Spatiotemporal patterns of cortical microstructural maturation in children and adolescents with diffusion MRI.

Neocortical maturation is a dynamic process that proceeds in a hierarchical manner; however, the spatiotemporal organization of cortical microstructure with diffusion MRI has yet to be fully defined. This study characterized cortical microstructural maturation using diffusion MRI (fwe-diffusion tensor imaging [DTI] and neurite orientation dispersion and density imaging [NODDI] multicompartment modeling) in a cohort of 637 children and adolescents between 8 and 21 years of age. We found spatially heterogeneous developmental patterns broadly demarcated into functional domains where NODDI metrics increased, and fwe-DTI metrics decreased with age. By applying nonlinear growth models in a vertex-wise analysis, we observed a general posterior-to-anterior pattern of maturation, where the fwe-DTI measures mean diffusivity and radial diffusivity reached peak maturation earlier than the NODDI metrics neurite density index. Using non-negative matrix factorization, we found occipito-parietal cortical regions that correspond to lower order sensory domains mature earlier than fronto-temporal higher order association domains. Our findings corroborate previous histological and neuroimaging studies that show spatially varying patterns of cortical maturation that may reflect unique developmental processes of cytoarchitectonically determined regional patterns of change.

Brain perivascular space imaging across the human lifespan.

Enlarged perivascular spaces (PVS) are considered a biomarker for vascular pathology and are observed in normal aging and neurological conditions; however, research on the role of PVS in health and disease are hindered by the lack of knowledge regarding the normative time course of PVS alterations with age. To this end, we characterized the influence of age, sex and cognitive performance on PVS anatomical characteristics in a large cross-sectional cohort (∼1400) of healthy subjects between 8 and 90 years of age using multimodal structural MRI data. Our results show age is associated with wider and more numerous MRI-visible PVS over the course of the lifetime with spatially-varying patterns of PVS enlargement trajectories. In particular, regions with low PVS volume fraction in childhood are associated with rapid age-related PVS enlargement (e.g., temporal regions), while regions with high PVS volume fraction in childhood are associated with minimal age-related PVS alterations (e.g., limbic regions). PVS burden was significantly elevated in males compared to females with differing morphological time courses with age. Together, these findings contribute to our understanding of perivascular physiology across the healthy lifespan and provide a normative reference for the spatial distribution of PVS enlargement patterns to which pathological alterations can be compared.

Weakly supervised perivascular spaces segmentation with salient guidance of Frangi filter.

PURPOSE: To develop a weakly supervised 3D perivascular spaces (PVS) segmentation model that combines the filter-based image processing algorithm and the convolutional neural network. METHODS: We present a weakly supervised learning method for PVS segmentation by combing a rule-based image processing approach Frangi filter with a canonical deep learning algorithm Unet using conditional random field theory. The weighted cross entropy loss function and the training patch selection were implemented for the optimization and to alleviate the class imbalance issue. The performance of the model was evaluated on the Human Connectome Project data. RESULTS: The proposed method increases the true positive rate compared to the rule-based method and reduces the false positive rate by 36% in the weakly supervised training experiment and 39.4% in the supervised training experiment compared to Unet, which results in superior overall performance. In addition, by training the model on manually quality controlled and annotated data which includes the subjects with the presence of white matter hyperintensities, the proposed method differentiates between PVS and white matter hyperintensities, which reduces the false positive rate by 78.5% compared to weakly supervised trained model. CONCLUSIONS: Combing the filter-based image processing algorithm and the convolutional neural network algorithm could improve the model's segmentation accuracy, while reducing the training dependence on the large scale annotated PVS mask data by the trained physician. Compared to the filter-based image processing algorithm, the data driven PVS segmentation model using quality-controlled data as the training target could differentiate the white matter hyperintensity from PVS resulting low false positive rate.

Imaging perivascular space structure and function using brain MRI.

In this article, we provide an overview of current neuroimaging methods for studying perivascular spaces (PVS) in humans using brain MRI. In recent years, an increasing number of studies highlighted the role of PVS in cerebrospinal/interstial fluid circulation and clearance of cerebral waste products and their association with neurological diseases. Novel strategies and techniques have been introduced to improve the quantification of PVS and to investigate their function and morphological features in physiological and pathological conditions. After a brief introduction on the anatomy and physiology of PVS, we examine the latest technological developments to quantitatively analyze the structure and function of PVS in humans with MRI. We describe the applications, advantages, and limitations of these methods, providing guidance and suggestions on the acquisition protocols and analysis techniques that can be applied to study PVS in vivo. Finally, we review the human neuroimaging studies on PVS across the normative lifespan and in the context of neurological disorders.

In Vivo Sex-Dependent Effects of Perinatal Pb2+ Exposure on Pilocarpine-Induced Seizure Susceptibility and Taurine Neuropharmacology.

Lead (Pb2+) is a developmental neurotoxicant that disrupts the GABA-shift and subsequently causes alterations in the brain's excitation-to-inhibition (E/I) balance. This finding suggests that neurodevelopmental Pb2+ exposures may increase the risk of brain excitability and/or seizure susceptibility. Prior studies have suggested that neurodevelopmental Pb2+ exposures may cause excitotoxicity of cholinergic neurons, but little to no research has further investigated these potential relationships. The present study sought to evaluate the potential for perinatal neurodevelopmental Pb2+ exposures of 150 ppm and 1000 ppm on pilocarpine-induced seizures through the M1 receptor. The study also evaluated the potential for sex- and treatment-dependent differences in brain excitability. The study revealed that Control females have elevated cholinergic brain excitability and decreased GABAergic inhibition in response to pilocarpine-induced seizures. At low Pb2+ exposures, males exhibited more cholinergic brain excitability, whereas at higher Pb2+ exposures, females exhibited more cholinergic brain excitability. Further, taurine was able to provide neuroprotection against pilocarpine-induced seizures in males, whereas females did not reveal such observations. Thus, the present study adds new insights into the potential for cholinergic seizure susceptibility as a function of sex and the dosage ofneurodevelopmental Pb2+ exposure and how taurine may provide selective pharmacodynamics to treat or recover cholinergic system aberrations induced by neurotoxicants.

Taurine-Derived Compounds Produce Anxiolytic Effects in Rats Following Developmental Lead Exposure.

Lead (Pb2+) is a developmental neurotoxicant that disrupts the GABA-shift and subsequently causes alterations in the brain's excitation-to-inhibition (E/I) balance. Taurine is a well-established neuroprotective and inhibitory compound for regulating brain excitability. Since mechanistically taurine can facilitate neuronal inhibition through the GABA-AR, the present study examined the anxiolytic potential of taurine derivatives. Treatment groups consisted of the following developmental Pb2+-exposures: Control (0 ppm) and Perinatal (150 ppm or 1,000 ppm lead acetate in the drinking water). Rats were scheduled for behavioral tests between postnatal days (PND) 36-45 with random drug assignments to either saline, taurine, or taurine-derived compound (TD-101, TD-102, or TD-103) to assess the rats' responsivity to each drug in mitigating the developmental Pb2+-exposure and anxiety-like behaviors through the GABAergic system. Long-Evans hooded rats were assessed using an open field (OF) test for preliminary locomotor assessment. Twenty-four hours later, the same rats were exposed to the elevated plus maze (EPM) and were given an i.p. injection of 43 mg/Kg of the saline, taurine, or TD drugs 15 min prior to testing. Each rat was tested using the triple-blind random assignment method for each drug condition. The OF data revealed that Control female rats had increased locomotor activity over Control male rats, and the Pb2+-exposed males and females had increased locomotor activity when compared to the Control male and female rats. However, in the EPM, the Control female rats exhibited more anxiety-like behaviors over Control male rats, and the Pb2+-exposed male and female rats showed selective responsivity to TD drugs when compared to taurine. For Pb2+-exposed males, TD-101 showed consistent recovery of anxiety-like behaviors similar to that of taurine regardless of Pb2+ dose, whereas in Pb2+-exposed females TD-101 and TD-103 showed greater anxiolytic responses in the EPM. The results from the present psychopharmacological study suggests that taurine and its derivatives are interesting drug candidates to explore sex-specific mechanisms and actions of taurine and the associated GABAergic receptor properties by which these compounds alleviate anxiety as a potential behavioral pharmacotherapy for neurodevelopmental Pb2+ exposure.

Developmental Lead Exposure in Rats Causes Sex-Dependent Changes in Neurobiological and Anxiety-Like Behaviors that Are Improved by Taurine Co-treatment.

Lead (Pb2+) is a developmental neurotoxicant that causes alterations in the brain's excitation-to-inhibition (E/I) balance by disrupting the development of the GABAergic systems. These GABAergic disruptions have persistent neurobiological and neurobehavioral structure-function relationships that can be examined using animal models of Pb2+ exposure. Further, taurine, a GABA-AR agonist, has been shown to offer neuroprotection against neurodevelopmental Pb2+ exposure and senescence. The present study evaluated the effects of Pb2+ exposure (i.e., at 150 ppm and 1,000 ppm doses) on Long Evans hooded rats during the perinatal period of development on locomotor activity in the open field (OF) and anxiety-like behaviors in the elevated plus maze (EPM). This was followed by an examination of brain mass using an encephalization quotient (EQ) and isotropic fractionation (ITF) of total cells and the number of neurons and non-neuronal cells in the prefrontal cortex, hippocampus, and diencephalon. The results suggest that neurodevelopmental Pb2+ exposure caused persistent anxiety-like behaviors in both the OF and EPM with associated changes in EQ, but not ITF-determined cell density. Further, taurine treatment was observed to compensate for Pb2+ exposure in the behavioral assessments although precise neurobiological mechanisms remain unknown. Thus, more work is required to evaluate the role of taurine and other anxiolytic compounds in the alleviation of neurotoxicant-induced neurobehavioral syndromes and their associated neurobiological correlates.

Microstructural properties within the amygdala and affiliated white matter tracts across adolescence.

The amygdala is a heterogenous set of nuclei with widespread cortical connections that continues to develop postnatally with vital implications for emotional regulation. Using high-resolution anatomical and multi-shell diffusion MRI in conjunction with novel amygdala segmentation, cutting-edge tractography, and Neurite Orientation Dispersion and Density (NODDI) methods, the goal of the current study was to characterize age associations with microstructural properties of amygdala subnuclei and amygdala-related white matter connections across adolescence (N = 61, 26 males; ages of 8-22 years). We found age-related increases in the Neurite Density Index (NDI) in the lateral nucleus (LA), dorsal and intermediate divisions of the basolateral nucleus (BLDI), and ventral division of the basolateral nucleus and paralaminar nucleus (BLVPL). Additionally, there were age-related increases in the NDI of the anterior commissure, ventral amygdalofugal pathway, cingulum, and uncinate fasciculus, with the strongest age associations in the frontal and temporal regions of these white matter tracts. This is the first study to utilize NODDI to show neurite density of basolateral amygdala subnuclei to relate to age across adolescence. Moreover, age-related differences were also notable in white matter microstructural properties along the anterior commissure and ventral amydalofugal tracts, suggesting increased bilateral amygdalae to diencephalon structural connectivity. As these basolateral regions and the ventral amygdalofugal pathways have been involved in associative emotional conditioning, future research is needed to determine if age-related and/or individual differences in the development of these microstructural properties link to socio-emotional functioning and/or risk for psychopathology.

The effect of body mass index on hippocampal morphology and memory performance in late childhood and adolescence.

Childhood obesity is associated with negative physiological and cognitive health outcomes. The hippocampus is a diverse subcortical structure involved in learned feeding behaviors and energy regulation, and research has shown that the hippocampus is vulnerable to the effects of excess adiposity. Previous studies have demonstrated reduced hippocampal volume in overweight and obese children; however, it is unclear if certain subregions are selectively affected. The purpose of this study was to determine how excess body weight influences regional hippocampal surface morphology and memory performance in a large cross-sectional cohort of 588 children and adolescents between 8.33 and 19.92 years of age using body mass index expressed as a percentage of the 95th percentile cutoff (%BMIp95). We demonstrate %BMIp95 is associated with reduced radial thickness in the superior anterior region of the left hippocampus, and this relationship is predominantly driven by children younger than 14 years. We also found %BMIp95 was associated with worse performance on a spatial episodic memory task and this relationship was partially mediated by the radial thickness of the significant shape cluster. These results demonstrate the differential influence of excess body weight on regional hippocampal structure and hippocampal-dependent behavior in children and adolescents.

Selective morphological and volumetric alterations in the hippocampus of children exposed in utero to gestational diabetes mellitus.

Prior epidemiological studies have found that in utero exposure to gestational diabetes mellitus (GDM) is associated with increased risk for neurodevelopmental disorders. However, brain alterations associated with GDM are not known. The hippocampus is pivotal for cognition and emotional regulation. Therefore, we assessed relationships between in utero exposure to GDM and hippocampal morphology and subfield structure during childhood. One hundred seventeen children aged 7-11 years (57% girls, 57% exposed to GDM), born at Kaiser Permanente Southern California, participated in the BrainChild Study. Maternal GDM status was determined from electronic medical records. Children underwent brain magnetic resonance imaging. Freesurfer 6.0 was used to measure hippocampal and individual hippocampal subfield gray matter volume (mm3 ). Morphological analyses on the hippocampal surface were carried out using shape analysis. GDM-exposed children exhibited reduced radial thickness in a small, spatially-restricted portion of the left inferior body of the hippocampus that corresponds to the CA1 subfield. There was a significant interaction between GDM-exposure and sex on the right hippocampal CA1 subfield. GDM-exposed boys had reduced right CA1 volume compared to unexposed boys, but this association was no longer significant after controlling for age. No significant group differences were observed in girls. Our results suggest that GDM-exposure impacts shape of the left hippocampal CA1 subfield in both boys and girls and may reduce volume of right hippocampal CA1 only in boys. These in-depth findings illuminate the unique properties of the hippocampus impacted by prenatal GDM-exposure and could have important implications for hippocampal-related functions.

Magnitude and timing of major white matter tract maturation from infancy through adolescence with NODDI.

White matter maturation is a nonlinear and heterogeneous phenomenon characterized by axonal packing, increased axon caliber, and a prolonged period of myelination. While current in vivo diffusion MRI (dMRI) methods, like diffusion tensor imaging (DTI), have successfully characterized the gross structure of major white matter tracts, these measures lack the specificity required to unravel the distinct processes that contribute to microstructural development. Neurite orientation dispersion and density imaging (NODDI) is a dMRI approach that probes tissue compartments and provides biologically meaningful measures that quantify neurite density index (NDI) and orientation dispersion index (ODI). The purpose of this study was to characterize the magnitude and timing of major white matter tract maturation with NODDI from infancy through adolescence in a cross-sectional cohort of 104 subjects (0.6-18.8 years). To probe the regional nature of white matter development, we use an along-tract approach that partitions tracts to enable more fine-grained analysis. Major white matter tracts showed exponential age-related changes in NDI with distinct maturational patterns. Overall, analyses revealed callosal fibers developed before association fibers. Our along-tract analyses elucidate spatially varying patterns of maturation with NDI that are distinct from those obtained with DTI. ODI was not significantly associated with age in the majority of tracts. Our results support the conclusion that white matter tract maturation is heterochronous process and, furthermore, we demonstrate regional variability in the developmental timing within major white matter tracts. Together, these results help to disentangle the distinct processes that contribute to and more specifically define the time course of white matter maturation.

Hippocampal Shape Maturation in Childhood and Adolescence.

The hippocampus is a subcortical structure critical for learning and memory, and a thorough understanding of its neurodevelopment is important for studying these processes in health and disease. However, few studies have quantified the typical developmental trajectory of the structure in childhood and adolescence. This study examined the cross-sectional age-related changes and sex differences in hippocampal shape in a multisite, multistudy cohort of 1676 typically developing children (age 1-22 years) using a novel intrinsic brain mapping method based on Laplace-Beltrami embedding of surfaces. Significant age-related expansion was observed bilaterally and nonlinear growth was observed primarily in the right head and tail of the hippocampus. Sex differences were also observed bilaterally along the lateral and medial aspects of the surface, with females exhibiting relatively larger surface expansion than males. Additionally, the superior posterior lateral surface of the left hippocampus exhibited an age-sex interaction with females expanding faster than males. Shape analysis provides enhanced sensitivity to regional changes in hippocampal morphology over traditional volumetric approaches and allows for the localization of developmental effects. Our results further support evidence that hippocampal structures follow distinct maturational trajectories that may coincide with the development of learning and memory skills during critical periods of development.

Assessing the Anxiolytic Properties of Taurine-Derived Compounds in Rats Following Developmental Lead Exposure: A Neurodevelopmental and Behavioral Pharmacological Pilot Study.

Lead (Pb2+) is a developmental neurotoxicant that causes alterations in the brain's excitation-to-inhibition (E/I) balance. By increasing chloride concentration through GABA-ARs, taurine serves as an effective inhibitory compound for maintaining appropriate levels of brain excitability. Considering this pharmacological mechanism of taurine facilitated inhibition through the GABA-AR, the present pilot study sought to explore the anxiolytic potential of taurine derivatives. Treatment groups consisted of the following developmental Pb2+-exposures: Control (0 ppm) and Perinatal (150 ppm or 1000 ppm lead acetate in the drinking water). Rats were scheduled for behavioral tests between postnatal days (PND) 36-45 with random assignments to either solutions of Saline, Taurine, or Taurine Derived compounds (i.e., TD-101, TD-102, or TD-103) to assess the rats' responsiveness to each drug in mitigating the developmental Pb2+-exposure through the GABAergic system. Long Evans Hooded rats were assessed using an Open Field (OF) test for preliminary locomotor assessment. Approximately 24-h after the OF, the same rats were exposed to the Elevated Plus Maze (EPM) and were given an i.p. injection of 43 mg/Kg of the Saline, Taurine, or TD drugs 15-min prior to testing. Each rat was tested using the random assignment method for each pharmacological condition, which was conducted using a triple-blind procedure. The OF data revealed that locomotor activity was unaffected by Pb2+-exposure with no gender differences observed. However, Pb2+-exposure induced an anxiogenic response in the EPM, which interestingly, was ameliorated in a gender-specific manner in response to taurine and TD drugs. Female rats exhibited more anxiogenic behavior than the male rats; and as such, exhibited a greater degree of anxiety that were recovered in response to Taurine and its derivatives as a drug therapy. The results from the present psychopharmacological pilot study suggests that Taurine and its derivatives could provide useful data for further exploring the pharmacological mechanisms and actions of Taurine and the associated GABAergic receptor properties by which these compounds alleviate anxiety as a potential behavioral pharmacotherapy for treating anxiety and other associated mood disorders.

Neuroanatomical morphometric characterization of sex differences in youth using statistical learning.

Exploring neuroanatomical sex differences using a multivariate statistical learning approach can yield insights that cannot be derived with univariate analysis. While gross differences in total brain volume are well-established, uncovering the more subtle, regional sex-related differences in neuroanatomy requires a multivariate approach that can accurately model spatial complexity as well as the interactions between neuroanatomical features. Here, we developed a multivariate statistical learning model using a support vector machine (SVM) classifier to predict sex from MRI-derived regional neuroanatomical features from a single-site study of 967 healthy youth from the Philadelphia Neurodevelopmental Cohort (PNC). Then, we validated the multivariate model on an independent dataset of 682 healthy youth from the multi-site Pediatric Imaging, Neurocognition and Genetics (PING) cohort study. The trained model exhibited an 83% cross-validated prediction accuracy, and correctly predicted the sex of 77% of the subjects from the independent multi-site dataset. Results showed that cortical thickness of the middle occipital lobes and the angular gyri are major predictors of sex. Results also demonstrated the inferential benefits of going beyond classical regression approaches to capture the interactions among brain features in order to better characterize sex differences in male and female youths. We also identified specific cortical morphological measures and parcellation techniques, such as cortical thickness as derived from the Destrieux atlas, that are better able to discriminate between males and females in comparison to other brain atlases (Desikan-Killiany, Brodmann and subcortical atlases).

The spatial organization of ascending auditory pathway microstructural maturation from infancy through adolescence using a novel fiber tracking approach.

Auditory perception is established through experience-dependent stimuli exposure during sensitive developmental periods; however, little is known regarding the structural development of the central auditory pathway in humans. The present study characterized the regional developmental trajectories of the ascending auditory pathway from the brainstem to the auditory cortex from infancy through adolescence using a novel diffusion MRI-based tractography approach and along-tract analyses. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to quantify the magnitude and timing of auditory pathway microstructural maturation. We found spatially varying patterns of white matter maturation along the length of the tract, with inferior brainstem regions developing earlier than thalamocortical projections and left hemisphere tracts developing earlier than the right. These results help to characterize the processes that give rise to functional auditory processing and may provide a baseline for detecting abnormal development.

Spatiotemporal patterns of cortical microstructural maturation in children and adolescents with diffusion MRI.

Neocortical maturation is a dynamic process that proceeds in a hierarchical manner; however, the spatiotemporal organization of cortical microstructure with diffusion MRI has yet to be fully defined. This study characterized cortical microstructural maturation using diffusion MRI (fwe-DTI and NODDI multi-compartment modeling) in a cohort of 637 children and adolescents between 8 and 21 years of age. We found spatially heterogeneous developmental patterns broadly demarcated into functional domains where NODDI metrics increased and fwe-DTI metrics decreased with age. Using non-negative matrix factorization, we found cortical regions that correspond to lower-order sensory regions mature earlier than higher-order association regions. Our findings corroborate previous histological and neuroimaging studies that show spatially-varying patterns of cortical maturation that may reflect unique developmental processes of cytoarchitectonically-determined regional patterns of change.

Investigating the factors that explain white matter hyperintensity load in older Indians.

White matter hyperintensities are areas of hyperintense signal on MRI that typically represent cerebrovascular pathology. While focal white matter hyperintensities are common among older individuals, extensive white matter hyperintensities have been found to accelerate the progression of dementia. However, little is currently known about how various socioeconomic, health, lifestyle and environmental factors affect the severity of these lesions, particularly in low- and middle-income countries such as India. We investigated this question using cross-sectional MRI data (n = 126) from a pilot neuroimaging sub-study of an ongoing, nationally representative epidemiological study of late-life cognition in India. As a screening step, we estimated white matter hyperintensity load from fluid-attenuated inversion recovery MRI using a fully automated technique and tested for associations with each factor separately, controlling for age, sex and estimated total intracranial volume in each case. A combined model of white matter hyperintensity load included five factors which were significant after multiple comparisons correction: systolic blood pressure, body mass index, urbanicity status (urban versus rural living), daily chore hours and the frequency of store trips. This model explained an additional 27% of the variance in white matter hyperintensity load (54 versus 27% for the baseline model with only age, sex and estimated total intracranial volume). We accounted for the possibility of reverse causality by additionally controlling for concurrent markers of neurodegeneration and cognitive impairment, with no substantial change in our findings. Overall, our findings suggest that controlling high blood pressure and maintaining both a healthy body mass index and high levels of physical activity may reduce white matter hyperintensity load in older Indian adults, helping to prevent or delay dementia.

The association between white matter hyperintensities and amyloid and tau deposition.

White matter hyperintensities (WMHs) frequently occur in Alzheimer's Disease (AD) and have a contribution from ischemia, though their relationship with ß-amyloid and cardiovascular risk factors (CVRFs) is not completely understood. We used AT classification to categorize individuals based on their ß-amyloid and tau pathologies, then assessed the effects of ß-amyloid and tau on WMH volume and number. We then determined regions in which ß-amyloid and WMH accumulation were related. Last, we analyzed the effects of various CVRFs on WMHs. As secondary analyses, we observed effects of age and sex differences, atrophy, cognitive scores, and APOE genotype. PET, MRI, FLAIR, demographic, and cardiovascular health data was collected from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3) (N = 287, 48 % male). Participants were categorized as A + and T + if their Florbetapir SUVR and Flortaucipir SUVR were above 0.79 and 1.25, respectively. WMHs were mapped on MRI using a deep convolutional neural network (Sepehrband et al., 2020). CVRF scores were based on history of hypertension, systolic and diastolic blood pressure, pulse rate, respiration rate, BMI, and a cumulative score with 6 being the maximum score. Regression models and Pearson correlations were used to test associations and correlations between variables, respectively, with age, sex, years of education, and scanner manufacturer as covariates of no interest. WMH volume percent was significantly associated with global ß-amyloid (r = 0.28, p < 0.001), but not tau (r = 0.05, p = 0.25). WMH volume percent was higher in individuals with either A + or T + pathology compared to controls, particularly within in the A+/T + group (p = 0.007, Cohen's d = 0.4, t = -2.5). Individual CVRFs nor cumulative CVRF scores were associated with increased WMH volume. Finally, the regions where ß-amyloid and WMH count were most positively associated were the middle temporal region in the right hemisphere (r = 0.18, p = 0.002) and the fusiform region in the left hemisphere (r = 0.017, p = 0.005). ß-amyloid and WMH have a clear association, though the mechanism facilitating this association is still not fully understood. The associations found between ß-amyloid and WMH burden emphasizes the relationship between ß-amyloid and vascular lesion formation while factors like CVRFs, age, and sex affect AD development through various mechanisms. These findings highlight potential causes and mechanisms of AD as targets for future preventions and treatments. Going forward, a larger emphasis may be placed on ß-amyloid's vascular effects and the implications of impaired brain clearance in AD.

Volumetric distribution of perivascular space in relation to mild cognitive impairment.

Vascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular spaces (PVS). Using magnetic resonance imaging, we show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered PVS presence and distribution, irrespective of Amyloid-ß. Surprisingly, we noted lower PVS presence in the anterosuperior medial temporal lobe (asMTL) (1.29 times lower PVS volume fraction in cognitively impaired individuals, p < 0.0001), which was associated with entorhinal neurofibrillary tau tangle deposition (beta (standard error) = -0.98 (0.4); p = 0.014), one of the hallmarks of early Alzheimer's disease pathology. We also observed higher PVS volume fraction in centrum semi-ovale of the white matter, but only in female participants (1.47 times higher PVS volume fraction in cognitively impaired individuals, p = 0.0011). We also observed PVS changes in participants with history of hypertension (higher in the white matter and lower in the asMTL). Our results suggest that anatomically specific alteration of the PVS is an early neuroimaging feature of cognitive impairment in aging adults, which is differentially manifested in female.

Vasopressin amplifies the production of proinflammatory mediators in traumatic brain injury.

Arginine vasopressin (AVP) has previously been shown to promote disruption of the blood-brain barrier, exacerbate edema, and augment the loss of neural tissue in various forms and models of brain injury. However, the mechanisms underlying these AVP actions are not well understood. These mechanisms were studied in AVP-deficient Brattleboro rats (Avp(di/di)), and their parental Long-Evans strain, using a controlled cortical impact model of traumatic brain injury (TBI). The increased influx of inflammatory cells into the injured cortex in wild-type versus Avp(di/di) rats was associated with higher levels of cortical synthesis of the CXC and CC chemokines found in wild-type versus Avp(di/di) rats. These chemokines were predominantly produced by the cerebrovascular endothelium and astrocytes. In astrocyte and brain endothelial cell cultures, AVP acted synergistically with tumor necrosis factor-alpha (TNF-alpha) to increase the TNF-alpha-dependent production of CXC and CC chemokines. These AVP actions were mediated by c-Jun N-terminal kinase (JNK), as shown by Western blotting and pharmacological inhibition of JNK activity. The activity of JNK was increased in response to injury, and the differences in the magnitude of its post-traumatic activation between Avp(di/di) and wild-type rats were observed. These data demonstrate that AVP plays an important role in exacerbating the brain inflammatory response to injury.