Fixel-Based Analysis Reveals Tau-Related White Matter Changes in Early Stages of Alzheimer's Disease.

Several studies have shown white matter (WM) abnormalities in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aß-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aß-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics.

Brain age of rhesus macaques over the lifespan.

Through the application of machine learning algorithms to neuroimaging data the brain age methodology was shown to provide a useful individual-level biological age prediction and identify key brain regions responsible for the prediction. In this study, we present the methodology of constructing a rhesus macaque brain age model using a machine learning algorithm and discuss the key predictive brain regions in comparison to the human brain, to shed light on cross-species primate similarities and differences. Structural information of the brain (e.g., parcellated volumes) from brain magnetic resonance imaging of 43 rhesus macaques were used to develop brain atlas-based features to build a brain age model that predicts biological age. The best-performing model used 22 selected features and achieved an R2 of 0.72. We also identified interpretable predictive brain features including Right Fronto-orbital Cortex, Right Frontal Pole, Right Inferior Lateral Parietal Cortex, and Bilateral Posterior Central Operculum. Our findings provide converging evidence of the parallel and comparable brain regions responsible for both non-human primates and human biological age prediction.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

Brain morphometry in former American football players: Findings from the DIAGNOSE CTE research project.

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (MRI). MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 58 age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each Traumatic Encephalopathy Syndrome (TES) diagnosis core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula temporal pole and superior frontal gyrus. Post-hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe age-by-group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs.

Matrix metalloproteinase 9 (MMP-9) activity, hippocampal extracellular free water, and cognitive deficits are associated with each other in early phase psychosis.

Increasing evidence points toward the role of the extracellular matrix, specifically matrix metalloproteinase 9 (MMP-9), in the pathophysiology of psychosis. MMP-9 is a critical regulator of the crosstalk between peripheral and central inflammation, extracellular matrix remodeling, hippocampal development, synaptic pruning, and neuroplasticity. Here, we aim to characterize the relationship between plasma MMP-9 activity, hippocampal microstructure, and cognition in healthy individuals and individuals with early phase psychosis. We collected clinical, blood, and structural and diffusion-weighted magnetic resonance imaging data from 39 individuals with early phase psychosis and 44 age and sex-matched healthy individuals. We measured MMP-9 plasma activity, hippocampal extracellular free water (FW) levels, and hippocampal volumes. We used regression analyses to compare MMP-9 activity, hippocampal FW, and volumes between groups. We then examined associations between MMP-9 activity, FW levels, hippocampal volumes, and cognitive performance assessed with the MATRICS battery. All analyses were controlled for age, sex, body mass index, cigarette smoking, and years of education. Individuals with early phase psychosis demonstrated higher MMP-9 activity (p < 0.0002), higher left (p < 0.05) and right (p < 0.05) hippocampal FW levels, and lower left (p < 0.05) and right (p < 0.05) hippocampal volume than healthy individuals. MMP-9 activity correlated positively with hippocampal FW levels (all participants and individuals with early phase psychosis) and negatively with hippocampal volumes (all participants and healthy individuals). Higher MMP-9 activity and higher hippocampal FW levels were associated with slower processing speed and worse working memory performance in all participants. Our findings show an association between MMP-9 activity and hippocampal microstructural alterations in psychosis and an association between MMP-9 activity and cognitive performance. Further, more extensive longitudinal studies should examine the therapeutic potential of MMP-9 modulators in psychosis.

BrainAGE, brain health, and mental disorders: A systematic review.

The imaging-based method of brainAGE aims to characterize an individual's vulnerability to age-related brain changes. The present study systematically reviewed brainAGE findings in neuropsychiatric conditions and discussed the potential of brainAGE as a marker for biological age. A systematic PubMed search (from inception to March 6th, 2023) identified 273 articles. The 30 included studies compared brainAGE between neuropsychiatric and healthy groups (n≥50). We presented results qualitatively and adapted a bias risk assessment questionnaire. The imaging modalities, design, and input features varied considerably between studies. While the studies found higher brainAGE in neuropsychiatric conditions (11 mild cognitive impairment/ dementia, 11 schizophrenia spectrum/ other psychotic and bipolar disorder, six depression/ anxiety, two multiple groups), the associations with clinical characteristics were mixed. While brainAGE is sensitive to group differences, limitations include the lack of diverse training samples, multi-modal studies, and external validation. Only a few studies obtained longitudinal data, and all have used algorithms built solely to predict chronological age. These limitations impede the validity of brainAGE as a biological age marker.

SARS-CoV-2 infection elucidates unique features of pregnancy-specific immunity.

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8 + T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.

Heart-brain mapping: Cardiac atrial function is associated with distinct cerebral regions with high free water in older adults.

Left atrial (LA) dysfunction has been linked to cognitive impairment and cerebrovascular dysfunction. Higher brain free-water (FW) derived from diffusion-MRI was associated with early and subtle cerebrovascular dysfunction and more severe cognitive impairment. We hypothesized that LA dysfunction would correlate with higher brain free-water (FW) among healthy older adults. 56 community older adults (73.13 ± 3.56 years; 24 female) with normal cognition and without known cardiovascular disease who had undergone cardiac-MRI, brain-MRI, and neuropsychological assessments were included. Whole-brain voxel-level general linear models were constructed to correlate brain FW measures with LA indices. We found lower scores in LA function measures were related to higher grey matter (GM) FW in regions including orbital frontal and right temporal regions (p < 0.01, family-wise error corrected). In parallel, LA dysfunction was associated with higher FW in white matter (WM) fibres including superior longitudinal fasciculus, internal capsule, and superior corona radiata. However, LA dysfunction was not related to WM tissue reduction and GM cortical thinning. Moreover, these cardiac-related higher brain FW were associated with lower executive function and higher serum B-type natriuretic peptide (p < 0.05, Holm-Bonferroni corrected). These findings may have implications for anti-ageing preventive strategies targeting cardiac and cerebral vascular functions to improve heart and brain outcomes.

DDParcel: Deep Learning Anatomical Brain Parcellation From Diffusion MRI.

Parcellation of anatomically segregated cortical and subcortical brain regions is required in diffusion MRI (dMRI) analysis for region-specific quantification and better anatomical specificity of tractography. Most current dMRI parcellation approaches compute the parcellation from anatomical MRI (T1- or T2-weighted) data, using tools such as FreeSurfer or CAT12, and then register it to the diffusion space. However, the registration is challenging due to image distortions and low resolution of dMRI data, often resulting in mislabeling in the derived brain parcellation. Furthermore, these approaches are not applicable when anatomical MRI data is unavailable. As an alternative we developed the Deep Diffusion Parcellation (DDParcel), a deep learning method for fast and accurate parcellation of brain anatomical regions directly from dMRI data. The input to DDParcel are dMRI parameter maps and the output are labels for 101 anatomical regions corresponding to the FreeSurfer Desikan-Killiany (DK) parcellation. A multi-level fusion network leverages complementary information in the different input maps, at three network levels: input, intermediate layer, and output. DDParcel learns the registration of diffusion features to anatomical MRI from the high-quality Human Connectome Project data. Then, to predict brain parcellation for a new subject, the DDParcel network no longer requires anatomical MRI data but only the dMRI data. Comparing DDParcel's parcellation with T1w-based parcellation shows higher test-retest reproducibility and a higher regional homogeneity, while requiring much less computational time. Generalizability is demonstrated on a range of populations and dMRI acquisition protocols. Utility of DDParcel's parcellation is demonstrated on tractography analysis for fiber tract identification.

Characterization of Vasogenic and Cytotoxic Brain Edema Formation After Experimental Traumatic Brain Injury by Free Water Diffusion Magnetic Resonance Imaging.

Brain edema formation is a key factor for secondary tissue damage after traumatic brain injury (TBI), however, the type of brain edema and the temporal profile of edema formation are still unclear. We performed free water imaging, a bi-tensor model based diffusion MRI analysis, to characterize vasogenic brain edema (VBE) and cytotoxic edema (CBE) formation up to 7 days after experimental TBI. Male C57/Bl6 mice were subjected to controlled cortical impact (CCI) or sham surgery and investigated by MRI 4h, 1, 2, 3, 5, and 7 days thereafter (n = 8/group). We determined mean diffusivity (MD) and free water (FW) in contusion, pericontusional area, ipsi- and contralateral brain tissue. Free (i.e., non-restricted) water was interpreted as VBE, restricted water as CBE. To verify the results, VBE formation was investigated by in-vivo 2-Photon Microscopy (2-PM) 48h after surgery. We found that MD and FW values decreased for 48h within the contusion, indicating the occurrence of CBE. In pericontusional tissue, MD and FW indices were increased at all time points, suggesting the formation of VBE. This was consistent with our results obtained by 2-PM. Taken together, CBE formation occurs for 48h after trauma and is restricted to the contusion, while VBE forms in pericontusional tissue up to 7 days after TBI. Our results indicate that free water magnetic resonance imaging may represent a promising tool to investigate vasogenic and cytotoxic brain edema in the laboratory and in patients.

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS.

AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSIONS: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.

Implications of fitting a two-compartment model in single-shell diffusion MRI.

It is becoming increasingly common for studies to fit single-shell diffusion MRI data to a two-compartment model, which comprises a hindered cellular compartment and a freely diffusing isotropic compartment. These studies consistently find that the fraction of the isotropic compartment (f) is sensitive to white matter (WM) conditions and pathologies, although the actual biological source of changes infhas not been validated. In this work we put aside the biological interpretation offand study the sensitivity implications of fitting single-shell data to a two-compartment model. We identify a nonlinear transformation between the one-compartment model (diffusion tensor imaging, DTI) and a two-compartment model in which the mean diffusivities of both compartments are effectively fixed. While the analytic relationship implies that fitting this two-compartment model does not offer any more information than DTI, it explains why metrics derived from a two-compartment model can exhibit enhanced sensitivity over DTI to certain types of WM processes, such as age-related WM differences. The sensitivity enhancement should not be viewed as a substitute for acquiring multi-shell data. Rather, the results of this study provide insight into the consequences of choosing a two-compartment model when only single-shell data is available.

Microstructural Cortical Gray Matter Changes Preceding Accelerated Volume Changes in Individuals at Clinical High Risk for Psychosis.

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is thought to result from an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate is crucial, as volume reduction likely indicates an underlying neurodegenerative process. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the 33 individuals at CHR who developed psychosis (CHR-P) from the 127 individuals at CHR who did not (CHR-NP). At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in most brain areas, the CHR-P group demonstrated significantly accelerated iFW increase and volume reduction with time than the CHR-NP group. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes are thus an early pathology at the prodromal stage of psychosis that may be useful for early detection and a better mechanistic understanding of psychosis development.

Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary.

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

Mapping acute neuroinflammation in vivo with diffusion-MRI in rats given a systemic lipopolysaccharide challenge.

It is becoming increasingly apparent that neuroinflammation plays a critical role in an array of neurological and psychiatric disorders. Recent studies have demonstrated the potential of diffusion MRI (dMRI) to characterize changes in microglial density and morphology associated with neuroinflammation, but these were conducted mostly ex vivo and/or in extreme, non-physiological animal models. Here, we build upon these studies by investigating the utility of well-established dMRI methods to detect neuroinflammation in vivo in a more clinically relevant animal model of sickness behavior. We show that diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) indicate widespread increases in diffusivity in the brains of rats given a systemic lipopolysaccharide challenge (n = 20) vs. vehicle-treated controls (n = 12). These diffusivity changes correlated with histologically measured changes in microglial morphology, confirming the sensitivity of dMRI to neuroinflammatory processes. This study marks a further step towards establishing a noninvasive indicator of neuroinflammation, which would greatly facilitate early diagnosis and treatment monitoring in various neurological and psychiatric diseases.

Altered microstructure of the contralesional ventral premotor cortex and motor output after stroke.

Cortical thickness analyses have provided valuable insights into changes in cortical brain structure after stroke and their association with recovery. Across studies though, relationships between cortical structure and function show inconsistent results. Recent developments in diffusion-weighted imaging of the cortex have paved the way to uncover hidden aspects of stroke-related alterations in cortical microstructure, going beyond cortical thickness as a surrogate for cortical macrostructure. We re-analysed clinical and imaging data of 42 well-recovered chronic stroke patients from 2 independent cohorts (mean age 64 years, 4 left-handed, 71% male, 16 right-sided strokes) and 33 healthy controls of similar age and gender. Cortical fractional anisotropy and cortical thickness values were obtained for six key sensorimotor areas of the contralesional hemisphere. The regions included the primary motor cortex, dorsal and ventral premotor cortex, supplementary and pre-supplementary motor areas, and primary somatosensory cortex. Linear models were estimated for group comparisons between patients and controls and for correlations between cortical fractional anisotropy and cortical thickness and clinical scores. Compared with controls, stroke patients exhibited a reduction in fractional anisotropy in the contralesional ventral premotor cortex (P = 0.005). Fractional anisotropy of the other regions and cortical thickness did not show a comparable group difference. Higher fractional anisotropy of the ventral premotor cortex, but not cortical thickness, was positively associated with residual grip force in the stroke patients. These data provide novel evidence that the contralesional ventral premotor cortex might constitute a key sensorimotor area particularly susceptible to stroke-related alterations in cortical microstructure as measured by diffusion MRI and they suggest a link between these changes and residual motor output after stroke.

Impacts of spaceflight experience on human brain structure.

Spaceflight induces widespread changes in human brain morphology. It is unclear if these brain changes differ with varying mission duration or spaceflight experience history (i.e., novice or experienced, number of prior missions, time between missions). Here we addressed this issue by quantifying regional voxelwise changes in brain gray matter volume, white matter microstructure, extracellular free water (FW) distribution, and ventricular volume from pre- to post-flight in a sample of 30 astronauts. We found that longer missions were associated with greater expansion of the right lateral and third ventricles, with the majority of expansion occurring during the first 6 months in space then appearing to taper off for longer missions. Longer inter-mission intervals were associated with greater expansion of the ventricles following flight; crew with less than 3 years of time to recover between successive flights showed little to no enlargement of the lateral and third ventricles. These findings demonstrate that ventricle expansion continues with spaceflight with increasing mission duration, and inter-mission intervals less than 3 years may not allow sufficient time for the ventricles to fully recover their compensatory capacity. These findings illustrate some potential plateaus in and boundaries of human brain changes with spaceflight.

Microstructural changes precede depression in patients with relapsing-remitting Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis lesions in the brain and spinal cord can lead to different symptoms, including cognitive and mood changes. In this study we explore the temporal relationship between early microstructural changes in subcortical volumes and cognitive and emotional function in a longitudinal cohort study of patients with relapsing-remitting Multiple Sclerosis. METHODS: In vivo imaging in forty-six patients with relapsing-remitting Multiple Sclerosis was performed annually over 3 years magnetic resonance imaging. Microstructural changes were estimated in subcortical structures using the free water fraction, a diffusion-based MRI metric. In parallel, patients were assessed with the Hospital Anxiety and Depression Scale amongst other tests. Predictive structural equation modeling was set up to further explore the relationship between imaging and the assessment scores. In a general linear model analysis, the cohort was split into patients with higher and lower depression scores. RESULTS: Nearly all subcortical diffusion microstructure estimates at the baseline visit correlate with the depression score at the 2 years follow-up. The predictive nature of baseline free water estimates and depression subscores after 2 years are confirmed in the predictive structural equation modeling analysis with the thalamus showing the greatest effect size. The general linear model analysis shows patterns of MRI free water differences in the thalamus and amygdala/hippocampus area between participants with high and low depression score. CONCLUSIONS: Our data suggests a relationship between higher levels of free-water in the subcortical structures in an early stage of Multiple Sclerosis and depression symptoms at a later stage of the disease.

Signals between the brain and spinal cord are disrupted in people with Multiple Sclerosis. For those with relapsing-remitting Multiple Sclerosis (RRMS), symptoms get periodically better and worse over time. We looked at whether changes in the brain of people with RRMS were associated with changes in their mood over time. People who had more changes in certain areas of the brain at the start of the study were more likely to have symptoms of depression later. This work suggests that early changes in the brain may be linked to increased symptoms of depression over time in people with RRMS. We believe this could be an opportunity to provide care to those suffering from RRMS to lessen the impact of severe depression symptoms before they arise.

Associations of Blood Cardiovascular Biomarkers With Brain Free Water and Its Relationship to Cognitive Decline: A Diffusion-MRI Study.

BACKGROUND AND OBJECTIVES: There is an increasing awareness of the "Heart-Brain Connection," whereby cardiovascular function is connected with cognition. Diffusion-MRI studies reported higher brain free water (FW) was associated with cerebrovascular disease (CeVD) and cognitive impairment. In this study, we investigated whether higher brain FW was related to blood cardiovascular biomarkers and whether FW mediated the associations between blood biomarkers and cognition. METHODS: Participants recruited from 2 Singapore memory clinics between 2010 and 2015 underwent collection of blood samples and neuroimaging at baseline and longitudinal neuropsychological assessments up to 5 years. We examined the associations of blood cardiovascular biomarkers (high-sensitivity cardiac troponin-T [hs-cTnT], N-terminal pro-hormone B-type natriuretic peptide [NT-proBNP], and growth/differentiation factor 15 [GDF-15]) with brain white matter (WM) and cortical gray matter (GM) FW derived from diffusion MRI using whole brain voxel-wise general linear regression. We then assessed the relationships among baseline blood biomarkers, brain FW, and cognitive decline using path models. RESULTS: A total of 308 older adults (76 with no cognitive impairment, 134 with cognitive impairment no dementia, and 98 with Alzheimer disease dementia and vascular dementia; mean [SD] age: 72.1 [8.3]) were included. We found that blood cardiovascular biomarkers were associated with higher FW in widespread WM regions and in specific GM networks including the default mode, executive control, and somatomotor networks at baseline (p < 0.01, family-wise error corrected). Baseline FW in widespread WM and network-specific GM fully mediated the associations of blood biomarkers with longitudinal cognitive decline over 5 years. Specifically, in GM, higher FW in the default mode network mediated the relationship with memory decline (hs-cTnT: ß = -0.115, SE = 0.034, p = 0.001; NT-proBNP: ß = -0.154, SE = 0.046, p = 0.001; GDF-15: ß = -0.073, SE = 0.027, p = 0.006); by contrast, higher FW in the executive control network was responsible for executive function decline (hs-cTnT: ß = -0.126, SE = 0.039, p = 0.001; NT-proBNP: ß = -0.110, SE = 0.038, p = 0.004; GDF-15: ß = -0.117, SE = 0.035, p = 0.001). Similar full mediation effects of brain FW were also identified for baseline cognition. DISCUSSION: Results suggested a role of brain FW in linking cardiovascular dysfunction to cognitive decline. These findings provide new evidence for brain-heart interactions, paving the way for prediction and monitoring of domain-specific cognitive trajectory.

Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection.

As severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections have been shown to affect the central nervous system, the investigation of associated alterations of brain structure and neuropsychological sequelae is crucial to help address future health care needs. Therefore, we performed a comprehensive neuroimaging and neuropsychological assessment of 223 nonvaccinated individuals recovered from a mild to moderate SARS-CoV-2 infection (100 female/123 male, age [years], mean ± SD, 55.54 ± 7.07; median 9.7 mo after infection) in comparison with 223 matched controls (93 female/130 male, 55.74 ± 6.60) within the framework of the Hamburg City Health Study. Primary study outcomes were advanced diffusion MRI measures of white matter microstructure, cortical thickness, white matter hyperintensity load, and neuropsychological test scores. Among all 11 MRI markers tested, significant differences were found in global measures of mean diffusivity (MD) and extracellular free water which were elevated in the white matter of post-SARS-CoV-2 individuals compared to matched controls (free water: 0.148 ± 0.018 vs. 0.142 ± 0.017, P < 0.001; MD [10-3 mm2/s]: 0.747 ± 0.021 vs. 0.740 ± 0.020, P < 0.001). Group classification accuracy based on diffusion imaging markers was up to 80%. Neuropsychological test scores did not significantly differ between groups. Collectively, our findings suggest that subtle changes in white matter extracellular water content last beyond the acute infection with SARS-CoV-2. However, in our sample, a mild to moderate SARS-CoV-2 infection was not associated with neuropsychological deficits, significant changes in cortical structure, or vascular lesions several months after recovery. External validation of our findings and longitudinal follow-up investigations are needed.