BackgroundTraumatic brain injury (TBI) is associated with increased dementia risk, yet its relationship to Alzheimer's disease (AD) neuropathology is unclear. Prior autopsy studies show inconsistent results, constrained by limited TBI ascertainment, semi-quantitative neuropathology methods, and selection bias.ObjectiveTo examine whether TBI with loss of consciousness (TBI-LOC) is associated with quantitative measures of tau and amyloid-β42 (Aβ42) pathology in a community-based autopsy cohort.MethodsThe analytic sample included 810 Adult Changes in Thought study brain donors with baseline TBI-LOC ascertainment and quantitative neuropathology data, weighted to represent the full living cohort (n = 5763). Modified Poisson regression estimated rate ratios (RRs) and 95% confidence intervals (CIs) for associations of TBI-LOC with percent-positive AT8 tau immunoreactivity and soluble Aβ42 (GuHCl and RIPA fractions) across brain regions. Models were adjusted for age at death, sex, education, and enrollment cohort; sensitivity analyses included unweighted and quantile models.ResultsWeighted models showed lower frontal tau (RR = 0.50, p = 0.047) and lower soluble Aβ42 in temporal and occipital cortices (p = 0.019-0.037) among donors with baseline TBI-LOC. In unweighted sensitivity analyses, lower temporal RIPA Aβ42 remained significant (p < 0.001), and select inverse associations were observed in duration-stratified analyses, particularly in small >1 h LOC subgroups. Quantile analyses of pathology burden similarly suggest reduced parietal Aβ42 (p = 0.02-0.04); effects were small and driven by sparse subgroups.ConclusionsTBI-LOC was not associated with greater tau or amyloid burden, and inverse associations likely reflect data sparsity rather than biological protection. These findings suggest that links between TBI and late-life cognitive decline may involve non-AD pathological processes.

Efficient cerebrovasculature is vital to neuronal health and cognition and evidence shows that most dementia patients have cerebrovascular abnormalities. Brain vasculature is regulated by Vascular Endothelial Growth Factors (VEGFs) binding VEGF receptor2 (VEGFR2) and stimulating angiogenesis and neuroprotection. Here we show that an ADAM17 cleavage of extracellular VEGFR2 produces the membrane-bound γ-secretase substrate VEGFR2/CTF1 (called VCTF1), comprising the transmembrane and intracellular domains of VEGFR2. VCTF1 binds full-length VEGFR2 monomers suppressing its dimerization a function that is required for VEGFR2 activation and downstream angiogenesis and neuroprotection. Presenilin1 (PS1) Familial Alzheimer's disease (FAD) mutants exert dominant negative effects on the γ-secretase processing of VCTF1 increasing its concentration and abolishing VEGF-A-induced VEGFR2 dimerization/activation and downstream VEGFR2 signaling, endothelial cell functions and angiogenesis. γ-Secretase inhibitors or PS1 reduction have similar effects on VCTF1 accumulation and VEGFR2 dimerization/activation and downstream signaling and functions as PS1 FAD mutants. Moreover, PS1 FAD mutants increase vulnerability of brain neurons to ischemic stress and abolish VEGF-A-induced neuroprotection and cognition. Together, these data show that VCTF1 suppresses VEGFR2 dimerization and downstream signaling and functions of the brain's VEGF-A-/VEGFR2 angiogenic and neuroprotection systems. Importantly, we detected molecular markers of decreased VEGFR2 dimerization and angiogenic dysfunction in human brain tissue from PS1 FAD mutant genotypes. Our data reveal a pathway through which FAD mutants may promote dementia by increasing accumulation of VCTF1 and decreasing angiogenesis, neuroprotection, and cognition, suggesting that PS1 FAD patients may benefit from therapeutic methods that decrease brain VCTF1.

The cheetah is a species known for its high-speed hunting, requiring sophisticated visuomotor and vestibulomotor skills. A recent study showed cheetahs have enlarged semicircular canals, suggesting enhanced vestibular information processing. We asked if the semicircular canal specializations might be reflected in the brainstem targets of vestibular input and in related cerebellar structures. We studied blocks of brain tissue with the medulla and pons from five US zoo-bred cheetahs (three different zoos), and one brainstem of an animal from a zoo in Sweden. We compared the cheetah brainstems with each other, and with the brainstem of the domestic cat. We found variations in several structures, most consistently in the cochlear nuclei, in the brains of the US zoo-bred cheetahs. There were differences among these brains in the nature and extent of these variations. Despite the unusual structural characteristics of the cochlear nuclei, no impairments in auditory function had been noted by the home zoos. The brain of the Swedish zoo cheetah did not show these atypical features. We also saw consistent differences between the US cheetahs and cats in the sizes of the cerebellar peduncles, the pyramidal tracts and the medial longitudinal fasciculus. The low genetic diversity of cheetahs, a consequence of one or more population bottlenecks, may underlie the persistence of genetic changes causing atypical brainstem development.

Background: Musculoskeletal disorders such as osteoarthritis, chronic low back pain, radicular syndromes and osteoporosis produce major clinical burdens, and noninvasive therapies capable of reaching deep anatomical structures are increasingly needed. Nuclear magnetic resonance therapy (molecular biophysical stimulation therapy; NMRT MBST) applies resonance-based magnetic fields to deliver uniform biophysical stimulation independent of tissue depth. This review synthesizes clinical and mechanistic evidence to evaluate the therapeutic potential of NMRT MBST and contextualize it within emerging deep-tissue biophysical treatment strategies. Methods: A systematic search of PubMed, Ovid Embase and peer-reviewed, published reviews identified 15 studies, including randomized trials, imaging investigations, observational cohorts, long-term follow-ups and blinded veterinary work. Experimental literature examining cellular, metabolic and molecular responses to NMRT MBST was reviewed to align biological effects with clinical outcomes. Results: NMRT MBST is consistently reported as safe, with no treatment-emergent adverse events. Clinical findings indicate improvements in pain, function and, in selected studies, imaging or densitometric parameters across osteoarthritis, spine-related pain, radicular syndromes and osteoporosis. Placebo-controlled effects were demonstrated in finger-joint osteoarthritis and radicular pain, while one robust knee osteoarthritis trial showed no short-term superiority over placebo. Mechanistic studies have shown anti-inflammatory, mitochondrial, redox, anabolic, neurotrophic, epigenetic and circadian effects that closely parallel near-infrared photobiomodulation, supporting the concept of NMRT MBST as a deep-penetrating analogue capable of reaching tissues inaccessible to light. This positions NMRT MBST within a broader therapeutic framework in which biophysical stimulation may modulate metabolic–inflammatory–regenerative axes in deep musculoskeletal and central nervous system (CNS) structures. Conclusions: NMRT/MBST appears to be a safe and biologically coherent deep-tissue biophysical therapy with promising clinical effects. Larger trials, optimized dosing, mechanistic biomarkers and head-to-head comparisons with established modalities are needed to define its therapeutic role and to clarify how deep-acting biophysical interventions may be integrated into future musculoskeletal and CNS care.

ABSTRACT Von Economo neurons (VENs) have been reported to be vulnerable to neurodegeneration in frontotemporal dementia (FTD), particularly the behavioral variant (bvFTD), but these findings have not been systematically assessed across independent brain banks. We conducted a meta‐analysis of neuropathological studies measuring VEN density in the anterior cingulate cortex or frontoinsular cortex in FTD using random‐effects models with cluster‐robust variance estimation. Seven studies (135 FTD, 68 controls) from four international brain banks showed significantly reduced VEN density in FTD with a large effect size (g = −1.45, 95% CI [−1.69, −1.21], p < 0.001) and remarkable consistency (I2 = 0%). VEN loss was greater in FTD than Alzheimer's disease and occurred across TDP‐43 and tau pathological subtypes.

Many Veterans who experienced blast-related traumatic brain injuries (TBI) during their military service suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast injuries designed to mimic the type of blast-related mild TBI that was so common in the conflicts in Iraq and Afghanistan develop delayed and persistent cognitive and PTSD-related traits that remain present for over 1 year after exposure. Boldine, an alkaloid derived from the Chilean Boldo tree (Peumus boldus), is a widely used herbal remedy with anti-oxidant, anti-inflammatory, hepatoprotective, and connexin hemichannel-blocking properties. We studied whether oral administration of boldine prevented development of PTSD-related behavioral traits in rats exposed to repetitive low-level blast. Treatment with boldine prevented appearance of the blast-induced PTSD-like phenotype including object recognition deficits and exaggerated cued fear learning. Boldine also prevented blast-induced elevation of the metabotropic glutamate receptor 2 (mGluR2) and the N-methyl-D-aspartate receptor 2b (NMDAR2b), but did not reverse decreases in the serotonin 5-HT2A receptor. Iba1 immunofluorescence staining suggested that boldine reduced blast-associated microglial process retraction (indicative of activation) in the somatosensory cortex. Transcriptomics analysis of hippocampus mRNA did not identify individual genes that remained significant after FDR correction. Exploratory analysis of 85 nominally significant candidates suggested that boldine induced coordinated transcriptional changes related to GO terms “Cognition” and “Neurotransmitter Transport,” consistent with modulation of activity-regulated transcription factors and neuroimmune signaling. These studies suggest that boldine may be beneficial for the neurobehavioral syndromes that follow blast exposure in military Veterans.

Repetitive low-level blast exposures in rats induce the development of a post-traumatic stress disorder (PTSD)-like phenotype and evolving chronic brain vascular alterations. These alterations included atherogenic-like lesions characterized by increased extravasation of blood elements into the arterial subendothelial layers, nuclear expression of c-Fos in endothelial and vascular smooth muscle cells, vascular hyperplasia, foam cell formation, and ultimately vascular rupture. Foam cells were mainly of macrophage/microglial or of vascular smooth muscle cell origin with upregulated expression of MHC II and of its co-stimulatory molecule CD86, which is characteristic of antigen-presenting cells. Foam cells also upregulated the lysosomal CD68 marker, indicating macrophage/microglial phagocytic and inflammatory activity. Foam cells of vascular smooth muscle cell origin were present at arteriolar bends, kinks, and bifurcations and were associated with a progressive arterial network degeneration in regions with enlarged perivascular spaces. Foam cell inclusions also contained the gelatinase MMP-9, which is involved in extracellular matrix degradation, and the pro-inflammatory cytokine TNF-α that further induces foam cell formation. These findings indicate that the chronic atherogenic lesions associated with blast-induced vascular degeneration may trigger a progressive pro-inflammatory state and expand the progressive vascular degeneration associated with the PTSD-like phenotype.

Extracellular Vesicles (EVs), the nano-sized extracellular membrane-bound vesicles, facilitate cell-to-cell communication by transporting bioactive molecules like proteins, lipids, and nucleic acids. Their unique cargo, determined by the cell of origin, makes them valuable tools for studying disease pathogenesis and potential drug delivery systems. Research suggests that EVs play a role in the pathogenesis of various diseases, including neurodegenerative and neurodevelopmental disorders. They have been implicated in diseases like Parkinson's disease (PD), Alzheimer's disease (AD), autism spectrum disorder (ASD) and Huntington’s disease (HD), where their presence and cargo can contribute to disease progression. EVs can cross physiological barriers, like blood-brain barrier (BBB), and placental barrier, and this unique property makes them promising candidates for therapeutic interventions aimed at neurological disorders. Current investigations explore the utility of EVs as potential drug delivery systems for neurological conditions, with their biocompatibility enhancing their suitability for delivering therapeutic cargo directly to brain cells. EVs have been observed to accumulate in the brains of animal models of neurodevelopmental and neurodegenerative diseases, thus offering valuable insights into underlying pathological mechanisms. The review highlights the growing interest in EVs and brain diseases, focusing on their roles in PD, AD, ASD, and HD, as well as their potential therapeutic applications. Furthermore, the implications of EVs for biomarker discovery and innovative drug delivery strategies in neurodevelopmental and neurodegenerative disorders are discussed, suggesting that they may pave the way for future therapeutic interventions.

In Alzheimer’s disease (AD), specific brain regions become vulnerable to pathology while others remain resilient. New methods of imaging such as highly multiplexed immunofluorescence (MxIF) provide an abundance of spatial information, while analytical techniques like machine learning (ML) can address questions of cellular contributors to this regional vulnerability. We performed MxIF staining for 26 markers and compared postmortem human samples from an AD-susceptible brain area, the prefrontal cortex (PFC, Brodmann’s areas 9, 10 or 46) to an AD-resilient brain area, the primary visual cortex (V1, area 17). Subjects included AD (n = 3, clinical dementia rating CDR 3, Thal stages 3-4, Braak stages V-VI), mild cognitive impairment (n = 4, CDR 0.5, Thal stages 1-3, Braak stages I-V), and age-matched healthy controls (n = 5, CDR 0, Thal stages 0-1, Braak stages I-II), including both females and males. We first used a custom Fiji plugin that leverages iterative ML to segment the images via DAPI or HUD signals. For the DAPI segmentation, ML subsequently classifies the cell type based on relevant channels. The second method used QuPath to segment exclusively using DAPI signal followed by cell-type classifications. Segmentations and classifications in QuPath used static thresholds. Using Fiji for HUD segmentation and filtering by the presence of nuclei, we found a decrease specifically in layer 5 PFC neurons from CDR 0 to CDR 0.5. Surprisingly, this decrease did not hold in QuPath when segmenting first using DAPI. Both methods found an increase in GFAP-expressing astrocytes primarily in layer 1. However, the pan-astrocyte marker ALDH1L1 showed an inverse relationship, with higher density found in layers 2 through 6. Both findings held true regardless of brain region or CDR. Finally, in addition to the white matter, both methods found an increase in oligodendrocytes (MBP+, MBP+/HUD+) within layer 4 of V1 and driven by CDR 0.5. Comparisons between the image analysis modalities demonstrate that the method by which cells are segmented and classified can impact the interpretation of MxIF data. Combining knowledge of disease biology with a deeper understanding of when and how to use these techniques will improve data precision.

The convoluted network of myelinated fibers that supports behavior, cognition, and sensory processing in the human brain is the source of its extraordinary complexity. Advancements in tissue optical clearing, 3D fluorescence microscopy, and automated image analysis have enabled unprecedented insights into the architecture of these networks. Here, we investigate the multiscale organization of myelinated fibers in human brain tissue from the brainstem, Broca's area, hippocampus, and primary visual cortex by exploiting a specific fiber staining method, light-sheet fluorescence microscopy (LSFM), and an advanced spatial orientation analysis tool. Using an optimized protocol that integrates tissue clearing with the lipophilic DiD probe to achieve uniform and deep myelinated fiber labeling, we generate micrometerresolution volumetric reconstructions of multiple brain regions through an inverted LSFM. Automated image processing, employing unsupervised 3D multiscale Frangi filters, provides orientation distribution functions and local orientation dispersion maps. This enables precise characterization of the directionality of white matter bundles, linking mesoscopic structural properties to orientation details computed at the native micrometric resolution of the LSFM apparatus. The presented workflow illustrates a robust platform for large-scale, high-resolution brain mapping, which may facilitate the investigation of pathological alterations with unparalleled spatial resolution and, furthermore, the validation of other neuroimaging modalities.

Primate species differ drastically from most other mammals in how they visually perceive their environments, which is particularly important for foraging, predator avoidance, and detection of social cues. Background/Objectives: Although it is well established that primates display diversity in color vision and various ecological specializations, it is not understood how visual system characteristics and ecological adaptations may be associated with gene expression levels within the primary visual cortex (V1). Methods: We performed RNA-Seq on V1 tissue samples from 28 individuals, representing 13 species of primates, including hominoids, cercopithecoids, and platyrrhines. We explored trait-dependent differential expression (DE) by contrasting species with differing visual system phenotypes and ecological traits. Results: Between 4–25% of genes were determined to be differentially expressed in primates that varied in type of color vision (trichromatic or polymorphic di/trichromatic), habitat use (arboreal or terrestrial), group size (large or small), and primary diet (frugivorous, folivorous, or omnivorous). Conclusions: Interestingly, our DE analyses revealed that humans and chimpanzees showed the most marked differences between any two species, even though they are only separated by 6–8 million years of independent evolution. These results show a combination of species-specific and trait-dependent differences in the evolution of gene expression in the primate visual cortex.

Background:Compared to other primates, humans display unique behaviors including language and complex tool use. These abilities are made possible in part by the cerebellum. This region of the hindbrain, comprising the flocculus, vermis, and lateral hemispheres, has expanded throughout primate evolution, particularly in great apes. Given the cerebellum's architecture-differing in connectivity, neuron content, and functions across subregions-examining subregional differences is crucial to understanding its evolutionary trajectory. Results:We performed bulk RNA-seq across samples from six primate species, representing 40-50 million years of evolutionary history, across four subregions of the cerebellum (vermis, flocculus, right lateral hemisphere, left lateral hemisphere). We analyzed changes in gene expression with respect to evolutionary relationships via the Ornstein-Uhlenbeck model and found that, on average, 8.5% of orthologous genes are differentially expressed in humans relative to other non-human primates. Subregion-specific gene expression patterns reveal that the primate lateral hemispheres exhibit significant differences in synaptic activity and glucose metabolism, which in turn are highly implicated in neural processing. Conclusions:This study provides a novel perspective on gene expression divergences across cerebellar subregions in multiple primate species, offering valuable insights into the evolution of this brain structure. Our findings reveal distinct subregional transcriptomic patterns, with the lateral hemispheres emerging as key sites of divergence across the six primate species. The enrichment of genes related to synaptic activity, glucose metabolism, locomotion, and vocalization highlights the cerebellum's crucial role in supporting the neural complexity underlying uniquely human and other species-specific primate behaviors.

Many Veterans who experienced blast-related traumatic brain injuries (TBIs) in Iraq and Afghanistan currently suffer from chronic cognitive and mental health problems that include depression and post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast develop chronic cognitive and PTSD-related behavioral traits that are present for more than 1 year after exposure. Psychedelic agents alter cognition as well as mood and agents such as psilocybin have gained attention as possible treatments for the mental health disorders that affect Veterans. The best-known action of psilocybin's metabolite psilocin is to stimulate the serotonin 2A receptor (5-HT2AR). The aim of this study was to determine whether 5-HT2AR levels are altered by blast exposure. 5-HT2AR expression was examined by Western blot in 7 cohorts of rats exposed to low level repetitive blast collected from 2 weeks to 12 months after blast exposure. The analysis included three brain regions (anterior cerebral cortex, hippocampus and amygdala) that were chosen based on being relevant to fear learning and the biological basis of PTSD. Possible correlations between Western blot data and behavioral outcomes were evaluated. 5-HT2AR was chronically decreased in anterior cortex of blast-exposed rats in all cohorts except the one studied at 2 weeks after blast exposure. 5-HT2AR levels were variably affected in the other regions. 5-HT2AR expression correlated differently in blast and control rats in some behavioral parameters. These findings have implications for understanding the neurochemical basis of blast-induced cognitive and behavioral changes. They also suggest 5-HT2AR as a potential therapeutic target for treatment of PTSD-related symptoms that follow blast injury.

INTRODUCTION:Cerebrovascular alterations are associated with the pathology of Alzheimer's disease (AD). Yet, the role of these alterations is not fully understood, partly due to a paucity of data from mesoscopic vasculature (24-240 µm diameter). METHODS:We used label-free, serial-sectioning optical coherence tomography to reconstruct mesoscopic cerebrovasculature of the dorsolateral prefrontal cortex (DLPFC) samples from AD and control subjects. We quantified three-dimensional alterations to the vascular networks and measured the correlations between vascular alterations and deposits of amyloid β protein (Aβ) and phosphorylated tau protein (p-tau). RESULTS:The AD group had significantly reduced volume fraction, vessel length density, and branch density. There were negative trends between a subset of the vascular metrics and the density of Aβ and p-tau. DISCUSSION:AD samples in DLPFC present with significant mesoscopic cerebrovasculature alterations. This insight helps close the knowledge gap between micro- and macroscopic cerebrovascular pathologies. HIGHLIGHTS:Volumetric imaging of mesoscopic cerebrovasculature with serial-sectioning optical coherence tomography (OCT). Vascular metrics: volume fraction, length density, branch density, and tortuosity. Human ex vivo samples from dorsolateral prefrontal cortex (Alxzheimer's disease [AD] and controls). Compared to controls, AD had reduced vascularity. Serial-sectioning OCT provides novel insights into mesoscopic cerebrovasculature.

Social behaviors in the African wild dog (Lycaon pictus) commonly involve a range of tactile aspects, including biting, pushing, embracing, mounting, face and muzzle licking, nose-chin and muzzle contact, paw placement, play fighting, and wrestling, supported by the vestibular system. We employed an array of architectural and immunohistochemical stains to provide a qualitative description of the somatosensory and vestibular systems in the brain of one representative African wild dog individual. The appearance of both systems does not appear to differ from that reported in other Carnivora. The six nuclei forming the vestibular system, and their relationship to each other and the incoming vestibular branch of the eighth cranial nerve, appear like those observed in many mammalian species. The location and appearance of the dorsal column nuclei, the trigeminal sensory column, the colliculi, somatosensory nuclei of the dorsal thalamus, and the five somatosensory cortical areas observed in the African wild dog are like those observed in the domestic dog and other Carnivora. This study of the somatosensory and vestibular systems of the African wild dog completes our series of studies describing the major sensory systems in the African wild dog brain. It appears reasonable to conclude that, at the systems level of analysis, no overt specializations of any of the sensory systems are present. Thus, the neural underpinnings of the complex sociality of the African wild dog may be supported by nonsensory neural systems, such as motor, neuromodulatory, limbic, or cognitive systems, or levels of organization like receptor expression patterns or connectivity.