of good cardiovascular health who were previously enrolled in the multi‐site randomized clinical trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP, DBP, and MRI data were collected approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions. WM integrity was assessed with WMH volume measurements (log transformed) on structural MRI and with measures of WM microstructure on diffusion MRI. Multiple linear regression analyses, adjusted for age, were used to test for associations of SBP and DBP with MRI measures.ResultThe median SBP was 128 (range 86‐180) and DBP was 77 (range 47‐106). Higher SBP (r=0.332;p=0.015) and DBP (r=0.346;p=0.007) were associated with higher WMH volumes. Among the WM tracts, higher SBP was associated with lower fractional anisotropy (FA) in lateral orbitofrontal gyrus WM (r=0.198;p=0.039) and sagittal stratum (r=0.226;p=0.043), and higher DBP was associated with lower FA in the superior occipital gyrus WM (r=0.370;p=0.045). Higher SBP and DBP were associated with higher mean diffusivity (MD) in the external capsule [(r=0.311;p=0.007);(r=375;p&lt;0.001)] and the fronto‐occipital fasciculus [(r=0.286;p=0.016); (r=0.303;p=0.008)]. Furthermore, higher DBP was associated with higher MD in the anterior corona radiata (r=0.233;p=0.039), internal capsule (r=0.303;p=0.042), and the middle (r=0.275; p=0.03) and superior frontal gyrus (r=0.269;p=0.03) WM.ConclusionElevated SBP and DBP measurements are associated with greater WM injury in postmenopausal women. In particular, the frontal lobe WM and its connecting tracts may be more vulnerable to elevation in SBP and DBP. Whether BP control reduces the risk for WM injury, a risk factor for dementia, in post‐menopausal women warrants study.

Associations between neuropsychiatric symptoms, white matter microstructural integrity, and diagnostic status in the spectrum of Alzheimer’s disease

AbstractBackgroundRecent studies have found that individuals who have undergone psychological stress and/or are affected by a chronic stress‐related disorder have an increased risk of developing Alzheimer’s Disease (AD). However, currently the biological mechanism underlying this relationship remains elusive. We hypothesized that white matter integrity loss may be a potential mediator between psychological stress and the development of AD. The goal of this study was to examine the relationship between neuropsychiatric symptoms as a proxy of stress responses, white matter microstructural integrity, and diagnostic status along the spectrum of AD.MethodWe evaluated the relationship between neuropsychiatric symptoms, white matter microstructural integrity, and diagnostic status along the spectrum of AD in 133 participants (ages 55.2‐90.4 years) selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐2). Total scores in a brief Neuropsychiatric Inventory Questionnaire (NPI‐Q) were used to represent individuals’ psychological stress responses. We quantified white matter integrity measures using diffusion tensor imaging scans processed by the FMRIB's Diffusion Toolbox followed by the FSL Tract‐Based Spatial Statistics toolbox.ResultNPI‐Q scores representing stress responses significantly differed across diagnostic groups. Specifically, patients with AD (N=40, mean age=74.39) showed significantly higher NPI‐Q scores compared with cognitively normal (CN) older adults (N=44, mean age=73.39) and patients with Mild Cognitive Impairment (MCI)(N=49, mean age=75.64). Whole brain voxel‐wise analyses with white matter integrity measures as quantified as fractional anisotropy (FA) and mean diffusivity (MD) showed significant FA and MD differences (p ≤ 0.01) in the splenium, cingulum, superior longitudinal fasciculus, posterior thalamic radiation and the corpus callosum regions when controlling for age and sex. These differences were greater for AD patients compared with CN participants than those with MCI. NPI‐Q scores, however, were not related to a degree of white matter integrity in this sample.ConclusionSignificant group differences are shown in stress responses and white matter integrity across the diagnostic groups in the AD spectrum, which is consistent with the literature. Future studies are warranted to integrate reliable biological markers of stress responses to assess the impact of stress responses on microstructural changes and AD pathologies.

White Matter Alterations in Spastic Paraplegia Type 5: A Multiparametric Structural MRI Study and Correlations with Biochemical Measurements.

In spastic paraplegia type 5, spinal cord atrophy and white matter signal abnormalities in the brain are the main MR imaging alterations. However, the specific mechanism remains unclear. We explored the microstructural changes occurring in spastic paraplegia type 5 and assessed the relation between MR imaging and clinical data. Seventeen patients with spastic paraplegia type 5 and 17 healthy controls were scanned with DTI and T1 mapping on a 3T MR imaging scanner. Fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, and T1 values were obtained using Tract-Based Spatial Statistics and the Spinal Cord Toolbox. Neurofilament light and myelin basic protein in the CSF were measured. The differences in MR imaging and biochemical data between patients with spastic paraplegia type 5 and healthy controls were compared using the Student t test. A widespread reduction of fractional anisotropy values and an elevation of mean diffusivity, T1, and radial diffusivity values were found in most cervical, T4, and T5 spinal cords; corona radiata; optic radiations; and internal capsules in spastic paraplegia type 5. A variation in axial diffusivity values was shown only in C2, C6, and the corona radiata but not in the gray matter. The levels of neurofilament light and myelin basic protein were higher in those with spastic paraplegia type 5 than in healthy controls (myelin basic protein, 3507 [SD, 2291] versus 127 [SD, 219] pg/mL; neurofilament light, 617 [SD, 207] versus 265 [SD, 187] pg/mL; P < .001). No correlation was found between the clinical data and MR imaging-derived measures. Multiparametric MR imaging and biochemical indicators demonstrated that demyelination (mainly) and axonal loss led to the white matter integrity loss without gray matter injury in spastic paraplegia type 5.