Gray Matter Areas Research Articles

SKELETAL MUSCLE MITOCHONDRIAL FUNCTION AND LONGITUDINAL CHANGES IN BRAIN STRUCTURE

Abstract Mitochondrial dysfunction, a hallmark of aging, has been associated with future cognitive impairment or dementia, as well as PET and blood biomarkers of Alzheimer’s disease and neurodegeneration. Whether mitochondrial dysfunction is associated with accelerated loss in brain volumes and microstructural integrity is unknown. We tested the longitudinal association between in vivo muscle mitochondrial oxidative capacity assessed via MR spectroscopy (post-exercise recovery rate of phosphocreatine, kPCr) and changes in brain MRI volumes and DTI microstructure over up to 12 years of follow-up in the Baltimore Longitudinal Study of Aging (2008-2020). In linear mixed effects models, adjusted for demographics, PCr deletion, and physical activity, higher kPCr was associated with less ventricular enlargement, less worsening in MRI-derived brain aging and Alzheimer’s disease scores, and less regional atrophy, especially the primary sensorimotor cortex, temporal white and gray matter, thalamus, occipital areas, cingulate cortex, and cerebellum (n=649). Higher kPCr was also associated with less microstructural integrity loss in white matter tracts connecting identified gray matter areas (n=598). Specific white matter tracts, including splenium of the corpus callosum and superior longitudinal fasciculus showed consistent longitudinal associations in radial diffusivity, but not axial diffusivity, which may indicate demyelination. Higher in vivo mitochondrial function is associated with less worsening in MRI-derived brain aging and Alzheimer’s disease scores, less brain atrophy in specific gray matter regions and less microstructural integrity loss in connecting white matter tracts. Future studies are warranted to investigate the role of CNS mitochondrial function in brain aging and neurodegeneration.

Early diagnosis of Alzheimer’s disease and mild cognitive impairment using MRI analysis and machine learning algorithms

Early diagnosis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) is crucial to prevent their progression. In this study, we proposed the analysis of magnetic resonance imaging (MRI) based on features including; hippocampus (HC) area size, HC grayscale statistics and texture features (mean, standard deviation, skewness, kurtosis, contrast, correlation, energy, homogeneity, entropy), lateral ventricle (LV) area size, gray matter area size, white matter area size, cerebrospinal fluid area size, patient age, weight, and cognitive score. Five machine learning classifiers; K-nearest neighborhood (KNN), support vector machine (SVM), random forest (RF), decision tree (DT), and multi-layer perception (MLP) were used to distinguish between groups: cognitively normal (CN) vs AD, early MCI (EMCI) vs late MCI (LMCI), CN vs EMCI, CN vs LMCI, AD vs EMCI, and AD vs LMCI. Additionally, the correlation and dependence were calculated to examine the strength and direction of association between each extracted feature and each classification of the group. The average classification accuracies in 20 trials were 95% (SVM), 71.50% (RF), 82.58% (RF), 84.91% (SVM), 85.83% (RF), and 85.08% (RF), respectively, with the best accuracies being 100% (SVM, RF, and MLP), 83.33% (RF), 91.66% (RF), 95% (SVM, and MLP), 96.66% (RF), and 93.33% (DT). Cognitive scores, HC and LV area sizes, and HC texture features demonstrated significant potential for diagnosing AD and its subtypes for all groups. RF and SVM showed better performance in distinguishing between groups. These findings highlight the importance of using 2D-MRI to identify key features containing critical information for early diagnosis of AD.

Genotype and corticosteroid treatment are distinctively associated with gray matter characteristics in patients with Duchenne muscular dystrophy

This study investigated if structural variation in specific gray matter areas is associated with corticosteroid treatment or genotype, and if cerebral morphological variations are related to neuropsychological and behavioral outcomes.The CAT12 toolbox in SPM was used for MRI segmentations, assessing subcortical structures, cortical thickness, gyrification, and sulci depths for DMD patients (n=40; 9-18 years) and age-matched controls (n=40). Comparisons were made between DMD vs. controls, daily vs. intermittent corticosteroid treatment (n=20 each), and Dp140+ vs. Dp140- gene mutations (n=15 vs. 25). MANCOVA, CAT12 3D statistics and Pearson correlations were conducted.DMD patients showed differences in volumes of distinct subcortical structures, left hemisphere cortical thickness, and gyrification in multiple brain areas compared with healthy controls. The daily treated DMD group exhibited differences in subcortical volumes and different patterns of cortical thickness, sulci depth, and gyrification compared to the intermittent treated DMD group. DMD Dp140+ patients displayed altered gyrification and sulci depth compared to DMD Dp140- patients. Finally, we found correlations between neurobehavioral outcomes and brain areas that showed differences in cortical morphology associated with corticosteroid treatment.Both genotype and corticosteroid treatment are associated with variations in subcortical volumes and cortical morphology, albeit in different ways. Corticosteroid treatment appears to have a more profound association with differences in gray matter characteristics of brain regions that are associated with functional outcomes.

Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease

Some specific lipid molecules in the brain act as signaling molecules, neurotransmitters, or neuromodulators, by binding to specific G protein-coupled receptors (GPCR) for neurolipids. One such receptor, sphingosine 1-phosphate receptor subtype 1 (S1P1), is coupled to Gi/o proteins and is involved in cell proliferation, growth, and neuroprotection. S1P1 constitutes an interesting target for neurodegenerative diseases like multiple sclerosis and Alzheimer's disease (AD), in which changes in the sphingolipid metabolism have been observed. This study analyzes S1P1 receptor-mediated activity in healthy brains and during AD progression using postmortem samples from controls and patients at different Braak's stages. Additionally, the distribution of S1P1 receptor activity in human brains is compared to that in commonly used rodent models, rats and mice, through functional autoradiography, measuring [35S]GTPγS binding stimulated by the S1P1 receptor selective agonist CYM-5442 to obtain the distribution of functional activity of S1P1 receptors.S1P1 receptor-mediated activity, along with that of the cannabinoid CB1 receptor, is one of the highest recorded for any GPCR in many gray matter areas of the brain, reaching maximum values in the cerebellar cortex, specific areas of the hippocampus and the basal forebrain. S1P1 signaling is crucial in areas that regulate learning, memory, motor control, and nociception, such as the basal forebrain and basal ganglia. In AD, S1P1 receptor activity is increased in the inner layers of the frontal cortex and underlying cortical white matter at early stages, but decreases in the hippocampus in advanced stages, indicating ongoing brain impairment. Importantly, we identified significant correlations between S1P1 receptor activity and Braak stages, suggesting that S1P1 receptor dysfunction is associated to disease progression, particularly in memory-related regions. The S1P signaling via S1P1 receptor is a promising neurological target due to its role in key neurophysiological functions and its potential to modify the progression of neurodegenerative diseases. Finally, rats are suggested as a preferred experimental model for studying S1P1 receptor-mediated responses in the human brain.

Neurotropic Murine β-Coronavirus Infection Causes Differential Expression of Connexin 47 in Oligodendrocyte Subpopulations Associated with Demyelination.

Gap junctions (GJs) play a crucial role in the survival of oligodendrocytes and myelination of the central nervous system (CNS). In this study, we investigated the spatiotemporal changes in the expression of oligodendroglial GJ protein connexin 47 (Cx47), its primary astroglial coupling partner, Cx43, and their association with demyelination following intracerebral infection with mouse hepatitis virus (MHV). Neurotropic strains of MHV, a β-coronavirus, induce an acute encephalomyelitis followed by a chronic demyelinating disease that shares similarities with the human disease multiple sclerosis (MS). Our results reveal that Cx47 GJs are persistently lost in mature oligodendrocytes, not only in demyelinating lesions but also in surrounding normal appearing white and gray matter areas, following an initial loss of astroglial Cx43 GJs during acute infection. At later stages after viral clearance, astroglial Cx43 GJs re-emerge but mature oligodendrocytes fail to fully re-establish GJs with astrocytes due to lack of Cx47 GJ expression. In contrast, at this later demyelinating stage, the increased oligodendrocyte precursor cells appear to exhibit Cx47 GJs. Our findings further highlight varying degrees of demyelination in distinct spinal cord regions, with the thoracic cord showing the most pronounced demyelination. The regional difference in demyelination correlates well with dynamic changes in the proportion of different oligodendrocyte lineage cells exhibiting differential Cx47 GJ expression, suggesting an important mechanism of progressive demyelination even after viral clearance.

Transcallosal white matter and cortical gray matter variations in autistic adults ages 30-73 years: A bi-tensor free water imaging approach.

Background: Autism spectrum disorder (ASD) has long been recognized as a lifelong condition, but brain aging studies in autistic adults aged >30 years are limited. Free water, a novel brain imaging marker derived from diffusion MRI (dMRI), has shown promise in differentiating typical and pathological aging and monitoring brain degeneration. We aimed to examine free water and free water corrected dMRI measures to assess white and gray matter microstructure and their associations with age in autistic adults. Methods: Forty-three autistic adults ages 30-73 years and 43 age, sex, and IQ matched neurotypical controls participated in this cross-sectional study. We quantified fractional anisotropy (FA), free water, and free water-corrected FA (fwcFA) across 32 transcallosal white matter tracts and 94 gray matter areas in autistic adults and neurotypical controls. Follow-up analyses assessed age effect on dMRI metrics of the whole brain for both groups and the relationship between dMRI metrics and clinical measures of ASD in regions that significantly differentiated autistic adults from controls. Results: We found globally elevated free water in 24 transcallosal tracts in autistic adults. We identified negligible differences in dMRI metrics in gray matter between the two groups. Age-associated FA reductions and free water increases were featured in neurotypical controls; however, this brain aging profile was largely absent in autistic adults. Additionally, greater autism quotient (AQ) total raw score was associated with increased free water in the inferior frontal gyrus pars orbitalis and lateral orbital gyrus in autistic adults. Limitations: All autistic adults were cognitively capable individuals, minimizing the generalizability of the research findings across the spectrum. This study also involved a cross-sectional design, which limited inferences about the longitudinal microstructural changes of white and gray matter in ASD. Conclusions: We identified differential microstructural configurations between white and gray matter in autistic adults and that autistic individuals present more heterogeneous brain aging profiles compared to controls. Our clinical correlation analysis offered new evidence that elevated free water in some localized white matter tracts may critically contribute to autistic traits in ASD. Our findings underscored the importance of quantifying free water in dMRI studies of ASD.

Ferritin is closely associated with microglia in amyotrophic lateral sclerosis.

Iron deposition is a hallmark of amyotrophic lateral sclerosis (ALS) and has been strongly implicated in its pathogenesis. As a byproduct of cellular oxidative stress, iron dysregulation modifies basal levels of the regulatory iron-binding protein ferritin. Examination of thoracic and lumbar spinal cord tissues found increased ferritin immunostaining in white matter axons that corresponded to areas of increased microgliosis in 8 ALS patients versus 8 normal subjects. Gray matter areas containing the motor neurons also demonstrated increased ferritin and microglia in ALS compared to controls but at lower levels than in the white matter. Motor neurons with or without TDP-43 inclusions did not demonstrate either increased ferritin or associated microglial activation. We also observed an association of ferritin with microglia in cerebral cortical tissue samples of ALS cases and in the spinal cord tissues of transgenic mice expressing the SOD1G93A mutation. Elevated ferritin levels were detected in the insoluble fraction from spinal cord tissues of individuals with ALS. These findings suggest that activated microglia and increased ferritin may play significant roles in ALS progression since they are found closely associated in areas of axonal and cortical degeneration.

Neuroprotective Effects of Inhaled Xenon Gas on Brain Structural Gray Matter Changes After Out-of-Hospital Cardiac Arrest Evaluated by Morphometric Analysis: A Substudy of the Randomized Xe-Hypotheca Trial.

We have earlier reported that inhaled xenon combined with hypothermia attenuates brain white matter injury in comatose survivors of out-of-hospital cardiac arrest (OHCA). A predefined secondary objective was to assess the effect of inhaled xenon on the structural changes in gray matter in comatose survivors after OHCA. Patients were randomly assigned to receive either inhaled xenon combined with target temperature management (33°C) for 24h (n = 55, xenon group) or target temperature management alone (n = 55, control group). A change of brain gray matter volume was assessed with a voxel-based morphometry evaluation of high-resolution structural brain magnetic resonance imaging (MRI) data with Statistical Parametric Mapping. Patients were scheduled to undergo the first MRI between 36 and 52h and a second MRI 10days after OHCA. Of the 110 randomly assigned patients in the Xe-Hypotheca trial, 66 patients completed both MRI scans. After all imaging-based exclusions, 21 patients in the control group and 24 patients in the xenon group had both scan 1 and scan 2 available for analyses with scans that fulfilled the quality criteria. Compared with the xenon group, the control group had a significant decrease in brain gray matter volume in several clusters in the second scan compared with the first. In a between-group analysis, significant reductions were found in the right amygdala/entorhinal cortex (p = 0.025), left amygdala (p = 0.043), left middle temporal gyrus (p = 0.042), left inferior temporal gyrus (p = 0.008), left parahippocampal gyrus (p = 0.042), left temporal pole (p = 0.042), and left cerebellar cortex (p = 0.005). In the remaining gray matter areas, there were no significant changes between the groups. In comatose survivors of OHCA, inhaled xenon combined with targeted temperature management preserved gray matter better than hypothermia alone. ClinicalTrials.gov: NCT00879892.

Depersonalization-Derealization Disorder: Etiological Mechanism, Diagnosis and Management

This comprehensive review delves into the complexities surrounding Depersonalization-Derealization disorder (DPDR), a dissociative disorder characterized by enduring feelings of detachment from one's self and surroundings. Tracing its historical roots back to 19th-century descriptions and its current classification as a singular disorder, the review meticulously explores the clinical presentation, epidemiology, etiology, diagnosis, and management of DPDR. Despite many trials and studies conducted the exact cause of this condition is still unknown. The best way to understand its etiology is by taking into account its clinical presentations and linking it to different structural and functional alterations of the brain. Alteration in cortical activity and structure associated with white matter, gray matter, caudate nucleus, amygdala, and other areas like Broadman’s areas of cortex are analyzed to be potential mechanisms for etiology. With a concerning rise in its prevalence globally and notable impact on adolescents and young adults, DPDR manifests through a spectrum of symptoms including depersonalization, and derealization, and often accompanies comorbidities such as anxiety and depression. While the precise cause remains elusive, factors such as traumatic experiences, stress, and genetic predispositions have been implicated, with modern neuroimaging studies offering insight into potential structural and functional brain alterations. Managing DPDR necessitates a multifaceted approach integrating psychotherapy, pharmacotherapy, and lifestyle interventions, with cognitive-behavioral therapy (CBT) and pharmacological agents like SSRIs and SNRIs emerging as primary interventions. The importance of early detection and intervention is crucial for improving its prognosis. Unfortunately, DPDR is highly understudied to date. Due to a scarcity of scientific literature about DPDR in recent years, it has become very challenging to get a proper in-depth understanding of this. Therefore, this review serves as an all-in-one source to get information about DPDR ranging from etiology to its management strategies.

Integrated Spatial Multi-Omics Study of Postmortem Brains of Alzheimer's Disease.

Pathological hallmark of Alzheimer's disease (AD) is characterized by the accumulation and aggregation of amyloid β (Aβ) peptides into extracellular plaques of the brain. Clarification of the process of how soluble Aβ starts to assemble into amyloid fibrils is an essential step in elucidating the pathogenesis of AD. In our previous study, Aβ proteoforms including full-length Aβ40 and Aβ42/43 with N- and C-terminal truncated forms were visualized in postmortem brains from AD patients with matrix-assisted laser desorption/ionization-based mass spectrometry imaging (MALDI-MSI). In this study, Aβ proteoforms were consistently visualized by an updated protocol, and uncharacterized peptides such as Aβ1-29 and Aβ10-40 in AD brains were also visualized. To decipher neurotoxic effects of Aβ in patients' brains, here we integrate liquid chromatography tandem mass spectrometry (LC-MS/MS) based shotgun proteomics with laser microdissection (LMD) excised tissue samples as well as direct tissue imaging with MALDI-MSI. With this approach, we have highlighted dynamic alterations of microtubule associating proteins (MAPs) including MAP1A, MAP1B and MAP2 as well as AD dominant proteins including APP, UCHL1, SNCA, and APOE. Of note, as lipid dysregulation has been implicated with AD pathology, we have challenged to integrate proteomics and lipid imaging for AD and control brain tissue. Spatial multi-omics is also valid to uncover molecular pathology of white matter as well as grey matter and leptomeningeal area, for example, by visualizing heme in patients' postmortem brains.

N-butyl-β-carboline-3-carboxylate (β-CCB) systemic administration promotes remyelination in the cuprizone demyelinating model in mice

Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAAR expressed in oligodendroglia is strongly potentiated by n-butyl-β-carboline-3-carboxylate (β-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then β-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that β-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2+ and a decrease in CC1+ cell populations, alterations that were importantly retrieved by β-CCB treatment. Thus, the promyelinating character of β-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug.

Clinical and Brain Morphometry Predictors of Deep Brain Stimulation Outcome in Parkinson’s Disease

Subthalamic deep brain stimulation (STN-DBS) is known to improve motor function in advanced Parkinson’s disease (PD) and to enable a reduction of anti-parkinsonian medication. While the levodopa challenge test and disease duration are considered good predictors of STN-DBS outcome, other clinical and neuroanatomical predictors are less established. This study aimed to evaluate, in addition to clinical predictors, the effect of patients’ individual brain topography on DBS outcome. The medical records of 35 PD patients were used to analyze DBS outcomes measured with the following scales: Part III of the Unified Parkinson’s Disease Rating Scale (UPDRS-III) off medication at baseline, and at 6-months during medication off and stimulation on, use of anti-parkinsonian medication (LED), Abnormal Involuntary Movement Scale (AIMS) and Non-Motor Symptoms Questionnaire (NMS-Quest). Furthermore, preoperative brain MRI images were utilized to analyze the brain morphology in relation to STN-DBS outcome. With STN-DBS, a 44% reduction in the UPDRS-III score and a 43% decrease in the LED were observed (p<0.001). Dyskinesia and non-motor symptoms decreased significantly [median reductions of 78,6% (IQR 45,5%) and 18,4% (IQR 32,2%) respectively, p=0.001 – 0.047]. Along with the levodopa challenge test, patients’ age correlated with the observed DBS outcome measured as UPDRS-III improvement (ρ= -0.466 – -0.521, p<0.005). Patients with greater LED decline had lower grey matter volumes in left superior medial frontal gyrus, in supplementary motor area and cingulum bilaterally. Additionally, patients with greater UPDRS-III score improvement had lower grey matter volume in similar grey matter areas. These findings remained significant when adjusted for sex, age, baseline LED and UPDRS scores respectively and for total intracranial volume (p=0.0041- 0.001). However, only the LED decrease finding remained significant when the analyses were further controlled for stimulation amplitude. It appears that along with the clinical predictors of STN-DBS outcome, individual patient topographic differences may influence DBS outcome. Clinical Trial Registration Number: NCT06095245, registration date October 23, 2023, retrospectively registered

Cervical and thoracic spinal cord gray matter atrophy is associated with disability in patients with amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS), there is an unmet need for more precise patient characterization through quantitative, ideally operator-independent, assessments of disease extent and severity. Radially sampled averaged magnetization inversion recovery acquisitions (rAMIRA) magnetic resonance imaging enables gray matter (GM) and white matter (WM) area quantitation in the cervical and thoracic spinal cord (SC) with optimized contrast. We aimed to investigate rAMIRA-derived SC GM and SC WM areas and their association with clinical phenotype and disability in ALS. A total of 36 patients with ALS (mean [SD] age 61.7 [12.6] years, 14 women) and 36 healthy, age- and sex-matched controls (HCs; mean [SD] age 63.1 [12.1] years, 14 women) underwent two-dimensional axial rAMIRA imaging at the inter-vertebral disc levels C2/3-C5/C6 and the lumbar enlargement level Tmax. ALS Functional Rating Scale-revised (ALSFRS-R) score, muscle strength, and sniff nasal inspiratory pressure (SNIP) were assessed. Compared to HCs, GM and WM areas were reduced in patients at all cervical levels (p < 0.0001). GM area (p = 0.0001), but not WM area, was reduced at Tmax. Patients with King's Stage 3 showed significant GM atrophy at all levels, while patients with King's Stage 1 showed significant GM atrophy selectively at Tmax. SC GM area was significantly associated with muscle force at corresponding myotomes. GM area at C3/C4 was associated with ALSFRS-R (p < 0.001) and SNIP (p = 0.0016). Patients with ALS assessed by rAMIRA imaging show significant cervical and thoracic SC GM and SC WM atrophy. SC GM area correlates with muscle strength and clinical disability. GM area reduction at Tmax may be an early disease sign. Longitudinal studies are warranted.

Neurodegeneration within the rostral spinal cord is associated with brain gray matter volume atrophy in the early stage of cervical spondylotic myelopathy.

Case-control study. Investigating the association between neurodegeneration within rostral spinal cord and brain gray matter volume (GMV) and assessing the relationship between remote neurodegenerative changes and clinical outcomes at the early phase of Cervical Spondylotic Myelopathy (CSM). University/hospital. Using Spinal Cord Toolbox, spinal cord morphometrics (cross-sectional area [CSA], gray matter area [GMA], white matter area [WMA]) of 40 patients with CSM and 28 healthy controls (HCs) were computed and compared using two-sample t test. Brain GMV of the two groups was analyzed using voxel-based morphometry approach. Pearson's correlation between spinal cord morphometrics and altered brain GMV and Spearman's relationship between remote neurodegenerations and clinical outcomes were conducted in CSM group. Compared to HCs, CSA and WMA at C2/3 and GMV in right postcentral gyrus (PoCG.R) and left supplementary motor area (SMA.L) were significantly decreased in patients with CSM. CSA and WMA at C2/3 were associated with GMV in SMA.L and MCG.R in patients with CSM. CSA at C2/3 and GMV in PoCG.R were related to modified Japanese Orthopedic Association score in patients with CSM. The associations between CSA and WMA at C2/3 and GMV in SMA.L and MCG.R suggest a concordant change pattern and adaptive mechanisms for neuronal plasticity underlying remote neurodegeneration in early CSM. The atrophy of CSA at C2/3 and GMV loss in PoCG.R can serve as potential neuroimaging biomarkers of early structural changes within spinal cord and brain preceding marked clinical disabilities in patients with CSM.

Are there any differences at gray matter sites between severe obstructive sleep apnea patients and healthy controls?

ObjectivesObstructive sleep apnea (OSA) is a disease that may cause many medical conditions. Neurocognitive disorders may be triggered by OSA. In recent studies, selectively decreased gray matter tissue was observed in patients with OSA. We aimed to determine if there was a substantial difference in patients with extreme OSA by comparing the microstructural changes in different gray matter sub-areas with healthy controls using diffusion-weighted imaging methods. MethodsWe studied 15 diagnosed severe OSA subjects before any treatment and 32 healthy control subjects. High resolution Magnetic Resonance Imaging (MRI) T1 and T2-weighted scans were visually examined to assess any major brain lesions. ResultsThere were no statistically significant differences of age and gender between the groups.The left and right globus pallidus, putamen and thalamus values did not differ significantly between OSA and control subjects. Right putamen values was negatively correlated with Apnea Hypopnea Index (AHI), supine AHI and non-REM AHI in OSA subjects, but no correlations appeared with left putamen values. The other gray matter parameters did not show any correlations with PSG parameters. AHI, Supine AHI, Non-Supine AHI, REM and NON-REM AHI values was not show any correlation with Right and Left Putamen volume sizes. ConclusionsWe made a morphological comparison of various gray matter areas of OSA patients and healthy volunteers in our study. We observed a significant decrease in right putamen gray matter volumes in patients with higher AHI values. Decreased cognitive functions are found in patients with OSA. In order to demonstrate this cognitive loss in patients with morphologically there is a need for further prospective studies with larger sample sizes.

The missing third dimension-Functional correlations of BOLD signals incorporating white matter.

Correlations between magnetic resonance imaging (MRI) blood oxygenation level-dependent (BOLD) signals from pairs of gray matter areas are used to infer their functional connectivity, but they are unable to describe how white matter is engaged in brain networks. Recently, evidence that BOLD signals in white matter are robustly detectable and are modulated by neural activities has accumulated. We introduce a three-way correlation between BOLD signals from pairs of gray matter volumes (nodes) and white matter bundles (edges) to define the communication connectivity through each white matter bundle. Using MRI images from publicly available databases, we show, for example, that the three-way connectivity is influenced by age. By integrating functional MRI signals from white matter as a third component in network analyses, more comprehensive descriptions of brain function may be obtained.

Vascular architecture mapping reveals sex-specific changes in cerebral microvasculature with aging

AbstractObjectives: Previous studies indicate region-specific age- and sex-related changes in cerebral microvasculature. Using whole-brain vascular architecture mapping (VAM), our objective was to map and assess these changes in human microvasculature in vivo.Materials and methods: Cardiovascular healthy women (n = 40) and men (n = 32) with unifocal low-grade glioma, matched for age [range: 20-70 years] and BMI, were examined on the non-tumor hemisphere with a combined spin and gradient echo echo-planar imaging sequence at 3 T MRI. Vessel vortex curves were obtained by pair-wise plotting changes in relaxation rates R2* and R2 during contrast agent bolus passage, which each generate a set of VAM parameters that characterize microvascular properties, such as vessel type, lumen size, or blood flow. Averaged VAM values of cortical grey matter, white matter, putamen, globus pallidus, caudate nucleus, thalamus, insular cortex, and hippocampus were assessed for age- and sex-related changes.Results: With age, dominant vessel types changed from capillaries to an arteriole-dominated profile, particularly in insula, thalamus, and globus pallidus. In white matter, blood flow velocity decreased significantly with aging for both sexes (r = −0.33, p = 0.004). In women, aging was associated with an increase in microvessel caliber, particularly in thalamus (r = 0.39, p = 0.01) and insula (r = 0.34, p = 0.03). In all grey matter areas, women had a higher microvessel density than men (4.33 ± 0.26ˑ102 ms-1/3 vs. 4.18 ± 0.26ˑ102 ms-1/3; p = 0.025, respectively).Conclusions: Aging affects microvasculature differently across brain regions in women and men, especially in thalamus and insula.

Developmental Regulation of Matrix Metalloproteinases in Response to Multifactorial, Severe Traumatic Brain Injuries during Immaturity

Introduction: A striking pattern in young children after severe TBI is when the entire cortical ribbon displays tissue damage: hemispheric hypodensity (HH). HH is often a result of abusive head trauma (AHT). We previously reported a model of HH in a gyrencephalic species where a combination of injuries consisting of (1) cortical impact, (2) midline shift, (3) subdural hematoma/subarachnoid hemorrhage, (4) traumatic seizures, and (5) brief apnea and hypoventilation resulted in extensive, hypoxic-ischemic-type injury. Importantly, this mechanism closely resembles that seen in children, with relative sparing of the contralateral cortex, thus ruling out a pure asphyxia mechanism. In this model, piglets of similar developmental stage to human toddlers (postnatal day 30, PND30) have extensive hypoxic-ischemic damage to the cortical ribbon with sparing of the contralateral hemisphere and deep gray matter areas. However, piglets of similar developmental stage to human infants (postnatal day 7, PND7) have less hypoxic-ischemic damage that is notably bilateral and patchy. We therefore sought to discover whether the extensive tissue damage observed in PND30 was due to a greater upregulation of matrix metalloproteinases (MMPs). Materials and Methods: In PND7 or PND30 piglets receiving AHT injuries (cortical impact, midline shift, subdural hematoma/subarachnoid hemorrhage, traumatic seizures, and brief apnea and hypoventilation) or a sham injury, the pattern of albumin extravasation and MMP-9 upregulation throughout the brain was determined via immunohistochemistry, brain tissue adjacent to the cortical impact where the tissue damage spreads was collected for Western blots, and the gelatinase activity was determined over time in peripheral plasma. EEG was recorded, and piglets survived up to 24 h after injury administration. Results: The pattern of albumin extravasation, indicating vasogenic edema, as well as increase in MMP-9, were both present at the same areas of hypoxic-ischemic tissue damage. Evidence from immunohistochemistry, Western blot, and zymogens demonstrate that MMP-2, -3, or -9 are constitutively expressed during immaturity and are not different between developmental stages; however, active forms are upregulated in PND30 but not PND7 after in response to AHT model injuries. Furthermore, peripheral active MMP-9 was downregulated after model injuries in PND7. Conclusions: This differential response to AHT model injuries might confer protection to the PND7 brain. Additionally, we find that immature gyrencephalic species have a greater baseline and array of MMPs than previously demonstrated in rodent species. Treatment with an oral or intravenous broad-spectrum matrix metalloproteinase inhibitor might reduce the extensive spread of injury in PND30, but the exposure to metalloproteinase inhibitors must be acute as to not interfere with the homeostatic role of matrix metalloproteinases in normal postnatal brain development and plasticity as well as post-injury synaptogenesis and tissue repair.

Anomia: Deciphering Functional Neuroanatomy in Primary Progressive Aphasia Variants.

Naming decline is one of the most common symptoms of primary progressive aphasia (PPA). Most studies on anomia in PPA are performed without taking into account PPA variants, especially for action naming. Only limited data are available for the neuroanatomical basis of anomia considering differences in the pathogenesis of PPAs. The aim of our study is to investigate the associations between anomia severity for both noun and verb naming and gray matter (GM) atrophy, as well as accompanying functional connectivity (FC) changes in three PPA variants. A total of 17 patients with non-fluent (nfvPPA), 11 with semantic (svPPA), and 9 with logopenic (lvPPA) PPA variants were included in the study and underwent cognitive/naming assessments and brain MRIs. Voxel-based morphometry was performed to evaluate GM volume. A resting-state functional MRI was applied to investigate FC changes in the identified GM areas. The study shows that different brain regions are involved in naming decline in each PPA variant with a predominantly temporal lobe involvement in svPPA, parietal lobe involvement in lvPPA, and frontal lobe involvement in nfvPPA. Separate data for object and action naming in PPA variants are provided. The obtained results mainly correspond to the current understanding of language processing and indicate that the evaluation of language impairments is preferable for each PPA variant separately. A further analysis of larger cohorts of patients is necessary to confirm these preliminary results.

Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner.

The main objectives were to test whether (1) a decrease in myelin is associated with enhanced rate of fibrillar tau accumulation and cognitive decline in Alzheimer's disease, and (2) whether apolipoprotein E (APOE) ε4 genotype is associated with worse myelin decrease and thus tau accumulation. To address our objectives, we repurposed florbetapir-PET as a marker of myelin in the white matter (WM) based on previous validation studies showing that beta-amyloid (Aβ) PET tracers bind to WM myelin. We assessed 43 Aβ-biomarker negative (Aβ-) cognitively normal participants and 108 Aβ+ participants within the AD spectrum with florbetapir-PET at baseline and longitudinal flortaucipir-PET as a measure of fibrillar tau (tau-PET) over ~ 2 years. In linear regression analyses, we tested florbetapir-PET in the whole WM and major fiber tracts as predictors of tau-PET accumulation in a priori defined regions of interest (ROIs) and fiber-tract projection areas. In mediation analyses we tested whether tau-PET accumulation mediates the effect of florbetapir-PET in the whole WM on cognition. Finally, we assessed the role of myelin alteration on the association between APOE and tau-PET accumulation. Lower florbetapir-PET in the whole WM or at a given fiber tract was predictive of faster tau-PET accumulation in Braak stages or the connected grey matter areas in Aβ+ participants. Faster tau-PET accumulation in higher cortical brain areas mediated the association between a decrease in florbetapir-PET in the WM and a faster rate of decline in global cognition and episodic memory. APOE ε4 genotype was associated with a worse decrease in the whole WM florbetapir-PET and thus enhanced tau-PET accumulation. Myelin alterations are associated in an APOE ε4 dependent manner with faster tau progression and cognitive decline, and may therefore play a role in the etiology of AD.