RESUMEN

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)-derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration-approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

Asunto(s)

Células Madre Pluripotentes Inducidas , Enfermedad por Cuerpos de Lewy , Organoides , alfa-Sinucleína , Humanos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Organoides/metabolismo , Organoides/efectos de los fármacos , Organoides/patología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/citología , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/genética , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/efectos de los fármacos , Evaluación Preclínica de Medicamentos

RESUMEN

The objectives of this study were to investigate the variable factors associated with cognitive function and cortical atrophy and estimated variable importance of those factors in affecting cognitive function and cortical atrophy in patients with EOAD and LOAD. Patients with EOAD (n = 40), LOAD (n = 34), and healthy volunteers with normal cognition were included (n = 65). All of them performed 3T MRI, [18F]THK5351 PET (THK), [18F]flutemetamol PET (FLUTE), and detailed neuropsychological tests. To investigate factors associated with neuropsychological test results and cortical thickness in each group, we conducted multivariable linear regression models, including amyloid, tau, cerebral small vessel disease markers on MRI, and vascular risk factors. Then, we estimated variable importance in associating cognitive functions and cortical thickness, using relative importance analysis. In patients with EOAD, global THK retention was the most important contributor to the model variances for most neuropsychological tests, except for memory. However, in patients with LOAD, multiple contributors beyond tau were important in explaining variance of neuropsychological tests. In analyses with mean cortical thickness, global THK retention was the main contributor in patients with EOAD, while in LOAD patients, multiple factors contributed equally to mean cortical thickness. Therefore, EOAD and LOAD may have different pathomechanistic courses.

Asunto(s)

Enfermedad de Alzheimer , Atrofia , Corteza Cerebral , Disfunción Cognitiva , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Masculino , Femenino , Anciano , Persona de Mediana Edad , Disfunción Cognitiva/patología , Disfunción Cognitiva/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Edad de Inicio , Proteínas tau/metabolismo

RESUMEN

Direct neuronal reprogramming is a promising approach to replace neurons lost due to disease via the conversion of endogenous glia reacting to brain injury into neurons. However, it is essential to demonstrate that the newly generated neurons originate from glial cells and/or show that they are not pre-existing endogenous neurons. Here, we use controls for both requirements while comparing two viral vector systems (Mo-MLVs and AAVs) for the expression of the same neurogenic factor, the phosphorylation-resistant form of Neurogenin2. Our results show that Mo-MLVs targeting proliferating glial cells after traumatic brain injury reliably convert astrocytes into neurons, as assessed by genetic fate mapping of astrocytes. Conversely, expressing the same neurogenic factor in a flexed AAV system results in artefactual labelling of endogenous neurons fatemapped by birthdating in development that are negative for the genetic fate mapping marker induced in astrocytes. These results are further corroborated by chronic live in vivo imaging. Taken together, the phosphorylation-resistant form of Neurogenin2 is more efficient in reprogramming reactive glia into neurons than its wildtype counterpart in vivo using retroviral vectors (Mo-MLVs) targeting proliferating glia. Conversely, AAV-mediated expression generates artefacts and is not sufficient to achieve fate conversion.

Asunto(s)

Astrocitos , Reprogramación Celular , Corteza Cerebral , Dependovirus , Vectores Genéticos , Neuronas , Animales , Astrocitos/metabolismo , Neuronas/metabolismo , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Ratones , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Dependovirus/genética , Reprogramación Celular/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ratones Endogámicos C57BL , Masculino , Retroviridae/genética

RESUMEN

Inflammation may be related to structural changes in the cerebral cortex. We aimed to explore whether cytokines mediate the link between these changes and primary headache. The summary statistics of genome-wide association study (GWAS) related to migraine and its subtypes, cluster headache were derived from the FinnGen Release 10 database, and tension-type headache data was from the GWAS Catalog. Ninety-one cytokines were obtained from genome-wide pQTL mapping data. GWAS data on cortical surface area (SA) and thickness (TH) came from the ENIGMA Consortium. The methods of Mendelian randomization (MR) analysis included the inverse-variance-weighted (IVW), MR-Egger, and weighted median. Migraine reduces the SA of paracentral[ß = -1.3645, OR = 0.2555, 95%CI (0.0660, 0.9898)] by fibroblast growth factor-23(FGF-23), with an intermediate ratio (IR) of 38.13%. Migraine may reduce the TH of superior parietal[ß = -0.0029, OR = 0.9971, 95%CI (0.9943, 0.9999)] by interleukin (IL)-15RA, with an absolute IR of 11.11%. Migraine without aura may reduce the TH of rostral anterior cingulate[ß = -0.0005, OR = 0.9995, 95%CI (0.9991, 0.9999)] by IL-18R1, with an IR of 11.63%. FGF23 and IL-15RA are associated with reduced SA or TH in migraine, while IL-18R1 is associated with increased TH in migraine without aura.

Asunto(s)

Corteza Cerebral , Citocinas , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Citocinas/sangre , Citocinas/genética , Citocinas/metabolismo , Trastornos Migrañosos/genética , Trastornos Migrañosos/sangre , Trastornos Migrañosos/patología

Asunto(s)

Enfermedad de Alzheimer , Calcinosis , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Calcinosis/genética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Masculino , Femenino , Persona de Mediana Edad , Presenilina-1/genética

RESUMEN

Previous research has shown a strong correlation between sepsis and brain structure. However, whether this relationship represents a causality remains elusive. In this study, we employed Mendelian randomization (MR) to probe the associations of genetically predicted sepsis and sepsis-related death with structural changes in specific brain regions. Genome-wide association study (GWAS) data for sepsis phenotypes (sepsis and sepsis-related death) were obtained from the IEU OpenGWAS. Correspondingly, GWAS data for brain structural traits (volume of the subcortical structure, cortical thickness, and surface area) were derived from the ENIGMA consortium. Inverse variance weighted was mainly utilized to assess the causal effects, while weighted median and MR-Egger regression served as complementary methods. Sensitivity analyses were implemented with Cochran Q test, MR-Egger regression, and MR-PRESSO. In addition, a reverse MR analysis was carried out to assess the possibility of reverse causation. We identified that genetic liability to sepsis was normally significantly associated with a reduced surface area of the postcentral gyrus (ß = -35.5280, SE = 13.7465, P = .0096). The genetic liability to sepsis-related death showed a suggestive positive correlation with the surface area of fusiform gyrus (ß = 11.0920, SE = 3.6412, P = .0023) and posterior cingulate gyrus (ß = 3.6530, SE = 1.6684, P = .0286), While it presented a suggestive negative correlation with surface area of the caudal middle frontal gyrus (ß = -11.4586, SE = 5.1501, P = .0261) and frontal pole (ß = -1.0024, SE = 0.4329, P = .0206). We also indicated a possible bidirectional causal association between genetic liability to sepsis-related death and the thickness of the transverse temporal gyrus. Sensitivity analyses verified the robustness of the above associations. These findings suggested that genetically determined liability to sepsis might influence the specific brain structure in a causal way, offering new perspectives to investigate the mechanism of sepsis-related neuropsychiatric disorders.

Asunto(s)

Corteza Cerebral , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Sepsis , Humanos , Sepsis/genética , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad

RESUMEN

BACKGROUND AND OBJECTIVES: Myelin and iron play essential roles in remyelination processes of multiple sclerosis (MS) lesions. χ-separation, a novel biophysical model applied to multiecho T2*-data and T2-data, estimates the contribution of myelin and iron to the obtained susceptibility signal. We used this method to investigate myelin and iron levels in lesion and nonlesion brain areas in patients with MS and healthy individuals. METHODS: This prospective MS cohort study included patients with MS fulfilling the McDonald Criteria 2017 and healthy individuals, aged 18 years or older, with no other neurologic comorbidities. Participants underwent MRI at baseline and after 2 years, including multiecho GRE-(T2*) and FAST-(T2) sequences. Using χ-separation, we generated myelin-sensitive and iron-sensitive susceptibility maps. White matter lesions (WMLs), cortical lesions (CLs), surrounding normal-appearing white matter (NAWM), and normal-appearing gray matter were segmented on fluid-attenuated inversion recovery and magnetization-prepared 2 rapid gradient echo images, respectively. Cross-sectional group comparisons used Wilcoxon rank-sum tests, longitudinal analyses applied Wilcoxon signed-rank tests. Associations with clinical outcomes (disease phenotype, age, sex, disease duration, disability measured by Expanded Disability Status Scale [EDSS], neurofilament light chain levels, and T2-lesion number and volume) were assessed using linear regression models. RESULTS: Of 168 patients with MS (median [interquartile range (IQR)] age 47.0 [21.7] years; 101 women; 6,898 WMLs, 775 CLs) and 103 healthy individuals (age 33.0 [10.5] years, 57 women), 108 and 62 were followed for a median of 2 years, respectively (IQR 0.1; 5,030 WMLs, 485 CLs). At baseline, WMLs had lower myelin (median 0.025 [IQR 0.015] parts per million [ppm]) and iron (0.017 [0.015] ppm) than the corresponding NAWM (myelin 0.030 [0.012]; iron 0.019 [0.011] ppm; both p < 0.001). After 2 years, both myelin (0.027 [0.014] ppm) and iron had increased (0.018 [0.015] ppm; both p < 0.001). Younger age (p < 0.001, b = -5.111 × 10-5), lower disability (p = 0.04, b = -2.352 × 10-5), and relapsing-remitting phenotype (RRMS, 0.003 [0.01] vs primary progressive 0.002 [IQR 0.01], p < 0.001; vs secondary progressive 0.0004 [IQR 0.01], p < 0.001) at baseline were associated with remyelination. Increment of myelin correlated with clinical improvement measured by EDSS (p = 0.015, b = -6.686 × 10-4). DISCUSSION: χ-separation, a novel mathematical model applied to multiecho T2*-images and T2-images shows that young RRMS patients with low disability exhibit higher remyelination capacity, which correlated with clinical disability over a 2-year follow-up.

Asunto(s)

Imagen por Resonancia Magnética , Esclerosis Múltiple , Remielinización , Sustancia Blanca , Humanos , Femenino , Masculino , Adulto , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Remielinización/fisiología , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Estudios Prospectivos , Vaina de Mielina/patología , Hierro/metabolismo , Estudios Transversales , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Estudios de Cohortes

RESUMEN

Niemann-Pick disease type C (NPC) is a rare and fatal neurological disorder caused by mutations in Npc1 or Npc2, with Npc1 accounting for 95% of cases. These mutations result in the functional loss of their respective proteins, causing cellular abnormalities characterized by disrupted lipid dysregulation, calcium dysfunction, elevated damage associated molecular patterns (DAMPs), and a pro-inflammatory environment. This cellular pathology ultimately triggers neurodegeneration, with the cerebellum being the earliest and most affected region. We have recently shown atypical activation of interferon signaling in the presymptomatic Npc1-/- mouse cerebellum and, to a lesser extent, in the cerebral cortex. In addition, we reported that the Amyloid Precursor Protein (APP) is an NPC disease modifier. Loss of APP function leads to widespread neurodegeneration in the NPC brain, including exacerbated interferon signaling in the cerebellum. To better understand the role of APP as a disease modifier throughout the NPC brain, here we carried out a transcriptomic analysis of the cerebral cortex and cerebellum from 3-week-old Npc1-/- mice as well as age-matched controls in the presence and absence of APP. We report differential effects of APP loss of function in the cerebral cortex and cerebellum, including cholesterol and tau dysregulation, in both brain regions. Our findings demonstrate a novel link between APP loss and early pathogenic mechanisms in NPC.

Asunto(s)

Precursor de Proteína beta-Amiloide , Cerebelo , Colesterol , Homeostasis , Interferones , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C , Transducción de Señal , Proteínas tau , Animales , Enfermedad de Niemann-Pick Tipo C/metabolismo , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ratones , Proteínas tau/metabolismo , Proteínas tau/genética , Colesterol/metabolismo , Fosforilación , Cerebelo/metabolismo , Cerebelo/patología , Interferones/metabolismo , Interferones/genética , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Ratones Noqueados , Modelos Animales de Enfermedad

RESUMEN

Metabolic syndrome exhibits associations with diverse neurological disorders, and its potential influence on the cerebral cortex may be one of the many potential factors contributing to these adverse outcomes. In this study, we aimed to investigate the causal relationship between metabolic syndrome and changes in cerebral cortex structure using Mendelian randomization analysis. Genome-wide association study data for the 5 components of metabolic syndrome were obtained from individuals of European descent in the UK Biobank. Genome-wide association study data for 34 known cortical functional regions were sourced from the ENIGMA Consortium. Data on Alzheimer's disease, major depression, and anxiety disorder were obtained from the IEU Open genome-wide association study database. The causal links between metabolic syndrome elements and cerebral cortex architecture were evaluated using inverse variance weighting, Mendelian randomization-Egger, and weighted median techniques, with inverse variance weighting as the primary method. Inverse variance weighting, Mendelian randomization Egger, weighted median, simple mode, and weighted mode methods were employed to assess the relationships between metabolic syndrome and neurological diseases (Alzheimer's disease, major depression, and anxiety disorder). Outliers, heterogeneity, and pleiotropy were assessed using Cochran's Q test, MR-PRESSO, leave-one-out analysis, and funnel plots. Globally, no causal link was found between metabolic syndrome and overall cortical thickness or surface area. However, regionally, metabolic syndrome may influence the surface area of specific regions, including the caudal anterior cingulate, postcentral, posterior cingulate, rostral anterior cingulate, isthmus cingulate, superior parietal, rostral middle frontal, middle temporal, insula, pars opercularis, cuneus, and inferior temporal. It may also affect the thickness of the medial orbitofrontal, caudal middle frontal, paracentral, superior frontal, superior parietal, and supramarginal regions. These findings were nominally significant and withstood sensitivity analyses, showing no substantial heterogeneity or pleiotropy. Furthermore, we found an association between metabolic syndrome and the risk of Alzheimer's disease, major depression, and anxiety disorder. This study suggests a potential association between metabolic syndrome and changes in cerebral cortex structure, which may underlie certain neurological disorders. Furthermore, we found an association between metabolic syndrome and the risk of Alzheimer's disease, major depression, and anxiety disorder. Early diagnosis of metabolic syndrome holds significance in preventing these neurological disorders.

Asunto(s)

Corteza Cerebral , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Síndrome Metabólico , Humanos , Síndrome Metabólico/genética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Femenino , Masculino , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Trastorno Depresivo Mayor/genética , Polimorfismo de Nucleótido Simple

RESUMEN

Mutations in the PSEN genes are the major cause of familial Alzheimer's disease, and presenilin (PS) is the catalytic subunit of γ-secretase, which cleaves type I transmembrane proteins, including the amyloid precursor protein (APP) to release Aß peptides. While PS plays an essential role in the protection of neuronal survival, PSEN mutations also increase the ratio of Aß42/Aß40. Thus, it remains unresolved whether PSEN mutations cause AD via a loss of its essential function or increases of Aß42/Aß40. Here, we test whether the knockin (KI) allele of Psen1 L435F, the most severe FAD mutation located closest to the active site of γ-secretase, causes age-dependent cortical neurodegeneration independent of Aß by crossing various Psen mutant mice to the App-null background. We report that removing Aß completely through APP deficiency has no impact on the age-dependent neurodegeneration in Psen mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases Aß42/Aß40 in the cerebral cortex while decreasing de novo production and steady-state levels of Aß42 and Aß40 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of Psen mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that Psen1 mutations cause age-dependent neurodegeneration independent of Aß, providing further support for a loss-of-function pathogenic mechanism underlying PSEN mutations.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Corteza Cerebral , Mutación , Presenilina-1 , Presenilina-1/genética , Presenilina-1/metabolismo , Animales , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/genética , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratones Transgénicos , Humanos

RESUMEN

Sustained compressive injury (SCI) in the brain is observed in numerous injury and pathological scenarios, including tumors, ischemic stroke, and traumatic brain injury-related tissue swelling. Sustained compressive injury is characterized by tissue loading over time, and currently, there are few in vitro models suitable to study neural cell responses to strain-dependent sustained compressive injury. Here, we present an in vitro model of sustained compressive neural injury via centrifugation. Spheroids were made from neonatal rat cortical cells seeded at 4000 cells/spheroid and cultured for 14 days in vitro. A subset of spheroids was centrifuged at 104, 209, 313 or 419 rads/s for 2 minutes. Modeling the physical deformation of the spheroids via finite element analyses, we found that spheroids centrifuged at the aforementioned angular velocities experienced pressures of 10, 38, 84 and 149 kPa, respectively, and compressive (resp. tensile) strains of 10% (5%), 18% (9%), 27% (14%) and 35% (18%), respectively. Quantification of LIVE-DEAD assay and Hoechst 33342 nuclear staining showed that centrifuged spheroids subjected to pressures above 10 kPa exhibited significantly higher DNA damage than control spheroids at 2, 8, and 24 hours post-injury. Immunohistochemistry of ß3-tubulin networks at 2, 8, and 24 hours post-centrifugation injury showed increasing degradation of microtubules over time with increasing strain. Our findings show that cellular injuries occur as a result of specific levels and timings of sustained tissue strains. This experimental SCI model provides a high throughput in vitro platform to examine cellular injury, to gain insights into brain injury that could be targeted with therapeutic strategies.

Asunto(s)

Supervivencia Celular , Neuritas , Esferoides Celulares , Animales , Esferoides Celulares/patología , Ratas , Neuritas/metabolismo , Neuritas/patología , Estrés Mecánico , Corteza Cerebral/patología , Células Cultivadas , Ratas Sprague-Dawley , Daño del ADN , Centrifugación

RESUMEN

Neuronal loss is a hallmark of stroke and other neurodegenerative diseases, and as such, neuronal loss caused by microglia has been thought to be a contributing factor to disease progression. Here, we show that microglia indeed contribute significantly to neuronal loss in a mouse model of stroke, but this microglial-dependent process of neuronal clearance specifically targets stressed and degenerating neurons in the ischemic cortical region and not healthy non-ischemic neurons. Nonspecific stimulation of microglia decreased the density of neurons in the ischemic cortical region, whereas specific inhibition of MFG-E8 signaling, which is required for microglial phagocytosis of neurons, had the opposite effect. In both scenarios, the effects were microglia specific, as the same treatments had no effect in mice whose microglia were depleted prior to stroke. Finally, even though the inhibition of MFG-E8 signaling increased neuronal density in the ischemic brain region, it substantially exacerbated the development of cortical infarction. In conclusion, microglia through MFG-E8 signaling contribute to the loss of ischemic neurons and, in doing so, minimize the development of cortical infarction after stroke.

Asunto(s)

Antígenos de Superficie , Microglía , Proteínas de la Leche , Neuronas , Transducción de Señal , Accidente Cerebrovascular , Animales , Microglía/metabolismo , Microglía/patología , Neuronas/metabolismo , Neuronas/patología , Ratones , Proteínas de la Leche/metabolismo , Antígenos de Superficie/metabolismo , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/complicaciones , Masculino , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Infarto Cerebral/patología , Infarto Cerebral/metabolismo , Infarto Cerebral/etiología , Encéfalo/metabolismo , Encéfalo/patología , Fagocitosis , Corteza Cerebral/metabolismo , Corteza Cerebral/patología

RESUMEN

Abnormal shifts in global climate, leading to extreme weather, significantly threaten the safety of individuals involved in outdoor activities. Hypothermia-induced coma or death frequently occurs in clinical and forensic settings. Despite this, the precise mechanism of central nervous system injury due to hypothermia remains unclear, hindering the development of targeted clinical treatments and specific forensic diagnostic indicators. The GEO database was searched to identify datasets related to hypothermia. Post-bioinformatics analyses, DEGs, and ferroptosis-related DEGs (FerrDEGs) were intersected. GSEA was then conducted to elucidate the functions of the Ferr-related genes. Animal experiments conducted in this study demonstrated that hypothermia, compared to the control treatment, can induce significant alterations in iron death-related genes such as PPARG, SCD, ADIPOQ, SAT1, EGR1, and HMOX1 in cerebral cortex nerve cells. These changes lead to iron ion accumulation, lipid peroxidation, and marked expression of iron death-related proteins. The application of the iron death inhibitor Ferrostatin-1 (Fer-1) effectively modulates the expression of these genes, reduces lipid peroxidation, and improves the expression of iron death-related proteins. Severe hypothermia disrupts the metabolism of cerebral cortex nerve cells, causing significant alterations in ferroptosis-related genes. These genetic changes promote ferroptosis through multiple pathways.

Asunto(s)

Corteza Cerebral , Ferroptosis , Hipotermia , Neuronas , Ferroptosis/genética , Animales , Hipotermia/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Neuronas/metabolismo , Hierro/metabolismo , Peroxidación de Lípido , Masculino , Ratas , Fenilendiaminas/farmacología , Ciclohexilaminas

RESUMEN

Rasmussen's encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherotomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Furthermore, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expression of cell-cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest the potential involvement of cell cycle regulators in the progression of RE.

Asunto(s)

Encefalitis , Humanos , Encefalitis/genética , Encefalitis/patología , Encefalitis/metabolismo , Masculino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Femenino , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Ciclo Celular/genética

RESUMEN

Structural covariance networks and causal effects within can provide critical information on gray matter reorganization and disease-related hierarchical changes. Based on the T1WI data of 43 classical trigeminal neuralgia patients and 45 controls, we constructed morphological similarity networks of cortical thickness, sulcal depth, fractal dimension, and gyrification index. Moreover, causal structural covariance network analyses were conducted in regions with morphological abnormalities or altered nodal properties, respectively. We found that patients showed reduced sulcal depth, gyrification index, and fractal dimension, especially in the salience network and the default mode network. Additionally, the integration of the fractal dimension and sulcal depth networks was significantly reduced, accompanied by decreased nodal efficiency of the bilateral temporal poles, and right pericalcarine cortex within the sulcal depth network. Negative causal effects existed from the left insula to the right caudal anterior cingulate cortex in the gyrification index map, also from bilateral temporal poles to right pericalcarine cortex within the sulcal depth network. Collectively, patients exhibited impaired integrity of the covariance networks in addition to the abnormal gray matter morphology in the salience network and default mode network. Furthermore, the patients may experience progressive impairment in the salience network and from the limbic system to the sensory system in network topology, respectively.

Asunto(s)

Corteza Cerebral , Imagen por Resonancia Magnética , Neuralgia del Trigémino , Humanos , Neuralgia del Trigémino/patología , Neuralgia del Trigémino/diagnóstico por imagen , Neuralgia del Trigémino/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Anciano , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/patología , Adulto , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Mapeo Encefálico

RESUMEN

PURPOSE: This study examined the relationship between structural brain networks and long-term treatment outcomes in patients with panic disorder (PD) using machine learning methods. METHOD: The study involved 80 participants (53 PD patients and 27 healthy controls) and included clinical assessments and MRI scans at baseline and after two years (160 MRIs). Patients were categorized based on their response to two-year pharmacotherapy. Brain networks were analyzed using white matter tractography and network-based statistics. RESULTS: Results showed structural network changes in PD patients, particularly in the extended fear network, including frontal regions, thalamus, and cingulate gyrus. Longitudinal analysis revealed that increased connections to the amygdala, hippocampus, and insula were associated with better treatment response. Conversely, overconnectivity in the amygdala and insula at baseline was associated with poor response, and similar patterns were found in the insula and parieto-occipital cortex related to non-remission. This study found that SVM and CPM could effectively predict treatment outcomes based on network pattern changes in PD. CONCLUSIONS: These findings suggest that monitoring structural connectome changes in limbic and paralimbic regions is critical for understanding PD and tailoring treatment. The study highlights the potential of using personalized biomarkers to develop individualized treatment strategies for PD.

Asunto(s)

Conectoma , Aprendizaje Automático , Imagen por Resonancia Magnética , Trastorno de Pánico , Humanos , Trastorno de Pánico/diagnóstico por imagen , Trastorno de Pánico/terapia , Masculino , Femenino , Adulto , Estudios Longitudinales , Resultado del Tratamiento , Estudios Transversales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Persona de Mediana Edad , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Imagen de Difusión Tensora/métodos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología

RESUMEN

Olfactory dysfunction is a common non-motor symptom of Parkinson's disease(PD) and may hold valuable insights into the disease's underlying pathophysiology. This study aimed to investigate cortical morphometry alterations in PD patients with severe hyposmia(PD-SH) and mild hyposmia(PD-MH) using surface-based morphometry(SBM) methods. Participants included 36 PD-SH patients, 38 PD-MH patients, and 40 healthy controls(HCs). SBM analysis revealed distinct patterns of cortical alterations in PD-SH and PD-MH patients. PD-MH patients exhibited reduced cortical thickness in the right supramarginal gyrus, while PD-SH patients showed widespread cortical thinning in regions including the bilateral pericalcarine cortex, bilateral lingual gyrus, left inferior parietal cortex, left lateral occipital cortex, right pars triangularis, right cuneus, and right superior parietal cortex. Moreover, PD-SH patients displayed reduced cortical thickness in the right precuneus compared to PD-MH patients. Fractal dimension analysis indicated increased cortical complexity in PD-MH patients' right superior temporal cortex and right supramarginal gyrus, as well as decreased complexity in the bilateral postcentral cortex, left superior parietal cortex, and right precentral cortex. Similarly, cortical gyrification index and cortical sulcal depth exhibited heterogeneous patterns of changes in PD-SH and PD-MH patients compared to HCs. These findings underscore the multifaceted nature of olfactory impairment in PD, with distinct patterns of cortical morphometry alterations associated with different degrees of hyposmia. The observed discrepancies in brain regions showing alterations reflect the complexity of PD's pathophysiology. These insights contribute to a deeper understanding of olfactory dysfunction in PD and provide potential avenues for early diagnosis and targeted interventions.

Asunto(s)

Anosmia , Corteza Cerebral , Imagen por Resonancia Magnética , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Anciano , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Anosmia/patología , Trastornos del Olfato/patología , Trastornos del Olfato/etiología , Trastornos del Olfato/diagnóstico por imagen , Trastornos del Olfato/fisiopatología

RESUMEN

PURPOSE: The discovery of the glymphatic system, crucial for cerebrospinal and interstitial fluid exchange, has enhanced our grasp of brain protein balance and its potential role in neurodegenerative disease prevention and therapy. Detecting early neurodegenerative shifts via noninvasive biomarkers could be key in identifying at-risk individuals for Alzheimer's disease (AD). Our research explores a diffusion tensor imaging (DTI) method that measures cortical mean diffusivity (cMD), potentially a more sensitive indicator of neurodegeneration than traditional macrostructural methods. MATERIALS AND METHODS: We analyzed 67 post-traumatic stress disorder (PTSD)-diagnosed veterans from the Alzheimer's Disease Neuroimaging Initiative database. Participants underwent structural MRI, DTI, Aß PET imaging, and cognitive testing. We focused on the DTI-ALPS technique to assess glymphatic function and its relation to cMD, cortical Aß accumulation, and thickness, accounting for age and APOE ε4 allele variations. RESULTS: The cohort, all male with an average age of 68.1 (SD 3.4), showed a strong inverse correlation between DTI-ALPS and cMD in AD-affected regions, especially in the entorhinal, parahippocampal, and fusiform areas. Higher DTI-ALPS readings were consistently linked with greater cortical thickness, independent of Aß deposits and genetic risk factors. Age and cMD emerged as inversely proportional predictors of DTI-ALPS, indicating a complex interaction with age. CONCLUSION: The study confirms a meaningful association between glymphatic efficiency and cMD in AD-sensitive zones, accentuating cortical microstructural alterations in PTSD. It positions DTI-ALPS as a viable biomarker for assessing glymphatic function in PTSD, implicating changes in DTI-ALPS as indicative of glymphatic impairment.

Asunto(s)

Enfermedad de Alzheimer , Corteza Cerebral , Imagen de Difusión Tensora , Sistema Glinfático , Trastornos por Estrés Postraumático , Veteranos , Humanos , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/patología , Masculino , Anciano , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Persona de Mediana Edad , Veteranos/psicología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Péptidos beta-Amiloides/metabolismo

RESUMEN

BACKGROUND: Anhedonia is an enduring symptom of subthreshold depression (StD) and predict later onset of major depressive disorder (MDD). Brain structural covariance describes the inter-regional distribution of morphological changes compared to healthy controls (HC) and reflects brain maturation and disease progression. We investigated neural correlates of anhedonia from the structural covariance. METHODS: T1-weighted brain magnetic resonance images were acquired from 79 young adults (26 StD, 30 MDD, and 23 HC). Intra-individual structural covariance networks of 68 cortical surface area (CSAs), 68 cortical thicknesses (CTs), and 14 subcortical volumes were constructed. Group-level hubs and principal edges were defined using the global and regional graph metrics, compared between groups, and examined for the association with anhedonia severity. RESULTS: Global network metrics were comparable among the StD, MDD, and HC. StD exhibited lower centralities of left pallidal volume than HC. StD showed higher centralities than HC in the CSAs of right rostral anterior cingulate cortex (ACC) and pars triangularis, and in the CT of left pars orbitalis. Less anhedonia was associated with higher centralities of left pallidum and right amygdala, higher edge betweenness centralities in the structural covariance (EBSC) of left postcentral gyrus-parahippocampal gyrus and LIPL-right amygdala. More anhedonia was associated with higher centralities of left inferior parietal lobule (LIPL), left postcentral gyrus, left caudal ACC, and higher EBSC of LIPL-left postcentral gyrus, LIPL-right lateral occipital gyrus, and left caudal ACC-parahippocampal gyrus. LIMITATIONS: This study has a cross-sectional design. CONCLUSIONS: Structural covariance of brain morphologies within the salience and limbic networks, and among the salience-limbic-default mode-somatomotor-visual networks, are possible neural correlates of anhedonia in depression.

Asunto(s)

Anhedonia , Trastorno Depresivo Mayor , Imagen por Resonancia Magnética , Humanos , Anhedonia/fisiología , Masculino , Femenino , Adulto Joven , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/patología , Adulto , Depresión/diagnóstico por imagen , Depresión/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/patología , Amígdala del Cerebelo/fisiopatología , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/patología , Giro del Cíngulo/fisiopatología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología

RESUMEN

OBJECTIVE: To explore the clinical, imaging, and genetic characteristics of an adult patient with sporadic Neuronal intranuclear inclusion disease (NIID). METHODS: A patient who had visited the First People's Hospital of Chenzhou on August 6, 2023 was selected as the study subject. Results of clinical examination, neuroimaging, and genetic testing were retrospectively analyzed along with a literature review. The number of GGC trinucleotide repeats in the 5'-untranslated region of the NOTCH2NLC gene was determined by GC-PCR. RESULTS: The patient had presented with episodic encephalopathy, with enhanced magnetic resonance imaging showing enhancement features of the posterior cerebral cortex during the period of acute episode. Genetic testing revealed an increased number of GGC repeats (n = 97) in the 5'- untranslated region of the NOTCH2NLC gene, which confirmed the diagnosis of NIID. CONCLUSION: Clinical attention should be paid to the enhanced MRI findings of patients with adult-onset NIID, for whom posterior cortical enhancement may be characteristic manifestation during the acute phase of encephalopathy-like episode.

Asunto(s)

Cuerpos de Inclusión Intranucleares , Enfermedades Neurodegenerativas , Humanos , Cuerpos de Inclusión Intranucleares/genética , Enfermedades Neurodegenerativas/genética , Imagen por Resonancia Magnética , Masculino , Pruebas Genéticas , Femenino , Persona de Mediana Edad , Receptor Notch2/genética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Adulto