Cerebral White Matter Integrity Research Articles

Abstract WMP13: The Modifying Effects of Psychosocial Health on the Association Between Cerebrovascular Health and Dementia Risk: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study

Introduction: Associations between magnetic resonance imaging (MRI) markers of vascular pathology and dementia risk in older adults have been established, but it remains less clear how lifestyle factors may modify this association. We hypothesized that a weaker association between MRI markers of vascular pathology and incident dementia will be present among older adults with strong as compared to poor psychosocial health in mid-life. Methods: Social support and social isolation were assessed among ARIC participants, aged 46 - 68, via self-reported questionnaires (1990 - 1992). Following categorization of both factors, participants were classified as having strong or poor mid-life psychosocial health. From 2011 - 2013, 1977 participants, aged 67 - 90, underwent 3T brain MRI quantifying white matter hyperintensity (WMH) volume, subcortical cerebral microbleeds (sCMB), infarcts, and white matter integrity through diffusion tensor imaging. Incident dementia cases were identified from time of imaging through December 31, 2019 (median follow-up: 6.4 years) with ongoing surveillance. Relative contributions of psychosocial health and MRI markers to incident dementia were evaluated with demographic and vascular risk factor-adjusted Cox-proportional hazard regression models. Results: Among 1612 dementia-free participants with measures of psychosocial health, MRI markers were associated with dementia risk in the hypothesized direction. Mid-life psychosocial health significantly modified the associations between sCMB and WMH, each, with incident dementia risk (Table 1; greater risk of dementia shown in individuals with poor psychosocial health). Conclusions: The elevated risk of dementia associated with sCMB and WMH is reduced in participants with strong psychosocial health in mid-life. Future studies evaluating social factors through the life course and the mechanisms by which they modify the relationship between pathology and dementia are needed.

Florbetapir PET Uptake in White Matter in Aging and Alzheimer’s Disease

AbstractBackgroundAmyloid PET tracers, typically used to track cerebral amyloid changes in Alzheimer’s Disease (AD) patients, have been recently suggested to measure cerebral white matter (WM) integrity due to structural similarity between myelin and amyloid. We previously reported significant associations of amyloid neuroimaging marker, Pittsburgh Compound B (PiB) PET, with WM hyperintensities as quantified by MRI and FLAIR data, in AD patients (Su et al. 2018, HAI). The goal of this study was to explore the association between Florbetapir (FBP) PET and WM integrity.MethodOur study population consisted of 673 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) sorted into the following groups of clinical severity: (1) Normal Controls (NC) participants who are amyloid negative and cognitively normal (CDR = 0) (A‐CDR‐); (2) Preclinical (Pre) who are cognitively normal (CDR = 0) and amyloid positive (A+CDR0); (3) Symptomatic AD who are both CDR and amyloid positive (A+CDR+); and (4) Suspected Other Dementia group consisting of cognitively impaired but amyloid negative participants. We analyzed baseline biomarkers as function of stage of AD and age, comparing groups using ANOVA and Scheffe’s Post Hoc Analysis, and linear regression, respectively. Associations between white matter and amyloid FBP uptake were quantified using Pearson correlation with Least Trimmed Square (LTS) regression. Lastly, rate of change of amyloid and white matter uptake of FBP PET were quantified to assess longitudinal biomarker changes using a one sample t‐test.ResultCross‐sectionally, baseline FBP uptake in white matter significantly declines with age (p = 0.027) and advancing disease stage with significant differences found between the Preclinical and Symptomatic AD group (p<2.2E‐06); and NC and Symptomatic AD group (p<0.003). Significant associations were also observed between baseline FBP uptake in white matter and amyloid (p<0.001).Longitudinally, rate of change of FBP uptake in white matter progressively declined with advancing disease stage while rate of change of FBP uptake in amyloid increased and plateaued in the Symptomatic group of patients.ConclusionAltogether, our results show declining FBP uptake by white matter, both cross‐sectionally and longitudinally, through the stages of AD and with age. Our results could have methodological implications on the quantification of amyloid burden using WM as a reference region.

The Effects of Hypertension on White Matter Microstructural and Vascular Imaging Metrics

AbstractBackgroundHypertension is one of the key vascular risk factors of AD and related dementia. Cerebral blood flow (CBF) and white matter (WM) integrity may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated if hypertension is related to WM microstructural and vascular imaging metrics in WM.MethodFour‐hundred‐seven subjects (age: 69.7±8.1 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including neurite orientation dispersion and density imaging (NODDI) and eight‐phase pseudo‐continuous ASL (PCASL). The subjects included 158 MCI, 111 APOE e4 allele carriers, 224 with hypertension, and 249 with impaired glycemic status which includes type 2 diabetes and prediabetics. Hypertension status was defined as SBP≥130mmHG and DBP≥80mmHG. The microstructural imaging metrics including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) were obtained from NODDI. The vascular imaging metric included CBF. CBF was obtained from PCASL sequence. Voxel‐wise linear regression analyses were performed to examine if CBF, ICVF, ISOVF, or ODI were related to hypertension adjusting for cognitive status, glycemic status, APOE e4 allele, age, sex, and years of education. All images were normalized into standard space. Tract‐based spatial statistics (TBSS) were used to normalize NODDI images. The false positive cluster thresholding was applied.ResultHypertensive subjects showed impairments in both microstructural and vascular imaging metrics. Based on Figures 1‐(A), 2‐(A) and 3‐(A), there are overlapping brain image voxels between the microstructural and vascular imaging metrics. Additionally, the hypertensive subjects showed significantly lower CBF, higher ISOVF, and higher ODI than normal subjects within the voxel clusters (Figures 1‐(B), 2‐(B), and 3‐(B)). Note that APOE e4 allele, glycemic status, and cognitive status also showed statistical significance in the NODDI parameters, but there was no association in CBF.ConclusionHypertension showed the potential association between the microstructural and vascular impairments in the WM. Each risk factor and cognitive status differently affected WM microstructural and vascular dynamic imaging parameters. These findings warrant further investigations of contributions of hypertension to the microstructural and vascular abnormalities in dementia.

The Effects of Hypertension on White Matter Microstructural and Vascular Imaging Metrics

AbstractBackgroundHypertension is one of the key vascular risk factors of AD and related dementia. Cerebral blood flow (CBF) and white matter (WM) integrity may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated if hypertension is related to WM microstructural and vascular imaging metrics in WM.MethodFour‐hundred‐seven subjects (age: 69.7±8.1 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including neurite orientation dispersion and density imaging (NODDI) and eight‐phase pseudo‐continuous ASL (PCASL). The subjects included 158 MCI, 111 APOE e4 allele carriers, 224 with hypertension, and 249 with impaired glycemic status which includes type 2 diabetes and prediabetics. Hypertension status was defined as SBP = 130mmHG and DBP = 80mmHG. The microstructural imaging metrics including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) were obtained from NODDI. The vascular imaging metric included CBF. CBF was obtained from PCASL sequence. Voxel‐wise linear regression analyses were performed to examine if CBF, ICVF, ISOVF, or ODI were related to hypertension adjusting for cognitive status, glycemic status, APOE e4 allele, age, sex, and years of education. All images were normalized into standard space. Tract‐based spatial statistics (TBSS) were used to normalize NODDI images. The false positive cluster thresholding was applied.ResultHypertensive subjects showed impairments in both microstructural and vascular imaging metrics. Based on Figures 1‐(A), 2‐(A) and 3‐(A), there are overlapping brain image voxels between the microstructural and vascular imaging metrics. Additionally, the hypertensive subjects showed significantly lower CBF, higher ISOVF, and higher ODI than normal subjects within the voxel clusters (Figures 1‐(B), 2‐(B), and 3‐(B)). Note that APOE e4 allele, glycemic status, and cognitive status also showed statistical significance in the NODDI parameters, but there was no association in CBF.ConclusionHypertension showed the potential association between the microstructural and vascular impairments in the WM. Each risk factor and cognitive status differently affected WM microstructural and vascular dynamic imaging parameters. These findings warrant further investigations of contributions of hypertension to the microstructural and vascular abnormalities in dementia.

Genetics to MRI‐DTI: HFE mutation delays AD white matter degeneration in ApoE4 carriers

AbstractBackgroundThe HFE gene involves iron metabolism that directly participates in white matter (WM) myelination process. ApoE4 are known to affect normal myelination through disruptions of iron and lipid metabolism in AD. Thus, we investigated the effect of HFE SNP concurred with the ApoE4 gene mutation in AD WM degeneration. Associations of a neuronal inflammation marker, CSF sTREM2, with DTI measures and cognitive decline were explored for a mechanism under the context of iron metabolism in AD WM degeneration.MethodWhite matter degeneration of ApoE4 carriers with and without HFEH63D polymorphism was investigated using DTI from ADNI database.1 Soluble TREM2 (sTREM2) and pathological protein concentrations in CSF were measured for each CN and AD patients with and without HFE SNP concurred with the ApoE4 gene mutation.ResultMean diffusivity and radial diffusivity of DTI demonstrated an extensive and precipitous age‐related WM degeneration in ADWT/ApoE4+ carriers (as shown in Figure1). This WM degeneration was significantly attenuated in the ADH63D/ApoE4+ subjects with lessened cognitive decline (as shown in Table1, Figure1). The decreased CDR‐cognitive impairment in AD subjects was negatively associated with sTREM2 and positively associated with RD of bilateral inferior longitudinal fasciculus and PTAU (as shown in Table2).ConclusionThe attenuation of WM degeneration and cognitive decline by HFEH63D in AD ApoE4 carriers during aging may involve an effect of reducing neuroinflammation during aging, consistent with reports that HFEH63D establishes a neuroprotective milieu2 and attenuates AD WM neurodegeneration.3 Our in‐vivo data establish a link between interactions of genetic mutation of ApoE with HFE and AD WM degeneration during aging.Reference1. Meadowcroft MD, Wang J, Purnell CJ, et al. Reduced Cerebral White Matter Integrity Assessed by DTI in Cognitively Normal H63D‐HFE Polymorphism Carriers. J Neuroimaging. 2018;28:126‐133.2. Wang L, Johnson EE, Shi HN, Walker WA, Wessling‐Resnick M, Cherayil BJ. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol. 2008;181:2723‐2731.3. Urrutia PJ, Hirsch EC, González‐Billault C, Núñez MT. Hepcidin attenuates amyloid beta‐induced inflammatory and pro‐oxidant responses in astrocytes and microglia. J Neurochem. 2017; 142:140‐152.

Neurovascular Correlates of Cobalamin, Folate, and Homocysteine in Dementia.

Cobalamin (Cbl) and folate are common supplements clinicians prescribe as an adjuvant therapy for dementia patients, on the presumption of their neurotrophic and/or homocysteine (Hcy) lowering effect. However, the treatment efficacy has been found mixed and the effects of Cbl/folate/Hcy on the human brain remain to be elucidated. To explore the neurovascular correlates of Cbl/folate/Hcy in Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD). Sixty-seven AD patients and 57 SIVD patients were prospectively and consecutively recruited from an outpatient clinic. Multimodal 3-Tesla magnetic resonance imaging was performed to quantitatively evaluate cerebral blood flow (CBF) and white matter integrity. The relationship between neuroimaging metrics and the serum levels of Cbl/folate/Hcy was examined by using the Kruskal-Wallis test, partial correlation analysis, and moderation analysis, at a significance level of 0.05. As a whole, CBF mainly associated with Cbl/folate while white matter hyperintensities exclusively associated with Hcy. As compared with AD, SIVD exhibited more noticeable CBF correlates (spatially widespread with Cbl and focal with folate). In SIVD, a bilateral Cbl-moderated CBF coupling was found between medial prefrontal cortex and ipsilateral basal ganglia, while in the fronto-subcortical white matter tracts, elevated Hcy was associated with imaging metrics indicative of increased injury in both axon and myelin sheath. We identified the neurovascular correlates of previously reported neurotrophic effect of Cbl/folate and neurotoxic effect of Hcy in dementia. The correlates exhibited distinct patterns in AD and SIVD. The findings may help improving the formulation of supplemental Cbl/folate treatment for dementia.

Deciphering the causal relationship between blood pressure and regional white matter integrity: A two-sample Mendelian randomization study.

Elevated arterial blood pressure (BP) is a common risk factor for cerebrovascular and cardiovascular diseases, but no causal relationship has been established between BP and cerebral white matter (WM) integrity. In this study, we performed a two-sample Mendelian randomization (MR) analysis with individual-level data by defining two nonoverlapping sets of European ancestry individuals (genetics-exposure set: N = 203,111; mean age = 56.71 years, genetics-outcome set: N = 16,156; mean age = 54.61 years) from UK Biobank to evaluate the causal effects of BP on regional WM integrity, measured by fractional anisotropy of diffusion tensor imaging. Two BP traits: systolic and diastolic blood pressure were used as exposures. Genetic variant was carefully selected as instrumental variable (IV) under the MR analysis assumptions. We existing large-scale genome-wide association study summary data for validation. The main method used was a generalized version of inverse-variance weight method while other MR methods were also applied for consistent findings. Two additional MR analyses were performed to exclude the possibility of reverse causality. We found significantly negative causal effects (FDR-adjusted p < .05; every 10 mmHg increase in BP leads to a decrease in FA value by .4% ~ 2%) of BP traits on a union set of 17 WM tracts, including brain regions related to cognitive function and memory. Our study extended the previous findings of association to causation for regional WM integrity, providing insights into the pathological processes of elevated BP that might chronically alter the brain microstructure in different regions.

Reduced temporal lobe cerebral blood flow is associated with regional white matter damage among apolipoprotein E ε4 carriers

AbstractBackgroundReduced cerebral blood flow (CBF) is a risk factor for white matter damage. Apolipoprotein E (APOE) e4, a genetic risk factor for Alzheimer’s disease and vascular health modifier, is associated with lower CBF. However, it remains unknown if lower CBF is associated with more severe white matter damage among APOE‐e4 carriers. We examine whether associations among regional CBF, cerebrovascular reactivity (CVR), and white matter integrity are modified by APOE‐e4 status in older adults.MethodVanderbilt Memory and Aging Project participants (n = 313, 73±7 years) underwent 3T brain MRI. Resting grey matter CBF and CVR (CBF response to hypercapnic stimulus, ΔCBF/100*ΔCO2) were quantified in regions of interest from pseudo‐continuous arterial spin labeling (ASL). Fractional anisotropy (FA) was quantified from diffusion tensor imaging in tracts of interest derived from tractography templates. Linear regressions related regional CBF and CVR to tract‐specific FA, adjusting for demographic and vascular variables, regional tissue volume, cognitive status, and APOE‐e4 status. Follow‐up models tested an APOE‐ε4 status x ASL variable interaction term.ResultIn main models, lower temporal lobe CBF was associated with lower FA in the occipital lobe, suggesting compromised white matter integrity (p = 0.02). Lower CBF and higher CVR in the occipital lobe were associated with compromised lower FA in all lobes (all p‐values&lt;0.04). Temporal lobe CBF and CVR interacted with APOE‐e4 status, such that lower temporal lobe CBF related to lower FA in the frontal lobe (p = 0.01) and higher temporal lobe CVR related to lower FA in the frontal (p = 0.001) and temporal (p = 0.007) lobes among APOE‐e4 carriers only. Frontal lobe CVR interacted with APOE‐e4 status, such that higher CVR related to lower FA in the frontal (p&lt;0.001) and temporal lobes (p = 0.008) in APOE‐e4 carriers only.ConclusionAmong older adults, APOE‐e4 modifies associations between cerebral hemodynamics and white matter integrity, such that reduced CBF and greater CVR in the temporal lobe are associated with greater white matter damage in APOE‐e4 carriers. APOE‐e4 carriers may be more susceptible to changes in temporal lobe hemodynamics, and vascular changes in the temporal lobe may have a stronger impact on brain health outcomes for carriers compared to non‐carriers.

Associations between Aortic Stiffness, Cerebral Artery Resistance and White Matter Integrity in Women with a History of Preeclampsia

Purpose: Preeclampsia is a pregnancy complication characterized by new-onset hypertension and systemic organ dysfunction. Women with a history of preeclampsia (hxPE) have a greater cerebral white matter ischemic damage burden and a three-fold elevated risk of vascular dementia later in life compared with healthy pregnancy independent of traditional cardiovascular risk factors. Aortic stiffness promotes the transmission of deleterious pulsatile pressure to the distal cerebral circulation, resulting in increased cerebrovascular resistance (CVR) that contributes to compromised brain blood flow and structure. We hypothesized that young women with hxPE would have greater aortic stiffness and CVR compared to healthy pregnancy, and CVR would be related to lower cerebral white matter microstructural integrity (WMI). Methods: Women with hxPE (N=10) were matched with healthy pregnancy controls (N=11) by age (28-42 years), educational attainment, body mass index, and postpartum duration (1-5 years). Aortic stiffness was quantified as carotid-femoral pulse wave velocity (CFPWV). 4D flow and diffusion tensor magnetic resonance images were acquired to evaluate internal carotid and middle cerebral artery (MCA) blood flow velocity and WMI (fractional anisotropy), respectively (3T MRI, GE). CVR index was calculated as the ratio of central mean arterial pressure to regional flow velocity. Results: Women with hxPE tended to exhibit higher CFPWV compared with controls (6.3±0.8 vs 5.6±0.7 m/s, P=0.09 adjusted for mean arterial pressure). CVR did not differ at the internal carotid artery (2.2±0.4 vs 2.0±0.3 mmHg s cm -1 , P=0.30) but was higher at the MCA among women with hxPE (2.4±0.3 vs 2.1±0.4 mmHg s cm -1 , P=0.08). In the entire group, CFPWV was associated with greater CVR at the internal carotid (r=0.41, P=0.07) and MCA (r=0.48, P=0.03). Although WMI did not differ between groups, greater MCA CVR was related to lower WMI overall (r=-0.45, P=0.049) and in select white matter tracts (corpus callosum genu, r=-0.53, P=0.02; cingulum hippocampus, r=-0.43, P=0.06; superior frontooccipital fasciculus, r=-0.46, P=0.04). Conclusions: Women with hxPE had elevated aortic stiffness that was associated with greater CVR. Greater CVR was related to lower WMI in subcortical watershed regions susceptible to reduced perfusion. These findings indicate that aortic stiffness may contribute to early declines in WMI via CVR in women with hxPE. Supported by AHA Transformational Project Award (969732) to GLP and NIH grant 1S10OD025025-01 to VM This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Patient-Reported Outcomes in Myotonic Dystrophy Type 2: Correlations with Motor and Cognitive Endpoints (S7.007)

<h3>Objective:</h3> To characterize patient-reported outcomes (PROs) and evaluate relationships between PROs and clinical endpoints in patients with myotonic dystrophy type 2 (DM2). <h3>Background:</h3> Although muscle weakness is the key feature in DM2, two-thirds of patients report that impaired cognition is among the most disabling symptoms and affects their quality of life. PROs of physical and mental status are extremely limited in DM2 but could serve as measures for clinical trial development. <h3>Design/Methods:</h3> Ten individuals with DM2 and ten age and gender-matched controls were enrolled. All participants underwent brain MRIs and a comprehensive battery of cognitive and motor measures. Additionally, they completed PROs, including the 36-Item Short Form (SF-36), PRO Measurement Information System (PROMIS-10), Beck Depression and Anxiety Inventory (BDI and BAI), and Apathy Evaluation Scale (AES). Paired t-test and Spearman’s correlation were used to determine group differences and correlations between PROs and clinical endpoints. <h3>Results:</h3> Of 20 participants (60% female), mean age and education were similar between groups. Compared to controls, the DM2 group showed a significant difference in BAI, AES, and SF-36 physical functioning (PF) subscale (<i>p</i>=0.004–0.024) and impaired PROMIS-Global Physical (GPH) and Mental Health (GMH). We found a strong correlation between SF-36 (PF) and PROMIS-GPH with a 6-minute walk test and gait speed (<i>rho</i>=0.68–0.75, <i>p</i>=0.02–0.04). Moderate correlations were observed between 1) BDI and verbal fluency test; 2) BAI and processing speed; 3) AES and a test of executive function and cerebral white matter integrity. <h3>Conclusions:</h3> Our pilot study demonstrates that changes in mental and physical health status are of significance for DM2 patient’s quality of life. The relationships between PROs (BAI, BDI, and AES) and cognitive endpoints suggest brain involvement. PROs, as measured by SF-36 and PROMIS-10, are associated with motor endpoints. These results support the use of PROs as a tool to measure disease burden in DM2. <b>Disclosure:</b> Dr. Jain has nothing to disclose. Dr. Olszewski has nothing to disclose. Dr. Flashman has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Archives of Clinical Neuropsychology. The institution of Dr. Flashman has received research support from NIH/NINDS. The institution of Dr. Flashman has received research support from Michael J Fox Foundation. Mrs. Burgos-Aguilar has nothing to disclose. Dr. Duncan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BrainQ Technologies. Dr. Duncan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for University of Pittsburg Pepper Center. Dr. Duncan has stock in CareDirections. The institution of Dr. Duncan has received research support from PCORI. The institution of Dr. Duncan has received research support from NIA and NINDS. The institution of Dr. Duncan has received research support from AHRQ. Dr. Duncan has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Nopoulos has received personal compensation in the range of $500-$4,999 for serving as a Consultant for norvartis. The institution of Dr. Puwanant has received research support from Muscular Dystrophy Association. The institution of Dr. Puwanant has received research support from NIH/NINDS. The institution of Dr. Puwanant has received research support from NIH/NINDS.

Diffusion tensor imaging (DTI) studies of cerebral white matter integrity in normal to moderate cardiovascular risk patients

Background &amp; Objectives: The cerebral small vessel disease (CSVD) manifest as white matter lesion (WML) in magnetic resonance imaging (MRI). The diffusion tensor imaging (DTI) study shows a lower white matter integrity in white matter lesion (WML) and its penumbra region, suggesting cerebral white matter damage. The aim of this study is to establish correlation between the DTI values of white matter with the age related white matter changes (ARWMC) visual rating score and identify predictors of ARWMC score. Methods: 63 brain MRI images of subjects were selected. Relevant clinical information of the subjects which satisfied QRISK2 risk factors were retrieved from the patients’ folder. DTI parameters were obtained via postprocessing at OsiriX DTImap workstation. Results: FA frontal (r = -0.36; p = 0.003) and AD frontal (r = -0.26; p = 0.040) had a substantial and negative correlation with the ARWMC score. There was a significant positive correlation shown between the ARWMC score and RD frontal (r = 0.30; p = 0.018). There were positive significant association between the ARWMC score and age (b(95%CI): 0.106 (0.061, 0.151); p&lt;0.001) and QRISK2 score (b(95%CI): 0.235 (0.036, 0.433)). Conclusion: DTI is a good method to study the cerebral white matter integrity. It was found that frontal lobe is the first region affected in relation to ageing, in particular the myelin integrity. Increasing age and higher QRISK2 cardiovascular risk factors were shown to increase the ARWMC score.

Dl-3-n-butylphthalide promotes synaptic plasticity by activating the Akt/ERK signaling pathway and reduces the blood-brain barrier leakage by inhibiting the HIF-1α/MMP signaling pathway in vascular dementia model mice.

DL-3-n-butylphthalide (NBP) exerts beneficial effects on global cognitive functions, but the underlying molecular mechanisms are still poorly understood. The present study aimed to investigate whether NBP mediates synaptic plasticity and blood-brain barrier (BBB) function, which play a pivotal role in the pathogenesis of vascular dementia (VaD), in a mouse model of bilateralcommon carotid artery stenosis (BCAS). NBP was administered to model mice at a dose of 80 mg/kg by gavage for 28 days after surgery. Cognitive function was evaluated by behavioral tests, and hippocampal synaptic plasticity was evaluated by in vivo electrophysiological recording. Cerebral blood flow (CBF), hippocampal volume, and white matter integrity were measured with laser speckle imaging (LSI) and MRI. In addition, BBB leakage and the expression of proteins related to the Akt/ERK and HIF-1α/MMP signaling pathways were assessed by biochemical assays. NBP treatment alleviated cognitive impairment, hippocampal atrophy, and synaptic plasticity impairment induced by BCAS. In addition, NBP treatmentincreased CBF, promoted white matter integrity, and decreased BBB leakage. Regarding the molecular mechanisms, in mice with BCAS,NBP may activate the Akt/ERK signaling pathway, which upregulates the expression of synapse-associated proteins, anditmayalso inhibit the HIF-1α/MMP signaling pathway, therebyincreasing the expression of tight junction (TJ) proteins. In conclusion, our results demonstrated the therapeutic effects of NBP in improving cognitive function via a wide range of targets in mice subjected to BCAS.

Inulin supplementation prior to mild traumatic brain injury mitigates gut dysbiosis, and brain vascular and white matter deficits in mice.

Mild traumatic brain injury (mTBI) has been shown to negatively alter bacterial diversity and composition within the gut, known as dysbiosis, in rodents and humans. These changes cause secondary consequences systemically through decreased bacterial metabolites such as short chain fatty acids (SCFAs) which play a role in inflammation and metabolism. The goal of the study was to identify if giving prebiotic inulin prior to closed head injury (CHI) could mitigate gut dysbiosis, increase SCFAs, and improve recovery outcomes, including protecting cerebral blood flow (CBF) and white matter integrity (WMI) in young mice. We fed mice at 2 months of age with either inulin or control diet (with cellulose as fiber source) for two months before the CHI and continued till the end of the study. We analyzed gut microbiome composition and diversity, determined SCFAs levels, and measured CBF and WMI using MRI. We compared the results with Naïve and Sham-injury mice at 24 hours, 1.5 months, and 3-4 months post-injury. We found that both CHI and Sham mice had time-dependent changes in gut composition and diversity after surgery. Inulin significantly reduced the abundance of pathobiont bacteria, such as E. coli, Desulfovibrio spp and Pseudomonas aeruginosa, in Sham and CHI mice compared to mice fed with control diet. On the other hand, inulin increased SCFAs-producing bacteria, such as Bifidobacterium spp and Lactobacillus spp, increased levels of SCFAs, including butyrate and propionate, and significantly altered beta diversity as early as 24 hours post-injury, which lasted up to 3-4 months post-injury. The mitigation of dysbiosis is associated with protection of WMI in fimbria, internal and external capsule, and CBF in the right hippocampus of CHI mice, suggesting protection of memory and cognitive functions. The results indicate that giving inulin prior to CHI could promote recovery outcome through gut microbiome modulation. As inulin, microbiome analysis, and MRI are readily to be used in humans, the findings from the study may pave a way for a cost-effective, accessible intervention for those at risk of sustaining a head injury, such as military personnel or athletes in contact sports.

Diffusion tensor imaging pipeline measures of cerebral white matter integrity: An overview of recent advances and prospects.

Cerebral small vessel disease (CSVD) is a leading cause of age-related microvascular cognitive decline, resulting in significant morbidity and decreased quality of life. Despite a progress on its key pathophysiological bases and general acceptance of key terms from neuroimaging findings as observed on the magnetic resonance imaging (MRI), key questions on CSVD remain elusive. Enhanced relationships and reliable lesion studies, such as white matter tractography using diffusion-based MRI (dMRI) are necessary in order to improve the assessment of white matter architecture and connectivity in CSVD. Diffusion tensor imaging (DTI) and tractography is an application of dMRI that provides data that can be used to non-invasively appraise the brain white matter connections via fiber tracking and enable visualization of individual patient-specific white matter fiber tracts to reflect the extent of CSVD-associated white matter damage. However, due to a lack of standardization on various sets of software or image pipeline processing utilized in this technique that driven mostly from research setting, interpreting the findings remain contentious, especially to inform an improved diagnosis and/or prognosis of CSVD for routine clinical use. In this minireview, we highlight the advances in DTI pipeline processing and the prospect of this DTI metrics as potential imaging biomarker for CSVD, even for subclinical CSVD in at-risk individuals.

Nighttime Sleep Characteristics and White Matter Integrity in Young Adults.

PurposeSleep is essential for life and plays a key role for optimal physiology, brain functioning, and health. Evidence suggests a relation between sleep and cerebral white matter integrity. Human studies report that sleep duration shows a U-shaped association with brain functioning. We hypothesized that participants with longer or shorter sleep time in the nighttime period show altered microstructural white matter integrity.Participants and MethodsSeventy-three young adult participants were evaluated. Sleep-wake cycle parameters were assessed objectively using actigraphy. Diffusion tensor imaging studies were performed to assess white matter integrity using fractional anisotropy and mean, axial, and radial diffusivities. Relations between white matter microstructure indexes and sleep parameters were investigated through tract-based spatial statistics. Participants were grouped according to their nocturnal total sleep time: 27 in the Reference sleep group (6.5–8.0 h), 23 in the Short sleep group (<6.5 h) and 23 in the Long sleep group (>8.0 h).ResultsCompared with the Reference sleep group, participants in the Long sleep group showed lower fractional anisotropy (p < 0.05) and higher radial diffusivity (p < 0.05) values in white matter tracts linked to sleep regulation (corona radiata, body of the corpus callosum, superior longitudinal fasciculus, and anterior thalamic radiation).ConclusionThis pattern of reduced fractional anisotropy and increased radial diffusivity in the Long sleep group indicates an association between sleep duration and lower integrity of myelin sheaths. Because myelin is continuously remodeled in the brain, nighttime sleep characteristics appear to be a key player for its quality and maintenance.

Cerebral Microbleeds and Structural White Matter Integrity in Patients With Traumatic Brain Injury-A Diffusion Tensor Imaging Study.

Diffuse axonal injury (DAI) is a common neuropathological manifestation of traumatic brain injury (TBI), presenting as traumatic alterations in the cerebral white matter (WM) microstructure and often leading to long-term neurocognitive impairment. These WM alterations can be assessed using diffusion tensor imaging (DTI). Cerebral microbleeds (CMBs) are a common finding on head imaging in TBI and are often considered a visible sign of DAI, although they represent diffuse vascular injury. It is poorly known how they associate with long-term white matter integrity. This study included 20 patients with TBI and CMBs, 34 patients with TBI without CMBs, and 11 controls with orthopedic injuries. DTI was used to assess microstructural WM alterations. CMBs were detected using susceptibility-weighted imaging (SWI) and graded according to their location in the WM and total lesion load was counted. Patients underwent SWI within 2 months after injury. DTI and clinical outcome assessment were performed at an average of eight months after injury. Outcome was assessed using the extended Glasgow Outcome Scale (GOSe). The Glasgow Coma Scale (GCS) and length of post-traumatic amnesia (PTA) were used to assess clinical severity of the injury. We found that CMB grading and total lesion load were negatively associated with fractional anisotropy (FA) and positively associated with mean diffusivity (MD). Patients with TBI and CMBs had decreased FA and increased MD compared with patients with TBI without CMBs. CMBs were also associated with worse clinical outcome. When adjusting for the clinical severity of the injury, none of the mentioned associations were found. Thus, the difference in FA and MD is explained by patients with TBI and CMBs having more severe injuries. Our results suggest that CMBs are not associated with greater WM alterations when adjusting for the clinical severity of TBI. Thus, CMBs and WM alterations may not be strongly associated pathologies in TBI.

Physical Frailty and Brain White Matter Abnormalities: The Atherosclerosis Risk in Communities Study.

Physical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty. Atherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline. In the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk. The current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

White Matter Integrity and Nicotine Dependence: Evaluating Vertical and Horizontal Pleiotropy.

Tobacco smoking is an addictive behavior that supports nicotine dependence and is an independent risk factor for cancer and other illnesses. Its neurogenetic mechanisms are not fully understood but may act through alterations in the cerebral white matter (WM). We hypothesized that the vertical pleiotropic pathways, where genetic variants influence a trait that in turn influences another trait, link genetic factors, integrity of cerebral WM, and nicotine addiction. We tested this hypothesis using individual genetic factors, WM integrity measured by fractional anisotropy (FA), and nicotine dependence-related smoking phenotypes, including smoking status (SS) and cigarettes per day (CPDs), in a large epidemiological sample collected by the UK Biobank. We performed a genome-wide association study (GWAS) to identify previously reported loci associated with smoking behavior. Smoking was found to be associated with reduced WM integrity in multiple brain regions. We then evaluated two competing vertical pathways: Genes → WM integrity → Smoking versus Genes → Smoking → WM integrity and a horizontal pleiotropy pathway where genetic factors independently affect both smoking and WM integrity. The causal pathway analysis identified 272 pleiotropic single-nucleotide polymorphisms (SNPs) whose effects on SS were mediated by FA, as well as 22 pleiotropic SNPs whose effects on FA were mediated by CPD. These SNPs were mainly located in important susceptibility genes for smoking-induced diseases NCAM1 and IREB2. Our findings revealed the role of cerebral WM in the maintenance of the complex addiction and provided potential genetic targets for future research in examining how changes in WM integrity contribute to the nicotine effects on the brain.

Pathological neural networks and artificial neural networks in ALS: diagnostic classification based on pathognomonic neuroimaging features

The description of group-level, genotype- and phenotype-associated imaging traits is academically important, but the practical demands of clinical neurology centre on the accurate classification of individual patients into clinically relevant diagnostic, prognostic and phenotypic categories. Similarly, pharmaceutical trials require the precision stratification of participants based on quantitative measures. A single-centre study was conducted with a uniform imaging protocol to test the accuracy of an artificial neural network classification scheme on a cohort of 378 participants composed of patients with ALS, healthy subjects and disease controls. A comprehensive panel of cerebral volumetric measures, cortical indices and white matter integrity values were systematically retrieved from each participant and fed into a multilayer perceptron model. Data were partitioned into training and testing and receiver-operating characteristic curves were generated for the three study-groups. Area under the curve values were 0.930 for patients with ALS, 0.958 for disease controls, and 0.931 for healthy controls relying on all input imaging variables. The ranking of variables by classification importance revealed that white matter metrics were far more relevant than grey matter indices to classify single subjects. The model was further tested in a subset of patients scanned within 6 weeks of their diagnosis and an AUC of 0.915 was achieved. Our study indicates that individual subjects may be accurately categorised into diagnostic groups in an observer-independent classification framework based on multiparametric, spatially registered radiology data. The development and validation of viable computational models to interpret single imaging datasets are urgently required for a variety of clinical and clinical trial applications.

Aberrant Neurogliovascular Unit Dynamics in Cerebral Small Vessel Disease: A Rheological Clue to Vascular Parkinsonism.

The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood–brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU—a crossroad of the immune–vascular–nervous system—which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets.