White Matter Regions Research Articles

Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology

AbstractBackgroundBrain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.MethodParticipants comprised community‐dwelling older adults (N = 175) from four studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B).Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p<0.05, after family‐wise error rate (FWER) correction for multiple testing.ResultArteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.ConclusionThe current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.

Characterization of various type of cognitive impairment using multiomics – a pilot imaging study from a local institution

AbstractBackgroundIn addition to clinical diagnosis, multi‐modal imaging has been employed for early detection of various types of dementia. Image features from various types of images provided information for accurate diagnosis. This study aimed to evaluate the role of multiple imaging, including MRI T1W, T2W, resting state functional MRI (rs‐fMRI) and 18‐F Flutemetamol PET image in diagnosis of various types of cognitive impairments.Methods56 participants (16 Alzheimer’s Disease (AD), 10 AD type Mild Cognitive impairment (A‐MCI), 18 vascular type MCI (V‐MCI), 12 Vascular dementia (VD) and 25 Healthy Control (HC) were recruited in an local memory clinic. All types of images were re‐orientated, segmentation and normalized to the whole brain mask template. 45 brain regional volumes (Vol) were calculated from T1w using Freesurfer. Brain regional white matter hyperintensities (WMH) were obtained from T2w images. Interhemispheric functional connectivity (IFC) of brain regions were measured from rs‐fMRI. Standard uptake value (SUV) were measured and calculated from the PET images. Also, patient demographics including age, sex and HK‐MoCa score (Demo) were recorded. 70% of each group of participants were assigned to the training group, whereas the rest 30% were assigned to test group. The neural network toolbox of MATLAB was employed to build four characterization models: Model 1 based Vol and WMH; Model 2 based on Vol, WMH and IFC; Model 3 based on Vol, WMH, IFC, and demo; Model 4 based on Vol, WMH, IFC, demo and SUV.ResultsThe receiver operating characteristics (ROC) curves showed that the Model 1, 2 and 3 achieved satisfactory accuracy, with 79%, 68% and 70% respectively. While Model 4 achieved excellent accuracy of 100%. The sensitivity and specificity of each model for each group was over 75% to 100%. The model with more image features attained higher accuracy in dementia diagnosis.ConclusionArtificial neural network model with multiomics can accurately differentiate AD, A‐MCI, V‐MCI, VD and HC. Further study is suggested with more participants for models verification.

Regional White Matter Hyperintensities are Associated with Diminished Blood Flow and Microstructure in Middle Age

AbstractBackgroundWhite matter hyperintensities (WMH) are areas of increased signal visualized on T2‐weighted FLAIR magnetic resonance imaging (MRI), thought to reflect macrostructural damage due to small vessel cerebrovascular disease. Previous work established an association of WMH severity, particularly in posterior regions, with risk and progression of AD in late onset and genetic forms of AD, suggesting a vascular component to disease pathogenesis and course. Examination of the emergence and correlates of cerebrovascular changes in middle age, a critical time when vascular risk appears to be most penetrant, can give insight into mechanisms linking vascular brain injury and risk for AD. In the current study, we examined the association of cerebral blood flow (CBF) and white matter microstructure with total and regional WMH volume in middle‐aged, community dwelling adults.MethodFour hundred and ninety‐two middle‐aged participants (55+/‐11 age = 28 ‐85 years) from the community‐based Offspring Study of Mechanisms for Racial Disparities in Alzheimer’s Disease received multi‐modal MRI scanning. Regional WMH volumes were derived with in‐house software that labeled clusters of voxels within a hyperintense intensity distribution. Pulsed arterial spin labeling (PASL) sequences were processed to quantify CBF. Fractional anisotropy (FA) maps were obtained from diffusion weighted data. Total and regional WMH volumes were used as predictors for whole brain voxel‐wise correlation analyses in separate models for CBF and FA.ResultThere were negative associations between WMH volume and CBF in frontal, parietal, and occipital regions. Higher white matter hyperintensity volume was associated with lower FA, particularly in the periventricular region.ConclusionWe found associations of increased WMH volume with diminished blood flow and white matter microstructure. Future studies are needed to explain the relationship between these changes and the risk of cognitive impairment in middle aged adults and risk for AD.

Sleep loss, caffeine, sleep aids and sedation modify brain abnormalities of mild traumatic brain injury

Little evidence exists about how mild traumatic brain injury (mTBI) is affected by commonly encountered exposures of sleep loss, sleep aids, and caffeine that might be potential therapeutic opportunities. In addition, while propofol sedation is administered in severe TBI, its potential utility in mild TBI is unclear. Each of these exposures is known to have pronounced effects on cerebral metabolism and blood flow and neurochemistry. We hypothesized that they each interact with cerebral metabolic dynamics post-injury and change the subclinical characteristics of mTBI. MTBI in rats was produced by head rotational acceleration injury that mimics the biomechanics of human mTBI. Three mTBIs spaced 48 h apart were used to increase the likelihood that vulnerabilities induced by repeated mTBI would be manifested without clinically relevant structural damage. After the third mTBI, rats were immediately sleep deprived or administered caffeine or suvorexant (an orexin antagonist and sleep aid) for the next 24 h or administered propofol for 5 h. Resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) were performed 24 h after the third mTBI and again after 30 days to determine changes to the brain mTBI phenotype. Multi-modal analyses on brain regions of interest included measures of functional connectivity and regional homogeneity from rs-fMRI, and mean diffusivity (MD) and fractional anisotropy (FA) from DTI. Each intervention changed the mTBI profile of subclinical effects that presumably underlie healing, compensation, damage, and plasticity. Sleep loss during the acute post-injury period resulted in dramatic changes to functional connectivity. Caffeine, propofol sedation and suvorexant were especially noteworthy for differential effects on microstructure in gray and white matter regions after mTBI. The present results indicate that commonplace exposures and short-term sedation alter the subclinical manifestations of repeated mTBI and therefore likely play roles in symptomatology and vulnerability to damage by repeated mTBI.

Global White Matter Changes and Associations with Cognition in Pediatric Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a genetic blood disorder affecting multiple organ systems, particularly the brain (Pinto, V.M. et al 2019). Neurocognitive deficits can occur in the presence or absence of overt brain injury, such as stroke or silent cerebral infarction (SCI). Using diffusion tensor imaging (DTI) metrics, multiple studies have identified widespread white matter alterations in individuals with SCD. DTI abnormalities, such as decreased fractional anisotropy (FA) and increased mean diffusivity (MD), have been associated with decreased processing speed in this population (Stotesbury et al. 2018). The goals of this study are to 1) define developmental differences in diffuse (brain-wide) white matter microstructure between SCD and control pediatric participants and 2) determine medical and neurocognitive characteristics of pediatric participants with SCD and abnormal DTI metrics. Methods: Thirty-eight participants between 8 to 12 years of age with no prior known history of stroke, SCI, or seizures were recruited for a prospective longitudinal study. Study groups consisted of 28 participants with SCD and 10 sibling or unrelated control participants. This study was a cross-sectional analysis of participants who completed DTI scans and neuropsychological testing at study entry (n=35). DTI was obtained on a 3T Philips research scanner 2.2mm nominal isotropic resolution; 32 diffusion directions obtained at b=700 s/mm 2. Preprocessing, tensor estimation, and calculation of FA and MD maps were performed using DTI Studio/MRICloud and its pediatric DTI atlas. Neurocognitive evaluation was performed and interpreted by a trained psychology associate with supervision from a board-certified neuropsychologist and included intelligence testing (Weschler Intelligence Scale for Children, WISC-5). Statistical analyses were performed using STATA 18 and MATLAB 2022a. We examined cohort-level demographics using chi-square tests, T-tests, and Wilcoxon rank sum tests (Table 1). To examine diffuse differences in white matter microstructure development, we used 19 bilateral white matter regions of interest [ROIs] shown in prior research to be important in patients with SCD with and without SCI. We examined MD and FA values within ANOVA models (each in terms of Group*Age + ROI) to assess group-level differences (SCD vs. control) and group x age interactions. We used ANOVA loadings to compute global MD and FA scores and computed 95% prediction intervals by age based on control participants. We identified participants with SCD with global scores suggestive of white matter microstructural differences (high MD and/or low FA) and compared their overall neurocognitive profiles. Results: The SCD and control participants were similar with regards to age, sex, and full-scale IQ. SCD participants had significantly lower median hemoglobin levels than control participants. There was one control participant who met criteria for SCI. SCD vs. control group status, age, and group x age interactions all significantly impacted our MD model (explaining 0.8%, 1.1%, and 0.8% of total variance, respectively; all p<0.001). MD decreased with age in the combined cohort (β=-9.3±1.6e-7/month) with significant flattening of this trend in children with SCD (group x age interaction: β=+7.9±2.0e-7/month). In contrast, only age significantly impacted our FA model (p<0.001, explaining 1.1% of variance); group status and group x age interactions each explained <0.2% of variance in FA. Four children with SCD had global DTI metrics suggestive of white matter injury (one with high MD and low FA; two with high MD only; one with low FA only). All 4 participants with abnormal DTI metrics had abnormal MRIs, three of whom had SCI and one of whom had lesions that did not meet the size criteria for SCI. Three participants had full scale IQs 1 standard deviation below the expected mean of 100 (<85). Conclusion: We identified differences in global white matter microstructural indices between SCD and control participants with an apparent blunting of expected decreases in mean diffusivity with age. Our continuing longitudinal study will explicitly assess DTI trajectories and implications for neurocognitive functioning in children with SCD.

Comparison of three magnetic resonance imaging measures of brain iron in healthy and cocaine use disorder participants.

Several magnetic resonance imaging (MRI) measures for quantifying endogenous nonheme brain iron have been proposed. These correspond to distinct physical properties with varying sensitivities and specificities to iron. Moreover, they may depend not only on tissue iron concentration, but also on the intravoxel spatial pattern of iron deposition, which is complex in many brain regions. Here, the three MRI brain iron measures of , magnetic field correlation (MFC), and magnetic susceptibility are compared in several deep gray matter regions for both healthy participants (HPs) and individuals with cocaine use disorder (CUD). Their concordance is assessed from their correlations with each other and their relative dependencies on age. In addition, associations between the iron measures and microstructure in adjacent white matter regions are investigated by calculating their correlations with diffusion MRI measures from the internal capsule, and associations with cognition are determined by using results from a battery of standardized tests relevant to CUD. It is found that all three iron measures are strongly correlated with each other for the considered gray matter regions, but with correlation coefficients substantially less than one indicating important differences. The age dependencies of all three measures are qualitatively similar in most regions, except for the red nucleus, where the susceptibility has a significantly stronger correlation with age than . Weak to moderate correlations are seen for the iron measures with several of the diffusion and cognitive measures, with the strongest correlations being obtained for . The iron measures differ little between the HP and CUD groups, although susceptibility is significantly lower in the red nucleus for the CUD group. For the comparisons made, the iron measures behave similarly in most respects, but with notable quantitative differences. It is suggested that these differences may be, in part, attributable to a higher sensitivity to the spatial pattern of iron deposition for and MFC than for susceptibility. This is supported most strongly by a sharp contrast between the values of the iron measures in the globus pallidus relative to those in the red nucleus. The observed correlations of the iron measures with diffusion and cognitive scores point to possible connections between gray matter iron, white matter microstructure, and cognition.

Total-Body Irradiation Alters White Matter Volume and Microstructural Integrity in Rhesus Macaques

Long-term survivors of brain irradiation can suffer from irreversible injury and cognitive impairment. T1-weighted and diffusion tensor magnetic resonance imaging are used to evaluate brain volumes and white matter (WM) microstructure in neurodevelopmental and neurodegenerative conditions. The goal of this study was to evaluate the long-term effects of single-dose total-body irradiation (TBI) or TBI with 5% partial-body sparing on brain volumetrics and WM integrity in macaques. We utilized MRI scans from a cohort of male rhesus macaques (age range: 3.6-22.8 years), to compare global and regional brain volumes and WM diffusion in survivors of TBI (T1w: n=137, DTI: n=121, dose range: 3.5-10 Gy) against unirradiated controls (T1w: n=48, DTI: n=38). In all ROIs, radiation affected the age-related changes in fractional anisotropy (FA); in general, FA increased across age in both groups, but to a lesser extent in the irradiated group (interaction p-values <0.01). Depending on the ROI, mean diffusivity (MD) decreased or remained the same across age in unirradiated animals, while it increased or did not change in irradiated animals. The increases in MD were driven by changes in radial diffusivity (RD) which followed similar trends across age. Axial diffusivity (AD) did not differ by irradiation status. Age-related changes in relative volumes in controls reflected normal trends in humans with increasing WM and decreasing gray matter (GM) until middle age. Cerebrospinal fluid (CSF) volume did not differ across age in controls. WM volume was lower and CSF volume was higher in young, irradiated macaques. WM volume was similar between groups and CSF volume reduced in older irradiated macaques. GM volume was unaffected by radiation. TBI results in delayed WM expansion and long-term disruption of WM integrity. Diffusion changes suggest that myelin injury in WM is a hallmark of late-delayed radiation induced brain injury.

Improved reconstruction of crossing fibers in the mouse optic pathways with orientation distribution function fingerprinting.

The accuracy of diffusion MRI tractography reconstruction decreases in the white matter regions with crossing fibers. The optic pathways in rodents provide a challenging structure to test new diffusion tractography approaches because of the small crossing volume within the optic chiasm and the unbalanced 9:1 proportion between the contra- and ipsilateral neural projections from the retina to the lateral geniculate nucleus, respectively. Common approaches based on Orientation Distribution Function (ODF) peak finding or statistical inference were compared qualitatively and quantitatively to ODF Fingerprinting (ODF-FP) for reconstruction of crossing fibers within the optic chiasm using in vivo diffusion MRI ( healthy C57BL/6 mice). Manganese-Enhanced MRI (MEMRI) was obtained after intravitreal injection of manganese chloride and used as a reference standard for the optic pathway anatomy. ODF-FP outperformed by over 100% all the tested methods in terms of the ratios between the contra- and ipsilateral segments of the reconstructed optic pathways as well as the spatial overlap between tractography and MEMRI. In this challenging model system, ODF-Fingerprinting reduced uncertainty of diffusion tractography for complex structural formations of fiber bundles.

A CAD system design using iteratively reweighted fuzzy c-means and deep tree training for Alzheimer's disease diagnosis

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and other cognitive abnormalities. In this research work, an MRI-based Computer-Aided Diagnosis (CAD) system is presented for clinical practice. While current algorithms used for detecting Alzheimer's disease perform inefficiently. Those algorithms are unable to detect minor changes in the disease due to discrepancies in feature extraction, segmentation, and classification methods. To overcome the issues in algorithm, a new iteratively reweighted adaptive spatial fuzzy c-means approach (IRW-ASFCM) is used to segment the brain tissue efficiently. Initially, the Magnetic resonance images (MRI) will pre-processed by using the Statistical parametric mapping (SPM) tool. After pre-processing, the segmentation is done using IRW-ASFCM to get effective tissue segments. Then, a 2-level selective Wavelet Kernel (2LS-WaveCNN ensemble) based CNN ensemble model will be used to extract the feature map from the Gray matter (GM), White matter (WM) and Cerebrospinal fluid (CSF) regions after segmenting the images. The Wave CNN networks built from hidden layers are trained using Deep Tree Training (DTT) for AD classification. The simulation results demonstrate that the suggested CAD system is superior to the state-of-the-art systems in terms of accuracy (99.54 %), sensitivity (99.26 %), and specificity (99.64 %) for multi-class problems.

Applicability of multiple quantitative magnetic resonance methods in genetic brain white matter disorders.

Magnetic resonance imaging (MRI) measures of tissue microstructure are important for monitoring brain white matter (WM) disorders like leukodystrophies and multiple sclerosis. They should be sensitive to underlying pathological changes. Three whole-brain isotropic quantitative methods were applied and compared within a cohort of controls and leukodystrophy patients: two novel myelin water imaging (MWI) techniques (multi-compartment relaxometry diffusion-informed MWI: MCR-DIMWI, and multi-echo T2 relaxation imaging with compressed sensing: METRICS) and neurite orientation dispersion and density imaging (NODDI). For 9 patients with different leukodystrophies (age range 0.4-62.4 years) and 15 control subjects (2.3-61.3 years), T1-weighted MRI, fluid-attenuated inversion recovery, multi-echo gradient echo with variable flip angles, METRICS, and multi-shell diffusion-weighted imaging were acquired on 3 Tesla. MCR-DIMWI, METRICS, NODDI, and quality control measures were extracted to evaluate differences between patients and controls in WM and deep gray matter (GM) regions of interest (ROIs). Pearson correlations, effect size calculations, and multi-level analyses were performed. MCR-DIMWI and METRICS-derived myelin water fractions (MWFs) were lower and relaxation times were higher in patients than in controls. Effect sizes of MWF values and relaxation times were large for both techniques. Differences between patients and controls were more pronounced in WM ROIs than in deep GM. MCR-DIMWI-MWFs were more homogeneous within ROIs and more bilaterally symmetrical than METRICS-MWFs. The neurite density index was more sensitive in detecting differences between patients and controls than fractional anisotropy. Most measures obtained from MCR-DIMWI, METRICS, NODDI, and diffusion tensor imaging correlated strongly with each other. This proof-of-concept study shows that MCR-DIMWI, METRICS, and NODDI are sensitive techniques to detect changes in tissue microstructure in WM disorders.

2 Rethinking the Neuropsychology of g: Structural and Functional Lesion Network Mapping of General Cognitive Ability

Objective:General cognitive ability (g) is central to our understanding of human cognition, as it accounts for nearly half of individual differences in performances on diverse cognitive tests. There is growing interest in the brain networks necessary for g because such knowledge could elucidate neural mechanisms of g. Prior work highlighted the association between g and frontoparietal functional networks. However, the specificity of this relationship has been questioned. Moreover, no studies have compared the relative importance of structural and functional networks for g, and most studies have relied on data from neurologically healthy individuals, which limits causal brain-behavior inference. Lesion network mapping (LNM) can overcome such limitations. LNM integrates lesion location and structural and functional brain network data, and allows for inference upon networks necessary for cognitive functions. Here, we used data from three cohorts of patients with focal brain lesions to perform a large-scale LNM study of g. We also compared the relative value of lesion-behavior mapping, and structural and functional LNM, for predicting g across cohorts.Participants and Methods:Using data from 402 individuals with chronic, focal brain lesions from the Iowa Neurological Patient Registry, we created a bifactor model to estimate g from the shared variance across neuropsychological tests. To create “cognitive comparisons,” we also estimated the unique aspects of domain-specific abilities (visuospatial processing, memory, and processing speed) by removing domain-general variance from each. Next, we used multivariate lesion-behavior mapping to create statistically weighted maps linking deficits in g and domain-specific abilities to regions of focal brain damage. To perform LNM, the local maxima of the lesion-behavior maps were used as seeds for structural and functional connectivity analyses based on normative diffusion-weighted imaging and resting-state functional connectivity data, respectively. The resulting maps were collapsed using principal components analysis (PCA). We quantified the overlap between each map and the lesion volumes of patients from two validation cohorts (n = 101, n = 100). We used these scores to predict observed g in the validation cohorts while controlling for lesion volume. We also compared the relative predictive value of the lesion-behavior maps, and the structural and functional LNMs.Results:Lesion-behavior mapping indicated that lesions of left frontal white matter, bilateral frontal operculum/insula, and a region of white matter in the posterior left hemisphere were associated with impairments in g. Across all lesion-behavior mapping and LNM results, only two of the structural LNM maps linked to g were statistically significantly predictive of g in both validation cohorts: a map corresponding to the anterior thalamic radiation, and another corresponding to left frontal pyramidal projections. Both added value beyond lesion-behavior mapping and functional LNM.Conclusions:The results are notable in several respects: they highlight the importance of structural networks for g, de-emphasize the relevance of functional networks for g, and suggest novel brain circuitry involved in g. Our findings are consistent with animal studies implicating anterior thalamic nuclei in working memory, a cognitive function central to g. Clinically, our study highlights the importance of considering domain-general deficits and the effects of focal lesions on distributed cognitive networks.

Characterization of Traumatic Brain Injury in a Gyrencephalic Ferret Model Using the Novel Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA).

Traumatic brain injury (TBI) results from mechanical force to the brain and leads to a series of biochemical responses that further damage neurons and supporting cells. Clinically, most TBIs result from an impact to the intact skull, making closed head TBI pre-clinical models highly relevant. However, most of these closed head TBI models use lissencephalic rodents, which may not transduce biomechanical load in the same manner as gyrencephalic humans. To address this translational gap, this study aimed to characterize acute axonal injury and microglial responses in ferrets-the smallest gyrencephalic mammal. Injury was induced in male ferrets (Mustela furo; 1.20-1.51 kg; 6-9 months old) with the novel Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) model. Animals were randomly allocated to either sham (n = 4), a 22J (joules) impact (n = 4), or a 27J impact (n = 4). Axonal injury was examined histologically with amyloid precursor protein (APP), neurofilament M (RMO 14.9) (RMO-14), and phosphorylated tau (AT180) and the microglial response with ionized calcium-binding adaptor molecule 1 at 24 h post-injury in gray and white matter regions. Graded axonal injury was observed with modest increases in APP and RMO-14 immunoreactivity in the 22J TBI group, mostly within the corpus callosum and fornix and more extensive diffuse axonal injury encompassing gray matter structures like the thalamus and hypothalamus in the 27J group. Accompanying microglial activation was only observed in the 27J group, most prominently within the white matter tracts in response to the larger amounts of axonal injury. The 27J, but not the 22J, group showed an increase in AT180 within the base of the sulci post-injury. This could suggest that the strain may be highest in this region, demonstrating the different responses in gyrencephalic compared to lissencephalic brains. The CHIMERA model in ferrets mimic many of the histopathological features of human closed head TBI acutely and provides a promising model to investigate the pathophysiology of TBI.

Central mechanisms in sympathetic nervous dysregulation in obesity.

Cardiovascular and metabolic complications associated with excess adiposity are linked to chronic activation of the sympathetic nervous system, resulting in a high risk of mortality among obese individuals. Obesity-related positive energy balance underlies the progression of hypertension, end-organ damage, and insulin resistance, driven by increased sympathetic tone throughout the body. It is, therefore, important to understand the central network that drives and maintains sustained activation of the sympathetic nervous system in the obese state. Experimental and clinical studies have identified structural changes and altered dynamics in both grey and white matter regions in obesity. Aberrant activation in certain brain regions has been associated with altered reward circuitry and metabolic pathways including leptin and insulin signaling along with adiposity-driven systemic and central inflammation. The impact of these pathways on the brain via overactivity of the sympathetic nervous system has gained interest in the past decade. Primarily, the brainstem, hypothalamus, amygdala, hippocampus, and cortical structures including the insular, orbitofrontal, temporal, cingulate, and prefrontal cortices have been identified in this context. Although the central network involving these structures is much more intricate, this review highlights recent evidence identifying these regions in sympathetic overactivity in obesity.

Cerebral Microstructural and Microvascular Changes in Non-Neuropsychiatric Systemic Lupus Erythematosus: A Study Using Diffusion Kurtosis Imaging and 3D Pseudo-Continuous Arterial Spin Labeling.

The purpose of this study was to observe cerebral microstructure and microcirculation features, as well as changes in white matter (WM) and gray matter (GM) among patients with non-neuropsychiatric systemic lupus erythematosus (non-NPSLE). We compared 36 female patients with non-NPSLE and 20 age- and gender-matched healthy controls (HCs) who underwent 3.0T MRI imaging with diffusion kurtosis imaging (DKI) and 3D pseudo-continuous Arterial Spin Labeling (pCASL). Mean kurtosis (MK), mean kurtosis tensor (MKT), and cerebral blood flow (CBF) values were obtained from 25 brain regions, including WM and GM. We analyzed the correlation between imaging indicators and clinical data. When compared with HCs, patients with non-NPSLE had reduced MK and MKT values in regional WM, deep GM, and the left frontal lobe cortical GM, and increased CBF in the right parietal lobe WM and right semioval center (SOC). The MK and MKT values were weakly correlated with CBF in some regions, including WM and GM. Complement 3 (C3) and Complement 4 (C4) showed a weak positive correlation with MK and MKT in some regions, including WM and deep GM, while platelet (PLT) was positively correlated with MKT in the left frontal lobe WM; dsDNA antibody was correlated negatively with MK in the right occipital lobe WM; and erythrocyte sedimentation rate (ESR) was correlated negatively with CBF in the left SOC. Our findings revealed the presence of brain microstructural and microvascular abnormalities in non-NPSLE patients, indicating microstructural damage in the cortical GM, which was less commonly reported. We found DKI and pCASL useful in detecting early brain lesions, and MK was a more sensitive and beneficial indicator.

Neuroanatomical differences in Latinx children from rural farmworker families and urban non-farmworker families and related associations with pesticide exposure

Exposure to pesticides in humans may lead to changes in brain structure and function and increase the likelihood of experiencing neurodevelopmental disorders. Despite the potential risks, there is limited neuroimaging research on the effects of pesticide exposure on children, particularly during the critical period of brain development. Here we used voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) from magnetic resonance images (MRI) to investigate neuroanatomical differences between Latinx children (n = 71) from rural, farmworker families (FW; n = 48) and urban, non-farmworker families (NFW; n = 23). Data presented here serves as a baseline for our ongoing study examining the longitudinal effects of living in a rural environment on neurodevelopment and cognition in children. The VBM analysis revealed that NFW children had higher volume in several distinct regions of white matter compared to FW children. Tract-based spatial statistics (TBSS) of DTI data also indicated NFW children had higher fractional anisotropy (FA) in several key white matter tracts. Although the difference was not as pronounced as white matter, the VBM analysis also found higher gray matter volume in selected regions of the frontal lobe in NFW children. Notably, white matter and gray matter findings demonstrated a high degree of overlap in the medial frontal lobe, a brain region predominantly linked to decision-making, error processing, and attention functions. To gain further insights into the underlying causes of the observed differences in brain structure between the two groups, we examined the association of organochlorine (OC) and organophosphate (OP) exposure collected from passive dosimeter wristbands with brain structure. Based on our previous findings within this data set, demonstrating higher OC exposure in children from non-farmworker families, we hypothesized OC might play a critical role in structural differences between NFW and FW children. We discovered a significant positive correlation between the number of types of OC exposure and the structure of white matter. The regions with significant association with OC exposure were in agreement with the findings from the FW-NFW groups comparison analysis. In contrast, OPs did not have a statistically significant association with brain structure. This study is among the first multimodal neuroimaging studies examining the brain structure of children exposed to agricultural pesticides, specifically OC. These findings suggest OC pesticide exposure may disrupt normal brain development in children, highlighting the need for further neuroimaging studies within this vulnerable population.

Advanced multiparametric magnetic resonance imaging of intra-axial posterior fossa tumors

Background: For early treatment planning, it is required that accurate diagnosis of intra-axial posterior fossa tumors can be done. However, imaging diagnosis can be challenging due to analogous magnetic resonance imaging (MRI) features. Aims and Objectives: The aim of the study was to determine the accuracy of advanced MRI sequences such as diffusion-weighted imaging and magnetic resonance spectroscopy (MRS) in diagnosis of intra-axial posterior fossa masses in a tertiary care center. Materials and Methods: This was a retrospective observational study including 43 patients with posterior fossa intra-axial space-occupying tumors. Mean of minimum apparent diffusion coefficient (ADC) values (mean ADCmin) was derived in tumor, and normal white matter regions and ADC ratio was estimated. On MRS, choline/creatinine (Cho/Cr) and Cho/N-acetyl aspartate (NAA) ratios were noted. Receiver operating characteristic (ROC) curve was used to determine cut-off values for mean tumor ADCmin, ADC ratio, Cho/Cr ratio, and Cho/NAA ratio. Results: The most common tumor was medulloblastoma (MB) (30.23%), followed by metastasis (25.58%), pilocytic astrocytoma (16.28%), brainstem glioma (9.3%), hemangioblastoma (6.98%), glioneuronal tumor (6.98%), and ependymoma (4.65%). MBs showed lowest mean tumor ADCmin (0.57±0.12×10-3 mm2/s) and ADC ratio (0.92±0.18) and highest Cho/Cr ratio (8.26±3.9) and Cho/NAA ratio (6.4±1.83) with significant difference from the group of remaining tumors. ROC curve analysis revealed cutoff values of ≤0.71×10-3mm2/s for ADCmin; ≤ 1.02 for ADC ratio; &gt;3.76 for Cho/Cr ratio, and &gt;3.2 for Cho/NAA ratio for the differentiation of MBs from other tumors. Conclusion: The combined use of ADCmin values, ADC ratio, Cho/Cr ratio, and Cho/NAA ratio can help in better non-invasive analysis of similarly appearing intra-axial posterior fossa tumors.

The neuropathology of intimate partner violence

Lifelong brain health consequences of traumatic brain injury (TBI) include the risk of neurodegenerative disease. Up to one-third of women experience intimate partner violence (IPV) in their lifetime, often with TBI, yet remarkably little is known about the range of autopsy neuropathologies encountered in IPV. We report a prospectively accrued case series from a single institution, the New York City Office of Chief Medical Examiner, evaluated in partnership with the Brain Injury Research Center of Mount Sinai, using a multimodal protocol comprising clinical history review, ex vivo imaging in a small subset, and comprehensive neuropathological assessment by established consensus protocols. Fourteen brains were obtained over 2 years from women with documented IPV (aged 3rd–8th decade; median, 4th) and complex histories including prior TBI in 6, nonfatal strangulation in 4, cerebrovascular, neurological, and/or psychiatric conditions in 13, and epilepsy in 7. At autopsy, all had TBI stigmata (old and/or recent). In addition, white matter regions vulnerable to diffuse axonal injury showed perivascular and parenchymal iron deposition and microgliosis in some subjects. Six cases had evidence of cerebrovascular disease (lacunes and/or chronic infarcts). Regarding neurodegenerative disease pathologies, Alzheimer disease neuropathologic change was present in a single case (8th decade), with no chronic traumatic encephalopathy neuropathologic change (CTE-NC) identified in any. Findings from this initial series then prompted similar exploration in an expanded case series of 70 archival IPV cases (aged 2nd–9th decade; median, 4th) accrued from multiple international institutions. In this secondary case series, we again found evidence of vascular and white matter pathologies. However, only limited neurodegenerative proteinopathies were encountered in the oldest subjects, none meeting consensus criteria for CTE-NC. These observations from this descriptive exploratory study reinforce a need to consider broad co-morbid and neuropathological substrates contributing to brain health outcomes in the context of IPV, some of which may be potentially modifiable.

Microstructural Organization of Distributed White Matter Associated With Fine Motor Control in US Service Members With Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) is the most common form of brain injury. While most individuals recover from mTBI, roughly 20% experience persistent symptoms, potentially including reduced fine motor control. We investigate relationships between regional white matter organization and subcortical volumes associated with performance on the Grooved Pegboard (GPB) test in a large cohort of military Service Members and Veterans (SM&Vs) with and without a history of mTBI(s). Participants were enrolled in the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. SM&Vs with a history of mTBI(s) (n = 847) and without mTBI (n = 190) underwent magnetic resonance imaging and the GPB test. We first examined between-group differences in GPB completion time. We then investigated associations between GPB performance and regional structural imaging measures (tractwise diffusivity, subcortical volumes, and cortical thickness) in SM&Vs with a history of mTBI(s). Lastly, we explored whether mTBI history moderated associations between imaging measures and GPB performance. SM&Vs with mTBI(s) performed worse than those without mTBI(s) on the non-dominant hand GPB test at a trend level (p < 0.1). Higher fractional anisotropy (FA) of tracts including the posterior corona radiata, superior longitudinal fasciculus, and uncinate fasciculus were associated with better GPB performance in the dominant hand in SM&Vs with mTBI(s). These findings support that the organization of several white matter bundles are associated with fine motor performance in SM&Vs. We did not observe that mTBI history moderated associations between regional FA and GPB test completion time, suggesting that chronic mTBI may not significantly influence fine motor control.

Assessment of white matter hyperintensity severity using multimodal magnetic resonance imaging.

White matter hyperintensities are radiological abnormalities reflecting cerebrovascular dysfunction detectable using MRI. White matter hyperintensities are often present in individuals at the later stages of the lifespan and in prodromal stages in the Alzheimer's disease spectrum. Tissue alterations underlying white matter hyperintensities may include demyelination, inflammation and oedema, but these are highly variable by neuroanatomical location and between individuals. There is a crucial need to characterize these white matter hyperintensity tissue alterations in vivo to improve prognosis and, potentially, treatment outcomes. How different MRI measure(s) of tissue microstructure capture clinically-relevant white matter hyperintensity tissue damage is currently unknown. Here, we compared six MRI signal measures sampled within white matter hyperintensities and their associations with multiple clinically-relevant outcomes, consisting of global and cortical brain morphometry, cognitive function, diagnostic and demographic differences and cardiovascular risk factors. We used cross-sectional data from 118 participants: healthy controls (n = 30), individuals at high risk for Alzheimer's disease due to familial history (n = 47), mild cognitive impairment (n = 32) and clinical Alzheimer's disease dementia (n = 9). We sampled the median signal within white matter hyperintensities on weighted MRI images [T1-weighted (T1w), T2-weighted (T2w), T1w/T2w ratio, fluid-attenuated inversion recovery (FLAIR)] as well as the relaxation times from quantitative T1 (qT1) and T2* (qT2*) images. qT2* and fluid-attenuated inversion recovery signals within white matter hyperintensities displayed different age- and disease-related trends compared to normal-appearing white matter signals, suggesting sensitivity to white matter hyperintensity-specific tissue deterioration. Further, white matter hyperintensity qT2*, particularly in periventricular and occipital white matter regions, was consistently associated with all types of clinically-relevant outcomes in both univariate and multivariate analyses and across two parcellation schemes. qT1 and fluid-attenuated inversion recovery measures showed consistent clinical relationships in multivariate but not univariate analyses, while T1w, T2w and T1w/T2w ratio measures were not consistently associated with clinical variables. We observed that the qT2* signal was sensitive to clinically-relevant microstructural tissue alterations specific to white matter hyperintensities. Our results suggest that combining volumetric and signal measures of white matter hyperintensity should be considered to fully characterize the severity of white matter hyperintensities in vivo. These findings may have implications in determining the reversibility of white matter hyperintensities and the potential efficacy of cardio- and cerebrovascular treatments.

Association of polygenic risk for bipolar disorder with grey matter structure and white matter integrity in youth

There is a gap in knowledge regarding the polygenic underpinnings of brain anomalies observed in youth bipolar disorder (BD). This study examined the association of a polygenic risk score for BD (BD-PRS) with grey matter structure and white matter integrity in youth with and without BD. 113 participants were included in the analyses, including 78 participants with both T1-weighted and diffusion-weighted MRI images, 32 participants with T1-weighted images only, and 3 participants with diffusion-weighted images only. BD-PRS was calculated using PRS-CS-auto and was based on independent adult genome-wide summary statistics. Vertex- and voxel-wise analyses examined the associations of BD-PRS with grey matter metrics (cortical volume [CV], cortical surface area [CSA], cortical thickness [CTh]) and fractional anisotropy [FA] in the combined sample, and separately in BD and HC. In the combined sample of participants with T1-weighted images (n = 110, 66 BD, 44 HC), higher BD-PRS was associated with smaller grey matter metrics in frontal and temporal regions. In within-group analyses, higher BD-PRS was associated with lower CTh of frontal, temporal, and fusiform gyrus in BD, and with lower CV and CSA of superior frontal gyrus in HC. In the combined sample of participants with diffusion-weighted images (n = 81, 49 BD, 32 HC), higher BD-PRS was associated with lower FA in widespread white matter regions. In summary, BD-PRS calculated based on adult genetic data was negatively associated with grey matter structure and FA in youth in regions implicated in BD, which may suggest neuroimaging markers of vulnerability to BD. Future longitudinal studies are needed to examine whether BD-PRS predicts neurodevelopmental changes in BD vs. HC and its interaction with course of illness and long-term medication use.