Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults.

Importance: Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease (AD). One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration; the effect of small vessel cerebrovascular disease on neurodegeneration may differ across racial and ethnic groups. Objective: To examine whether WMH volume is associated with cortical thinning over time and subsequent memory functioning and whether the association between WMH volume and cortical thinning differs among racial and ethnic groups. Design, Setting, and Participants: This longitudinal community-based cohort study included older adults from northern Manhattan who were participants in the Washington Heights-Inwood Columbia Aging Project. Participants underwent two 3T magnetic resonance imaging (MRI) scans a mean of 4 years apart. Data were collected from March 2011 to January 2020. Exposures: Total and regional WMH volumes. Main Outcomes and Measures: The association of total and regional WMH volumes with cortical thinning over time was tested using general linear models in a vertexwise analysis. Cortical thinning was measured vertexwise by symmetrized percent change between 2 time points. The association of changes in cortical thickness with memory and whether this association differed by race and ethnicity was also analyzed. Delayed memory was a secondary outcome. Results: In 303 participants (mean [SD] age, 73.16 [5.19] years, 181 [60%] women, 96 [32%] non-Hispanic White, 113 [37%] Non-Hispanic Black, 94 [31%] Hispanic), baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex (P = .001) and paracentral cortex (P = .04), whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex (P = .03) and right rostral middle frontal (P < .001), paracentral (P < .001), and pars triangularis (P = .02) cortices. Thinning of the right caudal middle frontal and left entorhinal cortices was related to lower scores on a memory test administered closest to the second MRI visit (right caudal middle frontal cortex: standardized ß = 0.129; unstandardized b = 0.335; 95% CI, 0.055 to 0.616; P = .01; left entorhinal cortex: ß = 0.119; b = 0.290; 95% CI, 0.018 to 0.563; P = .03). The association of total WMH with thinning in the right caudal middle frontal and right paracentral cortex was greater in non-Hispanic Black participants compared with White participants (right caudal middle frontal cortex: ß = -0.222; b = -0.059; 95% CI, -0.114 to -0.004; P = .03; right paracentral cortex: ß = -0.346; b = -0.155; 95% CI, -0.244 to -0.066; P = .001). The association of parietal WMH with cortical thinning of the right rostral middle frontal, right pars triangularis, and right paracentral cortices was also stronger among non-Hispanic Black participants compared with White participants (right rostral middle frontal cortex: ß = -0.252; b = -0.202; 95% CI, -0.349 to -0.055; P = .007; right pars triangularis cortex: ß = -0.327; b = -0.253; 95% CI, -0.393 to -0.113; P < .001; right paracentral cortex: ß = -0.263; b = -0.337; 95% CI, -0.567 to -0.107; P = .004). Conclusions and Relevance: In this study, small vessel cerebrovascular disease, operationalized as WMH, was associated with subsequent cortical atrophy in regions that overlap with typical AD neurodegeneration patterns, particularly among non-Hispanic Black older adults. Cerebrovascular disease may affect risk and progression of AD by promoting neurodegeneration and subsequent memory decline.

In vivo Monitoring and Assessment of Exogenous Mesenchymal Stem Cell-Derived Exosomes in Mice with Ischemic Stroke by Molecular Imaging.

PURPOSE: Mesenchymal stem cell-derived exosomes (MSC-exos) are considered an important restorative treatment for ischemic stroke. However, the migration ability and survival of exogenous MSC-exos remain unclear. Here, we investigated whether MSC-exos migrate into the ischemic brain and play a protective role against ischemic stroke. METHODS: MSC-exos labeled with DiR were injected intravenously into mice with ischemic stroke. Near-infrared fluorescence (NIRF) images were obtained on days 0, 1, 3, 5, 7, 10, and 14, and magnetic resonance (MR) images were obtained on days 1, 7 and 14. On day 14, the functional outcomes, angiogenesis, neurogenesis, and white matter remodeling were assessed, and Western blot assays were performed. RESULTS: Fluorescence signals from the MSC-exos appeared in the injured brain from day 1 and peaked on day 3. The immunofluorescence staining of the brain samples revealed that the MSC-exos were localized in neurons. The behavioral scores and T2-weighted imaging indicated that the MSC-exos improved neurological functional recovery after stroke. In addition, the in vivo MR-diffusion tensor imaging (DTI) indicated that the exogenous MSC-exos increased the fractional anisotropy (FA) value, fiber length, and fiber number ratio. Furthermore, in the mice with ischemic stroke treated with MSC-exos, angiogenesis and neurogenesis were significantly improved, and the expression of IL-1ß was reduced. CONCLUSION: MSC-exos can migrate into the brains of mice with ischemic stroke and exert therapeutic effects against ischemic stroke; therefore, MSC-exos may have broad clinical applications in the future.

Childhood violence exposure and social deprivation predict adolescent amygdala-orbitofrontal cortex white matter connectivity.

Childhood adversity is heterogeneous with potentially distinct dimensions of violence exposure and social deprivation. These dimensions may differentially shape emotion-based neural circuitry, such as amygdala-PFC white matter connectivity. Amygdala-orbitofrontal cortex (OFC) white matter connectivity has been linked to regulation of the amygdala's response to emotional stimuli. Using a preregistered analysis plan, we prospectively examined the effects of childhood exposure to two dimensions of adversity, violence exposure and social deprivation, on the adolescent amygdala-PFC white matter connectivity. We also reproduced the negative correlation between amygdala-PFC white matter connectivity and amygdala activation to threat faces. 183 15-17-year-olds were recruited from the Fragile Families and Child Wellbeing Study - a longitudinal, birth cohort, sample of predominantly low-income youth. Probabilistic tractography revealed that childhood violence exposure and social deprivation interacted to predict the probability of adolescent right hemisphere amygdala-OFC white matter connectivity. High violence exposure with high social deprivation related to less amygdala-OFC white matter connectivity. Violence exposure was not associated with white matter connectivity when social deprivation was at mean or low levels (i.e., relatively socially supportive contexts). Therefore, social deprivation may exacerbate the effects of childhood violence exposure on the development of white matter connections involved in emotion processing and regulation. Conversely, social support may buffer against them.

Diffusion tensor imaging in hyperthyroidism: assessment of microstructural white matter abnormality with a tract-based spatial statistical analysis.

BACKGROUND: Metabolic, morphological, and functional brain changes associated with a neurological deficit in hyperthyroidism have been observed. However, changes in microstructural white matter (WM), which can explain the underlying pathophysiology of brain dysfunctions, have not been researched. PURPOSE: To assess microstructural WM abnormality in patients with untreated or newly diagnosed hyperthyroidism using tract-based spatial statistics (TBSS). MATERIAL AND METHODS: Eighteen patients with hyperthyroidism and 14 age- and sex-matched healthy controls were included in this study. TBSS were used in this diffusion tensor imaging study for a whole-brain voxel-wise analysis of fractional anisotropy, mean diffusivity, axial diffusivity (AD), and radial diffusivity (RD) of WM. RESULTS: When compared to the control group, TBSS showed a significant increase in the RD of the corpus callosum, anterior and posterior corona radiata, posterior thalamic radiation, cingulum, superior longitudinal fasciculus, and the retrolenticular region of the internal capsule in patients with hyperthyroidism (P < 0.05), as well as a significant decrease in AD in the anterior corona radiata and the genu of corpus callosum (P < 0.05). CONCLUSION: This study showed that more regions are affected by the RD increase than the AD decrease in the WM tracts of patients with hyperthyroidism. These preliminary results suggest that demyelination is the main mechanism of microstructural alterations in the WM of hyperthyroid patients.

Multimodality MRI assessment of grey and white matter injury and blood-brain barrier disruption after intracerebral haemorrhage in mice.

In this study, we examined injury progression after intracerebral haemorrhage (ICH) induced by collagenase in mice using a preclinical 11.7 Tesla MRI system. On T2-weighted MRI, lesion and striatal volumes were increased on day 3 and then decreased from days 7 to 28. On day 3, with an increase in striatal water content, vasogenic oedema in the perihaematomal region presented as increased T2 and increased apparent diffusion coefficient (ADC) signal. With a synchronous change in T2 and ADC signals, microglial activation peaked on day 3 in the same region and decreased over time. Iron deposition appeared on day 3 around the haematoma border but did not change synchronously with ADC signals. Vascular permeability measured by Evans blue extravasation on days 1, 3, and 7 correlated with the T1-gadolinium results, both of which peaked on day 3. On diffusion tensor imaging, white matter injury was prominent in the corpus callosum and internal capsule on day 3 and then partially recovered over time. Our results indicate that the evolution of grey/white matter injury and blood-brain barrier disruption after ICH can be assessed with multimodal MRI, and that perihaematomal vasogenic oedema might be attributable to microglial activation, iron deposition, and blood-brain barrier breakdown.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging Suggests Normal Perfusion in Normal-Appearing White Matter in Multiple Sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system and has been associated with reduced perfusion in normal-appearing white matter (NAWM). The magnitude of this hypoperfusion is unclear. The present study aims to quantify NAWM perfusion with dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in patients with relapsing-remitting (RR) MS and in a control group. MATERIALS AND METHODS: The statistical power of a DCE-MRI acquisition to reveal hypoperfusion in MS was estimated using a Monte Carlo simulation: synthetic tissue curves with a contrast-to-noise ratio of 8 were generated for MS patients and control group using perfusion values reported in previous studies. A compartment-uptake model was fitted to these curves, yielding estimates of cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability-surface area product (PS). This was repeated 1000 times. Mean and standard deviation of the resulting distributions were used to calculate the statistical power of a DCE-MRI study to detect perfusion differences between 16 control subjects and 24 MS subjects.In an institutional review board-approved study, patients with RR-MS (n = 24; mean age, 36 years; 17 women, mean Enhanced Disability Status Scale score, 3.25) and patients without history or symptoms of neurological disorder (n = 16; mean age, 49 years; 9 women) underwent a DCE-MRI examination with a previously established MRI protocol (3D SPGR sequence; 2.1 seconds temporal resolution; 44 slices; spatial resolution, 1.7 × 1.7 × 3 mm). Regions were defined manually in the middle cerebral artery; in the frontal, periventricular, and occipital NAWM; in the pons; and in the thalamus, and CBF, CBV, and PS were quantified using a compartment-uptake model.Parameter differences between MS and control groups were evaluated using a mixed linear model with subjects as random effect and controlling for age and sex. A P value of less than 0.05 was considered to indicate statistical significance. RESULTS: For all but one of previously reported effect sizes, the simulation study estimated a statistical power of 80% to 100% to detect reduced CBF in MS. In the patient study, mean (standard deviation) CBF in NAWM was 11.0 (15.1) and 10.4 (8.2) mL/100 mL per minute in the MS and control groups, respectively. Mean CBV in NAWM was 0.50 (0.45) mL/100 mL in the MS group and 0.48 (0.28) mL/100 mL in the control group. Mean values of PS in NAWM were 0.002 mL (0.027)/100 mL per minute in the control group and -0.001 (0.015) mL/100 mL per minute in the MS patients. Differences between patient groups were not statistically significant for CBF, CBV, mean transit time, and PS (P = 0.44, P = 0.20, P = 0.78, P = 0.66, respectively). In both groups, the influence of age on any parameter was nonsignificant. Cerebral blood flow and CBV in the thalamus and pons were significantly higher than in NAWM regions (P < 1e-4); mean transit time was significantly shorter than in NAWM (P < 1e-4). Permeability-surface area product was not significantly different from zero (P > 0.25) in all evaluated regions. CONCLUSIONS: Despite high statistical power, we could not confirm previous reports of NAWM hypoperfusion in MS. This indicates that, at least in our patient cohort, potential hypoperfusion is much less pronounced than reported in previous studies.

Association of Aortic Compliance and Brachial Endothelial Function with Cerebral Small Vessel Disease in Type 2 Diabetes Mellitus Patients: Assessment with High-Resolution MRI.

Objective. To assess the possible association of aortic compliance and brachial endothelial function with cerebral small vessel disease in type 2 diabetes mellitus (DM2) patients by using 3.0 T high-resolution magnetic resonance imaging. Methods. Sixty-two clinically confirmed DM2 patients (25 women and 37 men; mean age: 56.8 ± 7.5 years) were prospectively enrolled for noninvasive MR examinations of the aorta, brachial artery, and brain. Aortic arch pulse wave velocity (PWV), flow-mediated dilation (FMD) of brachial artery, lacunar brain infarcts, and periventricular and deep white matter hyperintensities (WMHs) were assessed. Pearson and Spearman correlation analysis were performed to analyze the association between PWV and FMD with clinical data and biochemical test results. Univariable logistic regression analyses were used to analyze the association between PWV and FMD with cerebral small vessel disease. Multiple logistic regression analyses were used to find out the independent predictive factors of cerebral small vessel disease. Results. Mean PWV was 6.73 ± 2.00 m/s and FMD was 16.67 ± 9.11%. After adjustment for compounding factors, PWV was found significantly associated with lacunar brain infarcts (OR = 2.00; 95% CI: 1.14-3.2; P < 0.05) and FMD was significantly associated with periventricular WMHs (OR = 0.82; 95% CI: 0.71-0.95; P < 0.05). Conclusions. Quantitative evaluation of aortic compliance and endothelial function by using high-resolution MRI may be potentially useful to stratify DM2 patients with risk of cerebral small vessel disease.

Assessment of abnormal brain structures and networks in major depressive disorder using morphometric and connectome analyses.

BACKGROUND: It is hypothesized that the phenomenology of major depressive disorder (MDD) is subserved by disturbances in the structure and function of brain circuits; however, findings of structural abnormalities using MRI have been inconsistent. Generalized q-sampling imaging (GQI) methodology provides an opportunity to assess the functional integrity of white matter tracts in implicated circuits. METHODS: The study population was comprised of 16 outpatients with MDD (mean age 44.81±2.2 years) and 30 age- and gender-matched healthy controls (mean age 45.03±1.88 years). We excluded participants with any other primary mental disorder, substance use disorder, or any neurological illnesses. We used T1-weighted 3D MRI with voxel-based morphometry (VBM) and vertex-wise shape analysis, and GQI with voxel-based statistical analysis (VBA), graph theoretical analysis (GTA) and network-based statistical (NBS) analysis to evaluate brain structure and connectivity abnormalities in MDD compared to healthy controls correlates with clinical measures of depressive symptom severity, Hamilton Depression Rating Scale 17-item (HAMD) and Hospital Anxiety and Depression Scale (HADS). RESULTS: Using VBM and vertex-wise shape analyses, we found significant volumetric decreases in the hippocampus and amygdala among subjects with MDD (p<0.001). Using GQI, we found decreases in diffusion anisotropy in the superior longitudinal fasciculus and increases in diffusion probability distribution in the frontal lobe among subjects with MDD (p<0.01). In GTA and NBS analyses, we found several disruptions in connectivity among subjects with MDD, particularly in the frontal lobes (p<0.05). In addition, structural alterations were correlated with depressive symptom severity (p<0.01). LIMITATIONS: Small sample size; the cross-sectional design did not allow us to observe treatment effects in the MDD participants. CONCLUSIONS: Our results provide further evidence indicating that MDD may be conceptualized as a brain disorder with abnormal circuit structure and connectivity.

White Matter Associations With Performance Validity Testing in Veterans With Mild Traumatic Brain Injury: The Utility of Biomarkers in Complicated Assessment.

OBJECTIVE: Failure on performance validity tests (PVTs) is common in Veterans with histories of mild traumatic brain injury (mTBI), leading to questionable validity of clinical presentations. PARTICIPANTS: Using diffusion tensor imaging, we investigated white matter (WM) integrity and cognition in 79 Veterans with history of mTBI who passed PVTs (n = 43; traumatic brain injury [TBI]-passed), history of mTBI who failed at least 1 PVT (n = 13; TBI-failed), and military controls (n = 23; MCs) with no history of TBI. RESULTS: The TBI-failed group demonstrated significantly lower cognitive scores relative to MCs and the TBI-passed group; however, no such differences were observed between MCs and the TBI-passed group. On a global measure of WM integrity (ie, WM burden), the TBI-failed group showed more overall WM abnormalities than the other groups. However, no differences were observed between the MCs and TBI-passed group on WM burden. Interestingly, regional WM analyses revealed abnormalities in the anterior internal capsule and cingulum of both TBI subgroups relative to MCs. Moreover, compared with the TBI-passed group, the TBI-failed group demonstrated significantly decreased WM integrity in the corpus callosum. CONCLUSIONS: Findings revealed that, within our sample, WM abnormalities are evident in those who fail PVTs. This study adds to the burgeoning PVT literature by suggesting that poor PVT performance does not negate the possibility of underlying WM abnormalities in military personnel with history of mTBI.

White matter hypoperfusion and damage in dementia: post-mortem assessment.

Neuroimaging has revealed a range of white matter abnormalities that are common in dementia, some that predict cognitive decline. The abnormalities may result from structural diseases of the cerebral vasculature, such as arteriolosclerosis and amyloid angiopathy, but can also be caused by nonstructural vascular abnormalities (eg, of vascular contractility or permeability), neurovascular instability or extracranial cardiac or vascular disease. Conventional histopathological assessment of the white matter has tended to conflate morphological vascular abnormalities with changes that reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. However, histopathology is being supplemented by biochemical approaches, including the measurement of proteins involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage, vessel-associated proteins that allow rapid measurement of microvessel density, markers of blood-brain barrier dysfunction and axonal injury, and mediators of white matter damage. By combining neuroimaging with histopathology and biochemical analysis, we can provide reproducible, quantitative data on the severity of white matter damage, and information on its etiology and pathogenesis. Together these have the potential to inform and improve treatment, particularly in forms of dementia to which white matter hypoperfusion makes a significant contribution.

Longitudinal assessment of clinically isolated syndrome with diffusion tensor imaging and volumetric MRI.

The potential of diffusion tensor imaging (DTI) indices and volumes of focal lesions on conventional magnetic resonance imaging to predict conversion to multiple sclerosis (MS) was analyzed in subjects with clinically isolated syndrome (CIS) over 4 years. Twenty patients with CIS and 10 healthy controls were included in the study. The data showed an association between the volumes of T1 and fluid-attenuated inversion recovery (FLAIR) lesions and conversion to MS (T1: P=.02; FLAIR: P=.02). The worsening of DTI indices (mean diffusivity and fractional anisotropy) was primarily seen in patients progressing to MS, but clear-cut association with conversion could not be detected.

Assessment of the structural brain network reveals altered connectivity in children with unilateral cerebral palsy due to periventricular white matter lesions.

BACKGROUND: Cerebral palsy (CP) is a term to describe the spectrum of disorders of impaired motor and sensory function caused by a brain lesion occurring early during development. Diffusion MRI and tractography have been shown to be useful in the study of white matter (WM) microstructure in tracts likely to be impacted by the static brain lesion. AIM: The purpose of this study was to identify WM pathways with altered connectivity in children with unilateral CP caused by periventricular white matter lesions using a whole-brain connectivity approach. METHODS: Data of 50 children with unilateral CP caused by periventricular white matter lesions (5-17 years; manual ability classification system [MACS] I = 25/II = 25) and 17 children with typical development (CTD; 7-16 years) were analysed. Structural and High Angular Resolution Diffusion weighted Images (HARDI; 64 directions, b = 3000 s/mm(2)) were acquired at 3 T. Connectomes were calculated using whole-brain probabilistic tractography in combination with structural parcellation of the cortex and subcortical structures. Connections with altered fractional anisotropy (FA) in children with unilateral CP compared to CTD were identified using network-based statistics (NBS). The relationship between FA and performance of the impaired hand in bimanual tasks (Assisting Hand Assessment-AHA) was assessed in connections that showed significant differences in FA compared to CTD. RESULTS: FA was reduced in children with unilateral CP compared to CTD. Seven pathways, including the corticospinal, thalamocortical, and fronto-parietal association pathways were identified simultaneously in children with left and right unilateral CP. There was a positive relationship between performance of the impaired hand in bimanual tasks and FA within the cortico-spinal and thalamo-cortical pathways (r(2) = 0.16-0.44; p < 0.05). CONCLUSION: This study shows that network-based analysis of structural connectivity can identify alterations in FA in unilateral CP, and that these alterations in FA are related to clinical function. Application of this connectome-based analysis to investigate alterations in connectivity following treatment may elucidate the neurological correlates of improved functioning due to intervention.