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At least 19 recordsLinked to original sources
PubMed2026

Causal Effects Between Neurodegenerative Diseases, Metabolites, and Brain Volume.

INTRODUCTION/OBJECTIVE: Neurodegenerative diseases such as Alzheimer's disease (AD), Lewy dody dementia (LBD), and Parkinson's disease (PD) are linked to changes in brain volume. However, causal evidence on how these diseases affect brain volume and whether metabolites mediate these causal effects remains limited. METHODS: We applied mediation Mendelian randomization analysis using GWAS summary statistics. The inverse variance-weighted method was used to assess causal effects and identify potential metabolite mediators. RESULTS: The MR analyses indicated that bilateral thalamus and putamen volumes (FDR < 0.05) had causal effects on PD. AD and LBD showed causal effects on bilateral thalamus and hippocampus (FDR < 0.01), with LBD specifically showing a causal effect on bilateral putamen (FDR < 0.05). Mediation analyses revealed that AD had a genetically predicted association with Nervonoy- L-carnitine and 1-linoleoyl-2-arachidonoyl-GPC (p-value = 0.04 and 0.01, respectively). Moreover, Nervonoy-L-carnitine was suggestively negatively associated with hippocampus volume (p-value = 0.03 and 0.02, respectively). 1-linoleoyl-2-arachidonoyl-GPC exhibited a negative genetically predicted association with hippocampus volume (p-value < 0.05). Additionally, LBD showed a negative genetically predicted association on the ratio of retinol to linoleoyl-arachidonoyl- glycerol (p-value = 0.02), and a positive genetically predicted association on Nervonoy-L-- carnitine (p-value < 0.05) and 1-linoleoyl-2-arachidonoyl-GPC (p-value = 0.03). DISCUSSION: These results suggest that AD and LBD affect brain regions through causal pathways. The involvement of specific metabolites highlights potential mechanisms linking neurodegeneration to brain volume. CONCLUSION: Nervonoylcarnitine and 1-linoleoyl-2-arachidonoyl-GPC may mediate the predicted effects of AD and LBD on hippocampal volumes, while the ratio of retinol to linoleoyl-arachidonoyl- glycerol mediates only LBD.

Humans↗
PubMed2026

Effects of quetiapine on cognitive functioning in schizophrenia: evidence for the remyelination hypothesis?

Postmortem findings, neuroimaging data, and in-vitro models suggest a decrease in number and density of oligodendrocytes is driving cognitive deficits in schizophrenia (SCZ). Second-generation antipsychotics are discussed to improve oligodendrocyte dysfunction with most conclusive evidence available for quetiapine (QET). We postulate that sustained QET treatment leads to cognitive improvement in SCZ, particularly, in tests with high demands for working memory function. We further hypothesize that these effects are moderated by polygenic factors associated with hippocampus-related brain volumes, general white matter integrity, and/or oligodendroglia-related SCZ risk. Using data of the prospective PsyCourse study, we identified 166 patients with SCZ spectrum disorder receiving QET at one or two consecutive visits plus 166 matched patients without QET. Polygenic scores were calculated for subcortical brain volumes, measures of white matter integrity, and for cell type-specific genetic SCZ risks. QET treatment was consistently associated with improved cognitive function independent of time, specifically, in tests with high, but not with low to medium working memory load. Polygenic analyses did not reveal significant moderation effects. In contrary, low genetic SCZ risk specific for genes related to human oligodendrocyte function was associated with higher cognitive performance independent from QET. While we observed improved cognitive performance under QET in high working memory tests, we did not find evidence that polygenic factors associated with hippocampus-related brain volumes, white matter integrity, or oligodendroglia-related SCZ risk moderate this association. Thus, our tentative findings do not provide evidence for the hypothesis that polygenic estimates of hippocampal remyelination capacities influence the association between QET and cognitive performance in SCZ.

Humans↗
PubMed2026

Mapping Focal and Generalized Effects of Common Genetic Variants on Human Brain Structure.

Genome-wide association studies (GWAS) have advanced the quest to understand how specific genetic variants influence human brain structure and function. Recent work has identified hundreds of common variants associated with subcortical brain volumes, sparking interest in how these genetic markers overlap across brain networks. While this can be estimated by hierarchical clustering of the genetic correlation matrix to identify modular patterns of shared architecture, no brain-wide maps of these effects are available. To address this, we computed polygenic scores (PGS) from loci associated with ten brain volume regions of interest (ROIs): nine major subcortical structures and intracranial volume, with each locus weighted by its association with regional volume. In an independent sample from the discovery GWAS, we performed large-scale segmentation of 3D volumetric T1-weighted MRI scans using voxel-based morphometry (VBM) to map 3D profile of regions where gray matter volume (GMV) was associated with each PGS. We found statistically significant, localized effects for PGS defined for the amygdala, thalamus, and basal ganglia, but PGS for brainstem volume was associated with widespread differences throughout the brain. These brain-wide maps reveal patterns consistent with both localized and distributed genetic influences, offering a novel approach to interpret the genomic architecture of brain structure.

GWAS↗
PubMed2025

Associations Between Walking Pace, APOE-&#x3b5;4 Genotype, and Brain Health in Middle-Aged to Older Adults.

PURPOSE: This study aimed to investigate whether self-reported walking pace (a marker of physical function) and the presence of APOE-&#x3b5;4 allele interact to modify brain health outcomes. METHODS: We used data from a prospective cohort study of middle-aged to older adults from the UK Biobank who self-reported walking pace (slow or steady-to-brisk) and who were initially free of dementia ( n = 415,110). Incident all-cause dementia was obtained from hospital and death registry records, and structural brain volumes (right and left hippocampus volumes, total gray matter volume, and volume of white matter hyperintensities) were measured from a subset of participants ( n = 33,113). Cox proportional hazard models and generalized linear models were used to assess associations between exposures and outcomes. RESULTS: Slow walking pace and the presence of APOE-&#x3b5;4 allele were associated with increased dementia risk (HR = 1.79 [95% CI = 1.66-1.93], P < 0.001; HR = 3.06 [2.90-3.23], P < 0.001, respectively), and there was an interaction between these associations, indicating that the association of walking pace with dementia risk is modified by APOE-&#x3b5;4 status (reference group: HR Steady-Brisk/APOE-&#x3b5;4- = 1; HR Slow/APOE-&#x3b5;4- = 2.03 [1.84-2.25], P < 0.001; HR Steady-Brisk/APOE-&#x3b5;4+ = 3.21 [3.02-3.41], P < 0.001; HR Slow/APOE-&#x3b5;4+ = 4.99 [4.48-5.58], P < 0.001). Slow self-reported walking pace was associated with worse brain volume outcomes, and these associations were not modified by APOE-&#x3b5;4 genotype. CONCLUSIONS: These results suggest walking pace and APOE-&#x3b5;4 status independently influence brain volume outcomes, but both factors independently and jointly contribute to increased dementia risk. Individuals with both risk factors (slow walking pace and APOE-&#x3b5;4 allele) show the strongest associations with dementia risk.

Self Report↗
PubMed2025

A whole-brain voxel-based analysis of structural abnormalities in PTSD: An ENIGMA-PGC study.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group. METHODS: T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n&#xa0;=&#xa0;1309; controls n&#xa0;=&#xa0;2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9). RESULTS: PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges' g&#xa0;=&#xa0;0.22, pcorrected&#xa0;=&#xa0;.001), and smaller cerebellar WM volume (peak Hedges' g&#xa0;=&#xa0;0.14, pcorrected&#xa0;=&#xa0;.008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (p corrected &#xa0;=&#xa0;.003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (p corrected &#xa0;=&#xa0;.001). CONCLUSIONS: PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.

Humans↗
PubMed2026

Complementary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome.

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes, including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties, and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We first show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts on GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss-of-function in mice that will pave the way for future molecular studies into DESSH. These studies present two new vertebrate models that begin to uncover biological underpinnings of DESSH syndrome and elucidate the biology of Wac.

Animals↗
PubMed2025

Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome.

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments, neurobehavioral phenotypes including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We first show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts to GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss of function in mice that will pave the way for future molecular studies into DESSH. These studies present two new animals that begin to uncover some biological underpinnings of DESSH syndrome and elucidate the biology of Wac.

Journal Article↗
PubMed2025

Brain Health Loss Mediates the Effect of Infarct Volume on Functional Outcome in Ischemic Stroke.

IMPORTANCE: Brain health may facilitate resilience to detrimental consequences from neurological diseases. Infarct volume is associated with poor functional outcome after acute ischemic stroke (AIS), but potential mediating effects through stroke-related brain health loss have not been investigated. OBJECTIVE: To determine whether stroke-related brain health loss, quantified by change in MRI derived effective Reserve (eR), mediates the effect of acute infarct volume on functional outcome after AIS. DESIGN: Observational multicenter cohort study. SETTING: We analyzed data from the GASROS (n=488) and MRI-GENIE (n=560) cohorts, collected 2003-2011. PARTICIPANTS: Adult patients consecutively diagnosed with AIS, with available admission MRI. EXPOSURE: At admission, white matter hyperintensity (WMH) and normal-appearing brain volumes were assessed on T2-FLAIR, and acute infarct volume on diffusion weighted imaging. WMH was normalized by brain volume, creating WMH load. We quantified brain health using eR, a latent variable incorporating age, WMH load, and normal-appearing brain volume. &#x394;eR reflected the change in eR when acute infarct volume was included, representing stroke-related brain health decline. Mediation analysis was used to determine if &#x394;eR mediates the effect of infarct volume on functional outcome (modified Rankin Scale [mRS] at 90 days). MAIN OUTCOME MEASURE: Proportion of mediating effect. RESULTS: We included 1,048 patients (median age 67y, 38% females). At baseline, median NIHSS score was 3 (IQR 1-7), median infarct volume 3.1mL (IQR 0.9-15.5). At 90 days, median mRS score was 1 (IQR 1-3) and 51 (5%) patients had died. In mediation analysis, &#x394;eR significantly mediated 36% (95% CI 16-56%) of the total effect of infarct volume on functional outcome (direct effect (&#xdf;=0.15 [95% CI 0.09-0.22], p<0.001; indirect effect mediated through &#x394;eR: &#xdf;=0.09 [95% CI 0.04 to 0.14], p=0.001). In subgroup-analyses, the mediative effect was apparent among female but not male, and among patients aged >67y but not &#x2264;67y. CONCLUSIONS AND RELEVANCE: Stroke-related structural brain health loss mediates about one third of the effect of acute infarct volume on functional outcome after ischemic stroke, with important sex and age differences. Brain health significantly influences outcome and recovery potential, and may be considered a key biomarker when modeling outcome after AIS.

acute ischemic stroke↗
PubMed2026

FPR2/ALX stimulation modulates microglia and natural killer cells to restrict autoimmune astrocytopathy.

Autoantibody- and complement-mediated cytotoxicity can cause autoimmune astrocytopathy that leads to CNS inflammatory demyelination. Formyl peptide receptor 2 (FPR2/ALX) governs the activation and propagation of immune response. However, the precise role of FPR2/ALX in neuroinflammation and the effect of FPR2/ALX stimulation on autoimmune astrocytopathy are poorly understood. Using a mouse model of autoimmune astrocytopathy induced by AQP4-IgG- and complement-mediated cytotoxicity, we found that the stimulation of FPR2/ALX with the small-molecule agonist Quin-C1 led to reduced brain lesion volume, astrocyte loss and demyelination. This was accompanied by enhanced anti-inflammatory activity of microglia and reduced infiltration of lymphocytes in the brain. FPR2/ALX stimulation also led to increased phosphorylation of SYK and AKT in mice with autoimmune astrocytopathy. Notably, the benefits of FPR2/ALX stimulation were attenuated in mice with autoimmune astrocytopathy after microglial depletion using the CSF1R inhibitor PLX5622 or natural killer (NK) cell depletion using an anti-NK1.1 monoclonal antibody. Additionally, the protective effects of FPR2/ALX stimulation were diminished in mice with autoimmune astrocytopathy that received the SYK inhibitor R406. Collectively, our findings demonstrate that FPR2/ALX stimulation may represent a promising therapeutic strategy to attenuate detrimental neuroinflammation in autoimmune astrocytopathy by modulating microglia and NK cells. FPR2/ALX stimulation suppresses autoimmune astrocytopathy: Using a mouse model of autoimmune astrocytopathy, we demonstrated that FPR2/ALX stimulation with the small molecule Quin-C1 reduces the CNS infiltration of lymphocytes and augments the anti-inflammatory activity of microglia, leading to attenuated astrocyte pathology induced by AQP4-IgG and complement-mediated attacks. Mechanistically, the benefits of FPR2/ALX stimulation using Quin-C1 involve microglia, natural killer (NK) cells, and SYK-AKT signaling.

Animals↗
PubMed1976

[Change in the central and regional (brain) hemodynamics in the treatment of hypertension using beta-adrenergic blockaders].

The haemodynamic parameters were studied dynamically by way of noninvasive techniques--tetrapolar thoracic rheography in the course of treatment of 48 patients with essential hypertension Stage IB and IIA urth beta-blocking agents Obsidan and Visken. It was found that as early as by the 5th day of therapy the stroke volume and heart rate decreased, the maximum fall being noted after 2-3 weeks of treatment. The reflex elevation of the total peripheral resistance was moderate, as a result of which a gradual reduction of the arterial pressure developed. The state of the cerebral circulation significantly improved in the course of the treatment (as shown by rheoencephalography) and the tone of the cerebral arteries decreased. After 2-3 weeks of beta-blockers therapy favourable shifts were observed in the response of the general and cerebral haemodynamics to the orthostatic test.

Adolescent↗
PubMed2026

Large-Scale Neuroimaging and Genetic Analyses of the Human Thalamus in Loneliness.

BACKGROUND: Although loneliness is prevalent and significantly impacts society globally, its neural and genetic bases remain poorly understood. The thalamus, which receives sensory information from the environment, may have a more significant role in social interactions than previously recognized. Here, we integrate neuroimaging and genetic approaches to characterize structural differences within the thalamus associated with loneliness. METHODS: We obtained thalamic nuclei volumes on brain scans from 45,834 individuals (age range: 45-82 years) in the UK Biobank and grouped them into 6 anatomical groups. We investigated effects of loneliness and social isolation using self-reported data. Then, we performed a genome-wide association study (GWAS) analysis on the genetic overlap between thalamic volumes and loneliness. RESULTS: The volumes of the whole thalamus and its medial, lateral, and posterior nuclei are significantly reduced in individuals with loneliness compared with those who do not feel lonely. Loneliness with frequent social contact is associated with smaller volumes, whereas social isolation without loneliness shows no such reduction in thalamus volumes. Leveraging data from GWASs on thalamic volumes (n = 30,114) and loneliness (n = 370,342) in the UK Biobank, we identified shared loci between thalamus structure and loneliness. CONCLUSIONS: Our findings support the emerging view that the thalamus plays important roles in social interactions and in the experience of loneliness.

Genetic architecture↗
PubMed1975

Pathogenesis of neurogenic pulmonary oedema.

Evidence suggests that the initial phase of neurogenic pulmonary oedema results from a centrally mediated, massive, sympathetic discharge. It is postulated that this produces intense, generlised, but transient, vasoconstriction with a resultant shift of blood from the high-resistance systemic circulation to the low-resistance pulmonary circulation. Pronounced increases in pulmonary vascular pressures and blood-volume then produce pulmonary oedema because of the hydrostatic effect of increased pulmonary capillary pressure. In addition, pulmonary hypertension and hypervolaemia injure pulmonary blood-vessels, altering pulmonary capillary permeability and producing lung haemorrhage. After the transient systemic and pulmonary vascular hypertension subside, the patient is left with abnormal pulmonary capillary permeability, so that pulmonary oedema persists in the face of normal haemodynamic and cardiac function.

Blood Pressure↗
PubMed1978

Neurochemical anatomy of the neuroendocrine hypothalamus. Neurochemical anatomy of the hypothalamus.

Microdissection techniques for isolated removal of the various regions of the hypothalamus as well as the individual hypothalamic nuclei are detailed. Recent development of biochemical microassays have made it possible that the concentrations of neurohormones, neuropeptides, neurotransmitters and their related enzymes could be detected in such a small volume of brain tissue than the hypothalamic nuclei. Data available of the hypothalamic distribution of above substances are summarized. The possible role and origin of intra- and extrahypothalamic neurohormones as well as the existence of the so-called "hypophysiotrophic area" are discussed.

Animals↗
PubMed2022

Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS: We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 &#xd7; 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 &#xd7; 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS: Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION: Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Humans↗