Brain Changes Research Articles

Hepatic LRP-1 plays an important role in amyloidosis in Alzheimer's disease mice: Potential role in chronic heavy alcohol feeding

BackgroundHepatic lipoprotein receptor-related protein 1 (LRP-1) plays a central role in peripheral amyloid beta (Aβ) clearance, but its importance in Alzheimer's disease (AD) pathology is understudied. Our previous work showed that intragastric alcohol feeding to C57BL/6 J mice reduced hepatic LRP-1 expression which correlated with significant AD-relevant brain changes. Herein, we examined the role of hepatic LRP-1 in AD pathogenesis in APP/PS1 AD mice using two approaches to modulate hepatic LRP-1, intragastric alcohol feeding to model chronic heavy drinking shown by us to reduce hepatic LRP-1, and hepato-specific LRP-1 silencing. MethodsEight-month-old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7–11/group). Brain and liver Aβ were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP-1 (major peripheral Aβ regulator), blood-brain barrier (BBB) function (vascular Aβ regulator), and microglia (major brain Aβ regulator) using immunoassays. Spatial LRP-1 gene expression in the periportal versus pericentral hepatic regions was confirmed using NanoString GeoMx Digital Spatial Profiler. Further, hepatic LRP-1 was silenced by injecting LRP-1 microRNA delivered by the adeno-associated virus 8 (AAV8) and the hepato-specific thyroxine-binding globulin (TBG) promoter to 4-month-old male APP/PS1 mice (n = 6). Control male APP/PS1 mice received control AAV8 (n = 6). Spatial memory and locomotion were assessed 12 weeks after LRP-1 silencing using Y-maze and open-field test, respectively, and brain and liver Aβ were measured. ResultsAlcohol feeding reduced plaque-associated microglia in APP/PS1 mice brains and increased aggregated Aβ (p < 0.05) by ELISA and 6E10-positive Aβ load by immunostaining (p < 0.05). Increased brain Aβ corresponded with a significant downregulation of hepatic LRP-1 (p < 0.01) at the protein and transcript level, primarily in pericentral hepatocytes (zone 3) where alcohol-induced injury occurs. Hepato-specific LRP-1 silencing significantly increased brain Aβ and locomotion hyperactivity (p < 0.05) in APP/PS1 mice. ConclusionChronic heavy alcohol intake reduced hepatic LRP-1 expression and increased brain Aβ. The hepato-specific LRP-1 silencing similarly increased brain Aβ which was associated with behavioral deficits in APP/PS1 mice. Collectively, our results suggest that hepatic LRP-1 is a key regulator of brain amyloidosis in alcohol-dependent AD.

Discovering the gene-brain-behavior link in autism via generative machine learning.

Autism is traditionally diagnosed behaviorally but has a strong genetic basis. A genetics-first approach could transform understanding and treatment of autism. However, isolating the gene-brain-behavior relationship from confounding sources of variability is a challenge. We demonstrate a novel technique, 3D transport-based morphometry (TBM), to extract the structural brain changes linked to genetic copy number variation (CNV) at the 16p11.2 region. We identified two distinct endophenotypes. In data from the Simons Variation in Individuals Project, detection of these endophenotypes enabled 89 to 95% test accuracy in predicting 16p11.2 CNV from brain images alone. Then, TBM enabled direct visualization of the endophenotypes driving accurate prediction, revealing dose-dependent brain changes among deletion and duplication carriers. These endophenotypes are sensitive to articulation disorders and explain a portion of the intelligence quotient variability. Genetic stratification combined with TBM could reveal new brain endophenotypes in many neurodevelopmental disorders, accelerating precision medicine, and understanding of human neurodiversity.

Effects of Lithium Ions on tPA-Induced Hemorrhagic Transformation under Stroke.

Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several limitations, particularly the increased risk of hemorrhagic transformation (HT). Lithium salts show neuroprotective effects in stroke, but their effects on HT mechanisms are still unknown. In our study, we use the models of photothrombosis (PT)-induced brain ischemia and oxygen-glucose deprivation (OGD) to investigate the effect of Li+ on tPA-induced changes in brain and endothelial cell cultures. We found that tPA did not affect lesion volume or exacerbate neurological deficits but disrupted the blood-brain barrier. We demonstrate that poststroke treatment with Li+ improves neurological status and increases blood-brain barrier integrity after thrombolytic therapy. Under conditions of OGD, tPA treatment increased MMP-2/9 levels in endothelial cells, and preincubation with LiCl abolished this MMP activation. Moreover, we observed the effect of Li+ on glycolysis in tPA-treated endothelial cells, which we hypothesized to have an effect on MMP expression.

Developmental pyrethroid exposure in mouse leads to disrupted brain metabolism in adulthood

Environmental and genetic risk factors, and their interactions, contribute significantly to the etiology of neurodevelopmental disorders (NDDs). Recent epidemiology studies have implicated pyrethroid pesticides as an environmental risk factor for autism and developmental delay. Our previous research showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice caused male-biased changes in the brain and in NDD-relevant behaviors in adulthood. Here, we used a metabolomics approach to determine the broadest possible set of metabolic changes in the adult male mouse brain caused by low-dose pyrethroid exposure during development. Using a litter-based design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood and collected whole brain samples for untargeted high-resolution metabolomics analysis. Developmentally exposed mice had disruptions in 116 metabolites which clustered into pathways for folate biosynthesis, retinol metabolism, and tryptophan metabolism. As a cross-validation, we integrated metabolomics and transcriptomics data from the same samples, which confirmed previous findings of altered dopamine signaling. These results suggest that pyrethroid exposure during development leads to disruptions in metabolism in the adult brain, which may inform both prevention and therapeutic strategies.

Diabetes accelerates Alzheimer's disease progression in the first year post mild cognitive impairment diagnosis.

Mild cognitive impairment (MCI) heightens Alzheimer's disease (AD) risk, with diabetes mellitus (DM) potentially exacerbating this vulnerability. This study identifies the optimal intervention period and neurobiological targets in MCI to AD progression using the Alzheimer's Disease Neuroimaging Initiative dataset. Analysis of 980 MCI patients, categorized by DM status, used propensity score matching and inverse probability treatment weighting to assess rate of conversion from MCI to AD, neuroimaging, and cognitive changes. DM significantly correlates with cognitive decline and an increased risk of progressing to AD, especially within the first year of MCI follow-up. It adversely affects specific brain structures, notably accelerating nucleus accumbens atrophy, decreasing gray matter volume and sulcal depth. Findings suggest the first year after MCI diagnosis as the critical window for intervention. DM accelerates MCI-to-AD progression, targeting specific brain areas, underscoring the need for early therapeutic intervention. Diabetes mellitus (DM) accelerates mild cognitive impairment (MCI)-to-Alzheimer's disease (AD) progression within the first year after MCI diagnosis. DM leads to sharper cognitive decline within 12 months of follow-up. There is notable nucleus accumbens atrophy observed in MCI patients with DM. DM causes significant reductions in gray matter volume and sulcal depth. There are stronger correlations between cognitive decline and brain changes due to DM.

The value of synthetic MRI in detecting the brain changes and hearing impairment of children with sensorineural hearing loss.

Sensorineural hearing loss (SNHL) can arise from a diverse range of congenital and acquired factors. Detecting it early is pivotal for nurturing speech, language, and cognitive development in children with SNHL. In our study, we utilized synthetic magnetic resonance imaging (SyMRI) to assess alterations in both gray and white matter within the brains of children affected by SNHL. The study encompassed both children diagnosed with SNHL and a control group of children with normal hearing {1.5-month-olds (n = 52) and 3-month-olds (n = 78)}. Participants were categorized based on their auditory brainstem response (ABR) threshold, delineated into normal, mild, moderate, and severe subgroups.Clinical parameters were included and assessed the correlation with SNHL. Quantitative analysis of brain morphology was conducted using SyMRI scans, yielding data on brain segmentation and relaxation time.Through both univariate and multivariate analyses, independent factors predictive of SNHL were identified. The efficacy of the prediction model was evaluated using receiver operating characteristic (ROC) curves, with visualization facilitated through the utilization of a nomogram. It's important to note that due to the constraints of our research, we worked with a relatively small sample size. Neonatal hyperbilirubinemia (NH) and children with inner ear malformation (IEM) were associated with the onset of SNHL both at 1.5 and 3-month groups. At 3-month group, the moderate and severe subgroups exhibited elevated quantitative T1 values in the inferior colliculus (IC), lateral lemniscus (LL), and middle cerebellar peduncle (MCP) compared to the normal group. Additionally, WMV, WMF, MYF, and MYV were significantly reduced relative to the normal group. Additionally, SNHL-children with IEM had high T1 values in IC, and LL and reduced WMV, WMF, MYV and MYF values as compared with SNHL-children without IEM at 3-month group. LL-T1 and WMF were independent risk factors associated with SNHL. Consequently, a prediction model was devised based on LL-T1 and WMF. ROC for training set, validation set and external set were 0.865, 0.806, and 0.736, respectively. The integration of T1 quantitative values and brain volume segmentation offers a valuable tool for tracking brain development in children affected by SNHL and assessing the progression of the condition's severity.

Vascular Risk Factors and Brain Health in Aging: Insights from a Community-Based Cohort Study.

The aging population and high rates of Alzheimer's disease (AD) create significant medical burdens, prompting a need for early prevention. Targeting modifiable risk factors like vascular risk factors (VRFs), closely linked to AD, may provide a promising strategy for intervention. This study investigates how VRFs influence cognitive performance and brain structures in a community-based cohort. In this cross-sectional study, 4,667 participants over 50 years old, drawn from the Beijing Ageing Brain Rejuvenation Initiative project, were meticulously examined. Cognitive function and VRFs (diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking), were comprehensively assessed through one-to-one interviews. Additionally, a subset of participants (n = 719) underwent MRI, encompassing T1-weighted and diffusion-weighted scans, to elucidate gray matter volume and white matter structural network organization. The findings unveil diabetes as a potent detriment to memory, manifesting in atrophy within the right supramarginal gyrus and diminished nodal efficiency and degree centrality in the right inferior parietal lobe. Hypertension solely impaired memory without significant structural changes. Intriguingly, individuals with comorbid diabetes and hypertension exhibited the most pronounced deficits in both brain structure and cognitive performance. Remarkably, hyperlipidemia emerged as a factor associated with enhanced cognition, and preservation of brain structure. This study illuminates the intricate associations between VRFs and the varied patterns of cognitive and brain structural damage. Notably, the synergistic effect of diabetes and hypertension emerges as particularly deleterious. These findings underscore the imperative to tailor interventions for patients with distinct VRF comorbidities, especially when addressing cognitive decline and structural brain changes.

Genetic and environmental influences on structural brain development from childhood to adolescence: A longitudinal twin study on cortical thickness, surface area, and subcortical volume

The human brain undergoes structural development from childhood to adolescence, with specific regions in the sensorimotor, social, and affective networks continuing to grow into adulthood. While genetic and environmental factors contribute to individual differences in these brain trajectories, the extent remains understudied. Our longitudinal study, utilizing up to three biennial MRI scans (n=485), aimed to assess the genetic and environmental effects on brain structure (age 7) and development (ages 7–14) in these regions. Heritability estimates varied across brain regions, with all regions showing genetic influence (ranging from 18 % to 59 %) with additional shared environmental factors affecting the primary motor cortex (30 %), somatosensory cortex (35 %), DLPFC (5 %), TPJ (17 %), STS (17 %), precuneus (10 %), hippocampus (22 %), amygdala (5 %), and nucleus accumbens (10 %). Surface area was more genetically driven (38 %) than cortical thickness (14 %). Longitudinal brain changes were primarily driven by genetics (ranging from 1 % to 29 %), though shared environment factors (additionally) influenced the somatosensory cortex (11 %), DLPFC (7 %), cerebellum (28 %), TPJ (16 %), STS (20 %), and hippocampus (17 %). These findings highlight the importance of further investigating brain-behavior associations and the influence of enriched and deprived environments from childhood to adolescence. Ultimately, our study can provide insights for interventions aimed at supporting children's development.

Investigation of hemispheric asymmetry in Alzheimer’s disease patients during resting state revealed by fNIRS

Alzheimer's disease (AD) is characterized by the gradual deterioration of brain structures and changes in hemispheric asymmetry. Meanwhile, healthy aging is associated with a decrease in functional hemispheric asymmetry. In this study, functional connectivity analysis was used to compare the functional hemispheric asymmetry in eyes-open resting-state fNIRS data of 16 healthy elderly controls (mean age: 60.4 years, MMSE (Mini-Mental State Examination): 27.3 ± 2.52) and 14 Alzheimer's patients (mean age: 73.8 years, MMSE: 22 ± 4.32). Increased interhemispheric functional connectivity was found in the premotor cortex, supplementary motor cortex, primary motor cortex, inferior parietal cortex, primary somatosensory cortex, and supramarginal gyrus in the control group compared to the AD group. The study revealed that the control group had stronger interhemispheric connectivity, leading to a more significant decrease in hemispheric asymmetry than the AD group. The results show that there is a difference in interhemispheric functional connections at rest between the Alzheimer's group and the control group, suggesting that functional hemispheric asymmetry continues in Alzheimer's patients.

Brain image segmentation with fuzzy entropy clustering and PSO-GWO optimization techniques

In the field of brain MRI analysis, image segmentation serves various purposes such as quantifying and visualizing anatomical structures, analyzing brain changes, delineating pathological regions, and aiding in surgical planning and image-guided interventions. Over the past few decades, diverse segmentation techniques with varying degrees of accuracy and complexity have been developed. Real-world brain MRI images often encounter intensity in homogeneity, posing a significant challenge in accurate segmentation. The prevailing image segmentation algorithms, predominantly region-based, typically rely on the homogeneity of image intensities in specific regions of interest. However, these methods often fall short of providing precise segmentation results due to intensity in homogeneity. To address these challenges and enhance segmentation performance, this paper introduce a novel objective function named Fuzzy Entropy Clustering with Local Spatial Information and Bias Correction (FECSB). Additionally, we propose a novel hybrid algorithm that combines Particle Swarm Optimization (PSO) and Grey Wolf Optimization (GWO) to maximize the effectiveness of the FECSB function in MRI brain image segmentation. The proposed algorithm undergoes rigorous evaluation using benchmark MRI brain images, including those from the McConnell Brain Imaging Center (BrainWeb). The experimental results unequivocally demonstrate the superiority of the PSO-GWO clustering method over the traditional Fuzzy C Means (FCM) method. Across various image slices, the PSO-GWO method consistently outperforms FCM in terms of accuracy, showing improvements ranging from 1.28% to 1.46%, approximately achieving 99.37% accuracy.

Age-dependent functional development pattern in neonatal brain: An fMRI-based brain entropy study

The relationship between brain entropy (BEN) and early brain development has been established through animal studies. However, it remains unclear whether the BEN can be used to identify age-dependent functional changes in human neonatal brains and the genetic underpinning of the new neuroimaging marker remains to be elucidated. In this study, we analyzed resting-state fMRI data from the Developing Human Connectome Project, including 280 infants who were scanned at 37.5–43.5 weeks postmenstrual age. The BEN maps were calculated for each subject, and a voxel-wise analysis was conducted using a general linear model to examine the effects of age, sex, and preterm birth on BEN. Additionally, we evaluated the correlation between regional BEN and gene expression levels. Our results demonstrated that the BEN in the sensorimotor-auditory and association cortices, along the ‘S-A’ axis, was significantly positively correlated with postnatal age (PNA), and negatively correlated with gestational age (GA), respectively. Meanwhile, the BEN in the right rolandic operculum correlated significantly with both GA and PNA. Preterm-born infants exhibited increased BEN values in widespread cortical areas, particularly in the visual-motor cortex, when compared to term-born infants. Moreover, we identified five BEN-related genes (DNAJC12, FIG4, STX12, CETN2, and IRF2BP2), which were involved in protein folding, synaptic vesicle transportation and cell division. These findings suggest that the fMRI-based BEN can serve as an indicator of age-dependent brain functional development in human neonates, which may be influenced by specific genes.

Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aβ-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Early detection of dementia with default-mode network effective connectivity

Altered functional connectivity precedes structural brain changes and symptoms in dementia. Alzheimer’s disease is the largest contributor to dementia at the population level, and disrupts functional connectivity in the brain’s default-mode network (DMN). We investigated whether a neurobiological model of DMN effective connectivity could predict a future dementia diagnosis at the single-participant level. We applied spectral dynamic causal modeling to resting-state functional magnetic resonance imaging data in a nested case–control group from the UK Biobank, including 81 undiagnosed individuals who developed dementia up to nine years after imaging, and 1,030 matched controls. Dysconnectivity predicted both future dementia incidence (AUC = 0.82) and time to diagnosis (R = 0.53), outperforming models based on brain structure and functional connectivity. We also evaluated associations between DMN dysconnectivity and major risk factors for dementia, revealing strong relationships with polygenic risk for Alzheimer’s disease and social isolation. Neurobiological models of effective connectivity may facilitate early detection of dementia at population level, supporting rational deployment of targeted dementia-prevention strategies.

Mapping the interplay of atrial fibrillation, brain structure, and cognitive dysfunction.

Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. Understanding the cognitive sequelae and brain structural changes associated with AF is vital for addressing ensuing health care needs. We examined 1335 stroke-free individuals with AF and 2683 matched controls using neuropsychological assessments and multimodal neuroimaging. The analysis revealed that individuals with AF exhibited deficits in executive function, processing speed, and reasoning, accompanied by reduced cortical thickness, elevated extracellular free-water content, and widespread white matter abnormalities, indicative of small vessel pathology. Notably, brain structural differences statistically mediated the relationship between AF and cognitive performance. Integrating a comprehensive analysis approach with extensive clinical and magnetic resonance imaging data, our study highlights small vessel pathology as a possible unifying link among AF, cognitive decline, and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies. Highlights We investigated neuropsychological and multimodal neuroimaging data of 1335 individuals with atrial fibrillation (AF) and 2683 matched controls. Our analysis revealed AF-associated deficits in cognitive domains of attention, executive function, processing speed, and reasoning. Cognitive deficits in the AF group were accompanied by structural brain alterations including reduced cortical thickness and gray matter volume, alongside increased extracellular free-water content as well as widespread differences of white matter integrity. Structural brain changes statistically mediated the link between AF and cognitive performance, emphasizing the potential of structural imaging markers as a diagnostic tool in AF-related cognitive decline.

The brain in chronic insomnia and anxiety disorder: a combined structural and functional fMRI study.

Chronic insomnia disorder (CID) is usually associated with Generalized Anxiety Disorder (GAD), which may change brain structure and function. However, the possible brain markers, imaging characteristics, and pathophysiology are unknown. To look at the probable brain markers, imaging characteristics, and pathogenesis of CID in combination with GAD. A total of 57 patients with CID concomitant GAD and 57 healthy controls (HC) were enrolled. Voxel-based morphometry (VBM) and functional connectivity (FC) were utilized to measure gray matter volume (GMV) and functional changes. Correlation analysis was utilized to identify relationships between brain changes and clinical characteristics. Patients had decreased GMV in the left cerebellum, right cerebellar peduncle, and left insula; increased FC between the left cerebellum and right angular gyrus, as well as between the left insula and anterior left cingulate gyrus; and decreased FC in several areas, including the left cerebellum with the middle left cingulate gyrus and the left insula with the left superior postcentral gyrus. These brain changes related to CID and GAD. These data could be used to identify relevant brain markers, imaging features, and to better understand the etiology. The intensity of insomnia in patients was strongly related to the severity of anxiety. The lower GMV in the cerebellum could be interpreted as an imaging characteristic of CID. Reduced GMV in the insula, as well as aberrant function in the cingulate gyrus and prefrontal lobe, may contribute to the pathophysiology of CID and GAD. Abnormal function in the postcentral gyrus and angular gyrus may be associated with patients' clinical complaints.

Changes in primary visual and auditory cortex of blind and sighted adults following 10weeks of click-based echolocation training.

Recent work suggests that the adult human brain is very adaptable when it comes to sensory processing. In this context, it has also been suggested that structural "blueprints" may fundamentally constrain neuroplastic change, e.g. in response to sensory deprivation. Here, we trained 12 blind participants and 14 sighted participants in echolocation over a 10-week period, and used MRI in a pre-post design to measure functional and structural brain changes. We found that blind participants and sighted participants together showed a training-induced increase in activation in left and right V1 in response to echoes, a finding difficult to reconcile with the view that sensory cortex is strictly organized by modality. Further, blind participants and sighted participants showed a training induced increase in activation in right A1 in response to sounds per se (i.e. not echo-specific), and this was accompanied by an increase in gray matter density in right A1 in blind participants and in adjacent acoustic areas in sighted participants. The similarity in functional results between sighted participants and blind participants is consistent with the idea that reorganization may be governed by similar principles in the two groups, yet our structural analyses also showed differences between the groups suggesting that a more nuanced view may be required.

REVISÃO INTEGRATIVA SOBRE AS FERRAMENTAS DIAGNÓSTICAS E AVANÇOS NO TRATAMENTO DA DEMÊNCIA E DOENÇAS NEURODEGENERATIVAS

Dementias and neurodegenerative diseases pose an increasing public health challenge due to their high prevalence and significant impact on patients' quality of life. This integrative review aimed to compile and synthesize available evidence on diagnostic tools and advances in the treatment of these conditions. The studies analyzed included imaging tests, biomarkers, neuropsychological and genetic tests, as well as pharmacological treatments, non-pharmacological interventions, and innovative therapies. Key findings include the utility of magnetic resonance imaging in identifying structural brain changes, the relevance of amyloid biomarkers in assessing neurodegenerative disorders, the importance of neuropsychological tests in cognitive and behavioral evaluation, and the role of genetic tests in identifying disease-associated mutations. Furthermore, the benefits and limitations of pharmacological therapies, psychosocial interventions, and the potential of induced pluripotent stem cells were discussed. Clinical implications suggest the need for multifaceted diagnostic and therapeutic approaches and ongoing research to enhance early detection and management of these diseases.

Excessive interstitial free-water in cortical gray matter 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 suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. 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. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. 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 CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. 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 many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.

An Overview of Epigenetic Changes in the Parkinson's Disease Brain.

Parkinson's disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson's have been identified, much is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson's disease. We will also discuss the limitations of current epigenetic research in Parkinson's disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies.

Structural brain changes associated with cocaine use and digital cognitive behavioral therapy in cocaine use disorder treatment

BackgroundFew studies have investigated changes in brain structure and function associated with recovery from cocaine use disorder (CUD), and fewer still have identified brain changes associated with specific CUD treatments, which could inform treatment development and optimization. MethodsIn this longitudinal study, T1-weighted magnetic resonance imaging scans were acquired from 41 methadone-maintained individuals with CUD (15 women) at the beginning of and after 12 weeks of outpatient treatment. As part of a larger randomized controlled trial, these participants were randomly assigned to receive (or not) computer-based training for cognitive behavioral therapy (CBT4CBT), and galantamine (or placebo). ResultsIrrespective of treatment condition, whole-brain voxel-based morphometry analyses revealed a significant decrease in right caudate body, bilateral cerebellum, and right middle temporal gyrus gray matter volume (GMV) at post-treatment relative to the start of treatment. Subsequent region of interest analyses found that greater reductions in right caudate and bilateral cerebellar GMV were associated with higher relative and absolute levels of cocaine use during treatment, respectively. Participants who completed more CBT4CBT modules had a greater reduction in right middle temporal gyrus GMV. ConclusionsThese results extend previous findings regarding changes in caudate and cerebellar GMV as a function of cocaine use and provide the first evidence of a change in brain structure as a function of engagement in digital CBT for addiction. These data suggest a novel potential mechanism underlying how CBT4CBT and CBT more broadly may exert therapeutic effects on substance-use-related behaviors through brain regions implicated in semantic knowledge.