Cognitive Motor Research Articles

NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1-associated cognitive and motor impairment.

Cognitive or motor impairment is common among individuals with neurofibromatosis type 1 (NF1), an autosomal dominant tumor-predisposition disorder. As many as 70% of children with NF1 report difficulties with spatial/working memory, attention, executive function, and fine motor movements. In contrast to the utilization of various Nf1 mouse models, here we employ an NF1+/ex42del miniswine model to evaluate the mechanisms and characteristics of these presentations, taking advantage of a large animal species more like human anatomy and physiology. The prefrontal lobe, anterior cingulate, and hippocampus from NF1+/ex42del and wild-type miniswine were examined longitudinally, revealing abnormalities in mature oligodendrocytes and astrocytes, and microglial activation over time. Imbalances in GABA: Glutamate ratios and GAD67 expression were observed in the hippocampus and motor cortex, supporting the role of disruption in inhibitory neurotransmission in NF1 cognitive impairment and motor dysfunction. Moreover, NF1+/ex42del miniswine demonstrated slower and shorter steps, indicative of a balance-preserving response commonly observed in NF1 patients, and progressive memory and learning impairments. Collectively, our findings affirm the effectiveness of NF1+/ex42del miniswine as a valuable resource for assessing cognitive and motor impairments associated with NF1, investigating the involvement of specific neural circuits and glia in these processes, and evaluating potential therapeutic interventions.

Animal models to study cognitive impairment of chronic kidney disease.

Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD), and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives, and society. However, the underlying pathomechanisms are poorly understood, and current therapies mostly aim at supporting patients in their daily lives. This illustrates the urgent need to elucidate the pathogenesis and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modeling of cognitive disorders in CKD. We discuss the use of mice, rats, and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving the therapy of people with CKD and MCI.

Dravet Syndrome: An Electroclinical, Genetic, Treatment, and Outcome Study of 35 Patients in Argentina

AbstractWe analyzed the electroclinical features, molecular findings, treatment, disease course, and outcomes of patients with Dravet syndrome (DS) with positive genetic markers seen at a public hospital in Argentina. A retrospective study was conducted assessing the clinical records of 44 patients who met the diagnostic criteria for DS according to the 2022 classification of epilepsy of the International League Against Epilepsy seen at our center between March 2018 and June 2023. Of 44 patients, 35 (18 males and 17 females), in whom genetic studies yielded positive results, were included. Median age was 9 years (range 4 to 16 years), and the median time of follow-up was 10 years (range 3 to 14 years). The mean age at onset was 7 months. The first seizure was associated with febrile illness in all patients, and in 11 (31.4%), seizures were immediately preceded by either infectious disease or vaccination. Heterozygous pathogenic/likely pathogenic SCN1A variants were detected in 32 of the original 44 patients (73%), of which 47% were novel. Variants in other genes related to DS (HCN1, STXB1, and SCN1B) were identified in three patients. Cognitive delay and motor impairment were found to be more severe in patients that had multiple and drug-resistant seizures and in those who had the complete phenotype with myoclonic seizures. Novel SCN1A gene variants were identified in nearly half of the patients. The prognosis for cognitive development is unfavorable. Seizures are not well controlled with antiseizure medications and early treatment with ketogenic dietary therapy as well as cannabidiol should be considered.

Safranal alleviates pentetrazole-induced epileptic seizures in mice by inhibiting the NF-κB signaling pathway and mitochondrial-dependent apoptosis through GSK-3β inactivation

Ethnopharmacological relevanceSaffron, a traditional Chinese medicine, is derived from Crocus sativus L. stigmas and has been reported to possess neuroprotective properties and potentially contribute to the inhibition of apoptosis and inflammation. Safranal, a potent monothyral aldehyde, is a main component of saffron that has been reported to have antiepileptic activity. However, the specific mechanism by which safranal suppresses epileptic seizures via its antiapoptotic and anti-inflammatory properties is unclear. AimTo evaluate the effect of safranal on seizure severity, inflammation, and postictal neuronal apoptosis in a mouse model of pentetrazole (PTZ)-induced seizures and explore the underlying mechanism involved. Materials and methodsThe seizure stage and latency of stage 2 and 4 were quantified to assess the efficacy of safranal in mitigating PTZ-induced epileptic seizures in mice. Electroencephalography (EEG) was employed to monitor epileptiform afterdischarges in each experimental group. The cognitive abilities and motor functions of the mice were evaluated using the novel object recognition test and the open field test, respectively. Neurons were quantified using hematoxylin and eosin staining. Additionally, bioinformatics tools were utilized to predict the interactions between safranal and specific target proteins. Glycogen synthase kinase-3β (GSK-3β), mitochondrial apoptosis-related proteins, and inflammatory factor levels were analyzed through western blotting. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations in brain tissue were assessed by ELISA. ResultsSafranal decreased the average seizure stage and increased the lantency of stage 2 and 4 seizures in PTZ-induced epileptic mice. Additionally, safranal exhibited neuroprotective effects on hippocampal CA1 and CA3 neurons and reduced hyperactivity caused by postictal hyperexcitability. Bioinformatics analysis revealed that safranal can bind to five specific proteins, including GSK-3β. By promoting Ser9 phosphorylation and inhibiting GSK-3β activity, safranal effectively suppressed the NF-κB signaling pathway. Moreover, the findings indicate that safranal treatment can decrease TNF-α and IL-1β levels in the cerebral tissues of epileptic mice and downregulate mitochondrial apoptosis-related proteins, including Bcl-2, Bax, Bak, Caspase 9, and Caspase 3. ConclusionSafranal can suppress the NF-κB signaling pathway and mitochondrial-dependent apoptosis through GSK-3β inactivation, suggesting that it is a promising therapeutic agent for epilepsy treatment.

Effect of Capsaicin on 3-NP-Induced Neurotoxicity: A Pre-Clinical Study.

The study objectives are to investigate the ability of capsaicin to revert the toxic effects in glutamate and lipopolysaccharide (LPS)-induced neurotoxicity in Neuro2a (N2a) cells as well as thwarting cognitive impairments, mitochondrial deficits, and oxidative insults induced by 3-nitropropanoic acid (3-NP) in a rodent model of Huntington's disease. In-vitro study with N2a cells was performed through MTT and LDH assay and their biochemical examinations were also performed. 3-NP-administered mice (n = 6) were treated with capsaicin (5, 10, and 20mg/kg) through the per-oral (p.o.) route for 7 consecutive days. Physiological and behavioral studies were performed in drug-treated mice. After behavioral studies, biochemical parameters were performed for cytokines levels, various oxidative stress parameters, and mitochondrial enzyme complex activities with mitochondrial permeability. N2a cells treated with capsaicin demonstrated neuroprotective effects and reduced neurotoxicity. Based on experimental observation, in an in-vitro study, the effective dose of CAP was 50 µM. Moreover, a 100 µM dose of capsaicin had toxic effects on neuronal cells (N2a cells). On the other hand, the effective dose of 3-NP was 20mg/kg, (p.o.) in animals (in-vivo). All tested doses of capsaicin upturned the cognitive impairment and motor in-coordination effects induced by 3-NP. 3-NP-injected mice demonstrated substantially increased pro-inflammatory cytokine concentrations, defective mitochondrial complex activity, and augmented oxidative insult. However, capsaicin at different doses reduced oxidative damage and cytokines levels and improved mitochondrial complex activity along with mitochondrial permeability. Furthermore, capsaicin (10 and 20mg/kg) improved the TNF-α concentration. These findings suggested because of the anti-inflammatory and antioxidant effect, capsaicin can be considered a novel treatment for the management of neurodegenerative disorders by reverting the antioxidant enzyme activity, pro-inflammatory cytokines concentration, and mitochondrial functions.

POLA PENGASUHAN ORANG TUA DENGAN PERKEMBANGAN SOSIAL ANAK RETARDASI MENTAL

Mental retardation is a disorder in which mental development is halted or incomplete that can affect the level of intelligence or cognitive domains, including language, motor, and social skills. Children with mental retardation are less able to develop the abilities and skills of their peers. An increase in cases of mental retardation will result in a decrease in the quality of human resources. Therefore, in addition to environmental factors, the importance of completing proper nutrition will prevent neuroanatomical, neurochemical, and neurophysiological dysfunctions in humans. This study aims to analyze parenting patterns with the social development of children with mental retardation. This study used a cross-sectional design on 50 selected samples at SLB Cahaya Peureulak, East Aceh district. The results found that 62% of the sample had positive parenting patterns with 38% of children's social development achieved and 24% of children's social development that was not achieved. Thirty-eight percent of negative parenting patterns with social development achieved by only 12% and social development not achieved by 26%. The results of the bivariate test obtained a p-value of 0.04 (<0.05) meaning that there is a significant relationship between parenting patterns and the social development of mentally retarded children. Parental assistance for children with mental retardation dominantly influences children's interpersonal relationships. Mentally retarded children can focus on interesting things or media with repeated learning.

Association of Age with Dual-Task Objective Cognitive Indicators and Gait Parameters in Older Adults.

Early recognition of dementia like Alzheimer's disease is crucial for disease diagnosis and treatment, and existing objective tools for early screening of cognitive impairment are limited. To investigate age-related behavioral indicators of dual-task cognitive performance and gait parameters and to explore potential objective markers of early cognitive decline. The community-based cognitive screening data was analyzed. Hierarchical cluster analysis and Pearson correlation analysis were performed on the 9-item subjective cognitive decline (SCD-9) scores, walking-cognitive dual-task performance, walking speed, and gait parameters of 152 participants. The significant differences of indicators that may related to cognitive decline were statistically analyzed across six age groups. A mathematical model with age as the independent variable and motor cognition composite score as the dependent variable was established to observe the trend of motor cognition dual-task performance with age. Strong correlation was found between motor cognitive scores and SCD and age. Gait parameters like the mean value of ankle angle, the left-right difference rate of ankle angle and knee angle and the coefficient of variation of gait cycle showed an excellent correlation with age. Motor cognition scores showed a decreasing trend with age. The slope of motor cognition scores with age after 50 years (k = -1.06) was six times higher than that before 50 years (k = -0.18). Cognitive performance and gait parameters in the walking-cognitive dual-task state are promising objective markers that could characterize age-related cognitive decline.

MAPPING ALZHEIMER'S DISEASE PSEUDO-PROGRESSION WITH MULTIMODAL BIOMARKER TRAJECTORY EMBEDDINGS.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive degeneration and motor impairment, affecting millions worldwide. Mapping the progression of AD is crucial for early detection of loss of brain function, timely intervention, and development of effective treatments. However, accurate measurements of disease progression are still challenging at present. This study presents a novel approach to understanding the heterogeneous pathways of AD through longitudinal biomarker data from medical imaging and other modalities. We propose an analytical pipeline adopting two popular machine learning methods from the single-cell transcriptomics domain, PHATE and Slingshot, to project multimodal biomarker trajectories to a low-dimensional space. These embeddings serve as our pseudotime estimates. We applied this pipeline to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset to align longitudinal data across individuals at various disease stages. Our approach mirrors the technique used to cluster single-cell data into cell types based on developmental timelines. Our pseudotime estimates revealed distinct patterns of disease evolution and biomarker changes over time, providing a deeper understanding of the temporal dynamics of AD. The results show the potential of the approach in the clinical domain of neurodegenerative diseases, enabling more precise disease modeling and early diagnosis.

C.6 Sex differences in neurodevelopmental outcomes and brain development from early-life to 8-years in preterm males and females

Background: Sex is associated with differences in early outcomes with preterm males at greater risk for mortality and morbidity. The objective of this study was to examine preterm sex differences in neurodevelopmental outcomes and brain development from early-life to 8-years. Methods: A prospective cohort of preterm infants born 24-32 weeks gestation were followed to 8-years with standardized measures. MRI scans were performed after birth, term-equivalent age and 8-years. Associations between sex, risk factors, brain volumes, white matter fractional anisotropy (FA) and outcomes were assessed using generalized estimating equations. Results: Preterm males (N=83) and females (N=72) had similar risk factors, brain injury and pain exposure. Sex was a predictor of cognitive scores (P=0.02) and motor impairment (P=0.03), with males having lower cognitive scores and higher motor impairment over time. There was a sex effect for FA (P=0.04), with males having lower FA over time. There were significant sex-brain injury and sex-pain interactions for cognitive and motor outcomes. Conclusions: In this longitudinal study, preterm males had lower cognitive scores and greater motor impairment, which may relate to differences in white matter maturation. Effects of brain injury and pain on outcomes is moderated by sex, indicating a differential response to early-life adversity in preterm males and females.

Anti-inflammatory effects of khaya senegalensis bark and tinospora cordifolia leaf extracts on striatal ischemic injury in rats

The striatal synaptic pathways play a crucial role in the functioning of the basal ganglia and are an essential part of the cortical-basal ganglia loops that regulate motor function, emotion, and cognition. The purpose of this study was to examine the potential therapeutic benefits of extracts from the leaves of Tinospora cordifolia (TC) and Khaya senegalensis (KS) on striatal ischemia injury resulting from amitriptyline (AMT). Eleven groups (n = 5) comprising fifty-five adult male Wistar rats weighing between 184 and 254 g were created: Distilled water (2 milliliters per kilogram) was used as a control. The groups that included AMT (750 mg/kg), KS (200 mg/kg) + AMT, KS (300 mg/kg) + AMT, KS (400 mg/kg) + AMT; TC (200 mg/kg) + AMT; TC (300 mg/kg) + AMT; TC (400 mg/kg) + AMT; COM (200 mg/kg) + AMT; COM (300 mg/kg) + AMT and COM (400 mg/kg) + AMT. Treatment was given orally for a period of 14 days. Rats were neck dislocated to stop the experiment and brain tissues were removed and preserved in 10% buffered formal saline. TNF- α result showed a significant increase (p<0.05) by 708.9±28.05δ in AMT-treated rats compared to the control (324.8±7.58). And decreased significantly (328.5±5.24α, 380.4±3.43δ and 375.3±5.50δ) in the treated groups compared to AMT-treated rats. Normal cytoarchitecture of the striatal cells was intact in the control group. AMT rates (Ischemic stroke rats) revealed neurodegenerative changes, characterized by cellular hypertrophy and perivascular edema, and proliferation of reactive astrocytes and microglia. However, the treatment of KS, TC, and COM KS+TC remarkably ameliorates striatal cell degeneration by preserving striatal cell cytoarchitecture, especially with COM KS+TC 400 mg/kg treatment. Findings suggest that COM KS+TC possesses anti-inflammatory properties, which could be of potential benefit in the treatment and management of ischemic stroke.

Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation

Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.

Neurodevelopmental Outcomes Following Childhood Viral Meningitis in Canterbury New Zealand.

Most childhood meningitis is viral in countries with widespread conjugate vaccine use. This study assessed clinical features and neurodevelopmental outcomes in preschool children following enteroviral and parechoviral meningitis. Children 18-42 months of age in Canterbury, New Zealand were included, who had enterovirus (EV) or parechovirus (HPEV) meningitis from 2015 to 2021. Comprehensive neurodevelopmental assessments were completed by a psychologist using the Bayley Scale for Infant Development-3 (BSID-3). Mean composite and scaled scores and proportion below the cutoff were assessed in each domain. Clinical data was analyzed. There were 79 children 18-42 months old with previous EV or HPEV meningitis. BSID assessments were completed for 33 children (55% male), median age 32 months, from 2019 to 2022 including 23 with EV and 10 HPEV meningitis. At diagnosis, 32 (97%) received intravenous/intramuscular antibiotics, and 6 received a fluid bolus. Parents reported developmental speech concerns in 6 children, and delayed motor milestones in 1 child. There was no reported sensorineural hearing loss. BSID mean composite scores were in the expected range for cognition 102 (confidence interval: 98-106), language 96 (93-100) and motor 102 (98-106) domains. Overall, 12/33 (36%) children had below expected scores in 1 developmental domain, including scores 1-2 SD below the normative mean for cognition (2/33; 6%), receptive language (6/33; 18%), expressive language (5/33; 15%) and gross motor (6/33; 18%). There were no differences between scores in EV and HPEV meningitis. Following viral meningitis, more than a third of preschool children had a mild developmental delay with comprehensive neurodevelopmental assessment, suggesting targeted follow-up should be considered.

Novel Feature Generation for Classification of Motor Activity from Functional Near-Infrared Spectroscopy Signals Using Machine Learning.

Recent research in the field of cognitive motor action decoding focuses on data acquired from Functional Near-Infrared Spectroscopy (fNIRS) and its analysis. This research aims to classify two different motor activities, namely, mental drawing (MD) and spatial navigation (SN), using fNIRS data from non-motor baseline data and other motor activities. Accurate activity detection in non-stationary signals like fNIRS is challenging and requires complex feature descriptors. As a novel framework, a new feature generation by fusion of wavelet feature, Hilbert, symlet, and Hjorth parameters is proposed for improving the accuracy of the classification. This new fused feature has statistical descriptor elements, time-localization in the frequency domain, edge feature, texture features, and phase information to detect and locate the activity accurately. Three types of independent component analysis, including FastICA, Picard, and Infomax were implemented for preprocessing which removes noises and motion artifacts. Two independent binary classifiers are designed to handle the complexity of classification in which one is responsible for mental drawing (MD) detection and the other one is spatial navigation (SN). Four different types of algorithms including nearest neighbors (KNN), Linear Discriminant Analysis (LDA), light gradient-boosting machine (LGBM), and Extreme Gradient Boosting (XGBOOST) were implemented. It has been identified that the LGBM classifier gives high accuracies-98% for mental drawing and 97% for spatial navigation. Comparison with existing research proves that the proposed method gives the highest classification accuracies. Statistical validation of the proposed new feature generation by the Kruskal-Wallis H-test and Mann-Whitney U non-parametric test proves the reliability of the proposed mechanism.

Anomalies of Midbrain/Hindbrain Development: Malformations of Cerebellum: Diagnosis, Classification, and Rehabilitative Hypothesis

AbstractExtensive research has been conducted on the cerebellum, making it one of the most thoroughly investigated regions of the brain. It plays a fundamental role not only in motor control but also in motor learning and cognition. The development of the cerebellum is a lengthy process, beginning during the embryonic period up to the first years of life. This slow and protracted process makes it a vulnerable organ liable to different insults, responsible for many developmental disorders such as Dandy–Walker syndrome, medulloblastoma, dystroglicanopathy, pontocerebellar hypoplasia, thubulinopathies, and Jubert syndrome. Due to several factors, the true prevalence of cerebellar malformations is not known in most cases. The cerebellum undergoes development through following four fundamental stages:(1) Identification of the cerebellar region at the boundary between the midbrain and hindbrain.(2) Establishment of two cell proliferation compartments: firstly, Purkinje cells and deep cerebellar nuclei emerge from the ventricular zone of the metencephalic alar plate; secondly, granule cell precursors are generated from a separate proliferation compartment known as the upper rhombic lip.(3) Migration of granule cells toward the interior: granule precursor cells constitute the external granular layer (EGL), and during the initial postnatal year, granule cells migrate inward to their final position in the internal granular layer.(4) Formation of cerebellar circuitry and subsequent differentiation.Based on different types of involvement of the structures detected in the brain magnetic resonance, the classification of brainstem and cerebellar anomalies is divided into three categories: (1) mainly the cerebellum, (2) mainly the brain stem, and (3) both involved. This review will outline the developmental processes of the cerebellum and delve into common developmental disorders associated with it, including the Dandy–Walker syndrome, cerebellar hypoplasia, rhomboencephalosynapsis, lissencephaly, and gray matter heterotopias.

Resistance To Thyroid Hormone Receptor Alpha Due to Heterozygous Pathogenic Variant in THRA Gene: A Case Report from India

Background: Thyroid Hormone Receptor Alpha (THRA) gene mutation is a thyroid hormone resistance syndrome characterized by non-responsiveness of target tissues to the active form of TH (T3). Clinical Description: We describe a heterozygous missense variant in exon 8 of THRA gene detected in a 2-month-old female with clinical phenotype of hypothyroidism, low free thyroxine, elevated free triiodothyronine & normal levels of thyroid stimulating hormone. Management & Outcome: Clinical improvement in linear growth, motor development domain, hypotonia & constipation were noted with levothyroxine therapy but insufficiencies in cognitive and fine motor skills may remain. Conclusion: THRA gene mutation should be considered in patients with features of clinical hypothyroidism and elevated free T3, decreased/ normal free thyroxine & normal thyroid-stimulating hormone levels.

Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remain unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD for whom MRI and comprehensive neurobehavioural assessments were performed. These assessments comprised six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale) and gait function (based on the time and steps in the Timed Up and Go Test). We reconstructed five tracts connecting the ventral tegmental area (VTA) and dorsolateral prefrontal cortex (PFC), ventral lateral PFC, medial orbitofrontal cortex, anterior cingulate cortex (ACC) and nucleus accumbens within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). The PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of the VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Cognitive function groups in older people and risk factors

Risk stratification for cognitive impairment in communities originated from autopsies in cognitively healthy individuals. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) incorporates subjective and objective cognitive function (CF) measures to explore neurocognitive disorders (NCD). It can be applied in communities to explore the factors that may influence positively or negatively. To obtain the relationship between groups of CF classified using the DSM-5 categories, and sociodemographic factors, habits, comorbidities and motor function in older people living in the community. Cross-sectional study with a probabilistic sample (n = 347). The variables were sociodemographic, habits, comorbidities, and cognitive motor function. The participants were grouped considering subjective and objective CF, plus age, sex, and educational level, and defined according to NCD. 28.5% did not present cognitive disorder, 43.9% had mild disorder < 70 years (mildNCD < 70y), 19% with 70 years or more (mildNCD ≥ 70y), and with major disorder 8.6%. The associated factors for mildNCD < 70y were marital status (MS), physical activity (PA), diabetes mellitus, and frailty; for mildNCD > 70y: MS, occupation, living alone, and heart disease; for majorNCD: PA and grip strength. In the multivariate analysis it was observed greater likelihood in the mildNCD groups than in the non-NCD and majorNCD groups. 4 important groups were identified in a community. The mildNCD was mainly explained by sociodemographic factors, lifestyle, clinical conditions, and motor functionality.

Enhanced cognitive flexibility and phasic striatal dopamine dynamics in a mouse model of low striatal tonic dopamine.

The catecholamine neuromodulators dopamine and norepinephrine are implicated in motor function, motivation, and cognition. Although roles for striatal dopamine in these aspects of behavior are well established, the specific roles for cortical catecholamines in regulating striatal dopamine dynamics and behavior are less clear. We recently showed that elevating cortical dopamine but not norepinephrine suppresses hyperactivity in dopamine transporter knockout (DAT-KO) mice, which have elevated striatal dopamine levels. In contrast, norepinephrine transporter knockout (NET-KO) mice have a phenotype distinct from DAT-KO mice, as they show elevated extracellular cortical catecholamines but reduced baseline striatal dopamine levels. Here we evaluated the consequences of altered catecholamine levels in NET-KO mice on cognitive flexibility and striatal dopamine dynamics. In a probabilistic reversal learning task, NET-KO mice showed enhanced reversal learning, which was consistent with larger phasic dopamine transients (dLight) in the dorsomedial striatum (DMS) during reward delivery and reward omission, compared to WT controls. Selective depletion of dorsal medial prefrontal cortex (mPFC) norepinephrine in WT mice did not alter performance on the reversal learning task but reduced nestlet shredding. Surprisingly, NET-KO mice did not show altered breakpoints in a progressive ratio task, suggesting intact food motivation. Collectively, these studies show novel roles of cortical catecholamines in the regulation of tonic and phasic striatal dopamine dynamics and cognitive flexibility, updating our current views on dopamine regulation and informing future therapeutic strategies to counter multiple psychiatric disorders.

Differential Responses of Spinal Microglia to Low-Dose LPS Delivered in the Daily Rest vs Active Phase

Virtually all lung and neural disorders are associated with systemic and/or neuro-inflammation. Neuro-inflammation impairs important forms of neuroplasticity associated with cognitive and spinal motor learning ( e.g., respiratory motor plasticity). Microglia are resident CNS innate immune cells that regulate diverse processes including neuroinflammation and multiple forms of neuroplasticity via neuron-microglia interactions. Brain microglia exhibit profound diurnal rhythms in their response to pro-inflammatory stimuli, such as toll-like receptor 4 (TLR4) activation. Although hippocampal microglia develop a pro-inflammatory phenotype in response to TLR4 activation during the daily rest phase, little is known concerning spinal microglial responses to inflammatory stimuli across the daily rest/active cycle. Thus, we tested the hypothesis that ventral spinal microglia near the phrenic motor nucleus differentially respond to low-dose systemic lipopolysaccharide (LPS) delivered in the rest (12PM) vs active (12AM) phase. Specifically, we investigated microglial responses to systemic inflammation induced by low-dose LPS (0.1mg/kg, i.p.) in 2 populations of adult Sprague-Dawley rats (both 3-6 months old): 1) SD wildtype and 2) SD rats with humanized neuro-neutral apolipoprotein 3 (h APOE3) knock-in. All rats received intrapleural Cholera toxin B (CtB) injections 2 weeks prior to harvest to identify phrenic motor neurons. Twenty-four hours post-LPS or vehicle (0.9% saline), rats were perfused with 1X PBS and fixed with 4% PFA. Spinal tissues containing the phrenic motor nucleus (cervical 3-6) were harvested and dehydrated in 30% sucrose for immunohistochemistry. Activated microglia near phrenic motor neurons were visualized with an Iba-1 antibody and quantified and phenotyped based on morphology. Since no differences in microglia were found between wildtype and h APOE3 rats, data were combined into a single group for analyses. In vehicle-treated rats, robust Iba-1 staining near phrenic motor neurons was observed in the active, but not rest phase. In contrast, Iba-1 staining in LPS treated rats was elevated only when LPS was administered in the rest (not active) phase. After rest-phase LPS injections, microglial cell bodies were larger and had more processes compared to rest-phase controls. In the active phase, spinal microglia were similar between vehicle and LPS injected rats. Thus, spinal microglia exhibit a profound diurnal rhythm in (morphological) responses to systemic inflammation ( i.e. LPS). Further studies are needed to identify specific molecules driving time-of-day differences in spinal microglial responses to pro-inflammatory stimuli. Nevertheless, these findings increase our understanding of how diurnal rhythms impact cellular responses to physiological challenges, such as inflammation. Further, our results yield clues concerning diurnal variations in phrenic motor plasticity, since reciprocal phrenic motor neuron/microglial communication is an important regulator of phrenic motor plasticity. NIH R01HL148030 (GSM), NIH R01HL149800 (GSM), NIH T32HL134621-5 (ABM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Rotavirus Hospitalization in Early Childhood: Fine Motor Skills and Cognition at 6 Years Old in a Population-Based Cohort Study.

Rotavirus is linked to severe childhood gastroenteritis and neurological complications, but its impact on neurodevelopment remains uncertain. We examined data from 1 420 941 Korean children born between 2009 and 2011, using the Korean National Health Insurance System. We assessed neurodevelopmental outcomes at age 6 years using the validated Korean Developmental Test, covering 6 major domains, with propensity score-based inverse probability weighting including consideration of covariates sex, birth weight, changes in body weight from birth to 4-6 months of age, head circumference at 4-6 months of age, residence at birth, economic status, infant feeding types, and birth year. The main analysis that encompassed 5451 children with rotavirus hospitalization and 310 874 unexposed individuals revealed heightened odds of suspected delays in fine motor skills and cognition among exposed children. Our results suggest an association between rotavirus-related hospitalization in infancy and suspected delays in fine motor function and cognition in 6 year olds.