Severe Cognitive Dysfunction Research Articles

A-253 Does Wearing a Watch Influence Performance on the Clock Drawing Test?

Abstract Objective: The present study examines whether individuals who regularly wear a watch will perform better than those who do not on The Clock Drawing Test (CDT) within a memory disorder clinic population. Method: Data from 69 memory disorder clinic patients was utilized, ages 59-94 (M = 80.45, SD = 7.231; 52% female). Participants were included in this study if they had a diagnosis of cognition within normal limits, mild cognitive impairment, or unspecified neurocognitive disorder. Dementia diagnoses were excluded due to the potential impact of more severe cognitive dysfunction on task performance. Patients’ scores on the CDT and responses to questions regarding watch wearing were obtained as part of a brief neuropsychological evaluation. Regular watch wearing was defined by those who responded affirmatively to the question “do you regularly wear a watch?”; individuals reported wearing a watch at least 2 times per week, with the majority (N=30) reporting wearing a watch 5 or more times per week. Results: The 38 participants who wear a watch regularly (M=9.13, SD=.811) performed significantly better on the CDT compared to the 29 participants who do not (M=8.83, SD=1.1441), t(65) = 4.210, p=.044. Similarly, those who wear a watch regularly (M=.85, SD=.812) made significantly fewer errors on the CDT compared to those who do not (M=1.17, SD=1.17), t(65)=4.101, p=.047. Conclusion: Results indicate that individuals who regularly wear a watch perform better on the CDT, making fewer errors than those who do not. This finding might suggest increased planning and organization skills in those who wear watches regularly.

Gene Editing and Rett Syndrome: Does It Make the Cut?

Rett syndrome (RTT) is a rare neurogenetic disorder caused by pathogenic variants of the Methyl CpG binding protein 2 (MECP2) gene. The RTT is characterized by apparent normal early development followed by regression of communicative and fine motor skills. Comorbidities include epilepsy, severe cognitive impairment, and autonomic and motor dysfunction. Despite almost 60 clinical trials and the promise of a gene therapy, no cure has yet emerged with treatment remaining symptomatic. Advances in understanding RTT has provided insight into the complexity and exquisite control of MECP2 expression, where loss of expression leads to RTT and overexpression leads to MECP2 duplication syndrome. Therapy development requires regulated expression that matches the spatiotemporal endogenous expression of MECP2 in the brain. Gene editing has revolutionized gene therapy and promises an exciting strategy for many incurable monogenic disorders, including RTT, by editing the native locus and retaining endogenous gene expression. Here, we review the literature on the currently available editing technologies and discuss their limitations and applicability to the treatment of RTT.

Calcium/calmodulin-dependent protein kinase IIα heterozygous knockout mice show electroencephalogram and behavioral changes characteristic of a subpopulation of schizophrenia and intellectual impairment

Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity. The immature dentate gyrus (iDG) has been replicated in several mouse models, most notably the CaMKIIα heterozygous mouse (CaMKIIα-hKO). The current study characterizes behavioral phenotypes of CaMKIIα-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKIIα-hKO mice were hypoactive in home-cage environment; however, they displayed less anxiety-like phenotype, suggestive of impulsivity-like behavior. In addition, severe cognitive dysfunction was evident in CaMKIIα-hKO mice as examined by novel object recognition and contextual fear conditioning. Several EEG phenomena established in both patients and relevant animal models indicate key pathological changes associated with the disease, include auditory event-related potentials and time–frequency EEG oscillations. CaMKIIα-hKO mice showed altered event-related potentials characterized by an increase in amplitude of the N40 and P80, as well as increased P80 latency. These mice also showed increased power in theta range time–frequency measures. Additionally, CaMKIIα-hKO mice showed spontaneous bursts of spike wave activity, possibly indicating absence seizures. The GABAB agonist baclofen increased, while the GABAB antagonist CGP35348 and the T-Type Ca2+ channel blocker Ethosuximide decreased spike wave burst frequency. None of these changes in event-related potentials or EEG oscillations are characteristic of those observed in general population of patients with schizophrenia; yet, CaMKIIα-hKO mice likely model a subpopulation of patients with schizophrenia.

Rapid improvement in severe long COVID following perispinal etanercept

Background This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. Methods Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 m Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25 mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration. Results Following perispinal etanercept administration there was immediate neurological improvement. At 24 h, there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measurable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved. Conclusion Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.

Neuroinflammation in Vascular Cognitive Impairment and Dementia: Current Evidence, Advances, and Prospects.

Vascular cognitive impairment and dementia (VCID) is a major heterogeneous brain disease caused by multiple factors, and it is the second most common type of dementia in the world. It is caused by long-term chronic low perfusion in the whole brain or local brain area, and it eventually develops into severe cognitive dysfunction syndrome. Because of the disease’s ambiguous classification and diagnostic criteria, there is no clear treatment strategy for VCID, and the association between cerebrovascular pathology and cognitive impairment is controversial. Neuroinflammation is an immunological cascade reaction mediated by glial cells in the central nervous system where innate immunity resides. Inflammatory reactions could be triggered by various damaging events, including hypoxia, ischemia, and infection. Long-term chronic hypoperfusion-induced ischemia and hypoxia can overactivate neuroinflammation, causing apoptosis, blood–brain barrier damage and other pathological changes, triggering or aggravating the occurrence and development of VCID. In this review, we will explore the mechanisms of neuroinflammation induced by ischemia and hypoxia caused by chronic hypoperfusion and emphasize the important role of neuroinflammation in the development of VCID from the perspective of immune cells, immune mediators and immune signaling pathways, so as to provide valuable ideas for the prevention and treatment of the disease.

Aesthetic Preference for Negatively-Valenced Artworks Remains Stable in Pathological Aging: A Comparison Between Cognitively Impaired Patients With Alzheimer's Disease and Healthy Controls.

BackgroundDespite severe cognitive dysfunction in Alzheimer's disease (AD), aesthetic preferences in AD patients seem to retain some stability over time, similarly to healthy controls. However, the underlying mechanisms of aesthetic preference stability in AD remain unclear. We therefore aimed to study the role of emotional valence of stimuli for stability of aesthetic preferences in patients with AD compared to cognitively unimpaired elderly adults.MethodsFifteen AD patients (Mini-Mental State Examination (MMSE) score 12–26) without visual impairment and/or psychiatric disorder, as well as 15 healthy controls without cognitive impairment (MMSE ≥ 27) matched in age, sex, art interest and highest level of education were included in this study. All participants were asked to rank-order eight artworks per stimulus category (positive, negative, neutral in emotional valence) according to their preference twice with a 2-week span in-between. Based on these two rankings a preference change score was calculated. In order to assess explicit recognition memory of the artworks in the second testing session, four artworks of each stimulus category used in the preference ranking task were presented together with a content-matched distractor artwork painted by the same artist. Participants had to indicate which of the stimuli they had seen 2 weeks previously.ResultsAD patients [MMSE (M) = 18.9 ± 3.6; Age (M) = 85.4 ± 6.9; 33.3% male] had no explicit recognition memory of the artworks (recognition at chance level), whereas healthy controls [MMSE (M) = 27.7 ± 1.4; Age (M) = 84.3 ± 6.7; 33.3% male] correctly recognized 85% of stimuli after 2 weeks. AD patients had equally stable preferences compared to the control group for negative artworks, but less stable preferences for positive and neutral images (Bonferroni-corrected significance levels; p < 0.017).ConclusionEven in cognitively impaired AD patients, aesthetic preference for negatively-valenced artworks remains relatively stable. Our study provides novel evidence that AD patients may have a somewhat preserved implicit valence system for negative compared to neutral or positive visual information, especially in the domain of aesthetics. However, more studies need to further uncover the details of the underlying neurocognitive mechanisms of preference stability in pathological aging.

Long-term body weight change assessed by non-contact load cells under the bed in older people with and without eating assistance: a preliminary study

Utilizing automatic daily body weight (BW) measurements may be helpful for assessing nutritional status and detecting underlying diseases particularly in older people who require nursing care. This preliminary study aimed to verify effectiveness of eating assistance for maintaining BW in older people using a contact-free load cells under the bed (Bed Sensor System: BSS). BW was measured every night for 3 months in eight nursing home older people with severe cognitive and physical dysfunctions. Body composition of the subject's trunk and each limb was measured using a segmented multi-frequency bioelectrical impedance analyzer (BIA). A monthly BW loss was estimated as a slope of linear regression of the daily BW plot. BSS successfully measured daily BW for the study period in all participants. The 4 residents with eating assistance gained slightly more weight, while the 4 residents without eating assistance lost weight. There was a significant difference between the two groups in the monthly BW change (− 0.79 ± 0.51 kg/month versus 0.20 ± 0.49 kg/month, P = 0.030). None of the BIA-derived parameters was associated with the monthly BW change. BSS revealed effectiveness of eating assistance to maintain BW in nursing home residents with severe cognitive and physical dysfunctions.

Optical Sensor Array for the Early Diagnosis of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and has complicated pathobiology, leading to irreversible memory loss and severe cognitive dysfunction. For patients with AD, the advent of the disease usually occurs after years of pathological changes. The early diagnosis and monitoring of AD are of great significance as the early-stage intervention and treatment may be the most effective. Biomarkers, such as beta-amyloid and tau levels in cerebrospinal fluid (CSF) and brain, offer one of the most promising paths and are combined with neuroimaging and immunological detection for AD diagnosis. However, high expense and radiation of neuroimaging and low sensitivity of immunosorbent assay limited their applications. Meanwhile, the relevance of Aβ peptides and tau proteins to the development of AD remains highly debatable, meaning that detecting one specific biomarker holds limited prospects in achieving early and accurate detection of AD. Optical sensor arrays based on pattern recognition enable the discrimination of multiple analytes in complicated environments and are thus highly advantageous for the detection of AD with multi-biomarkers. In this review, we survey the recent advances of optical sensor arrays for the diagnosis of AD, as well as the remaining challenges.

Montreal Cognitive Assessment (MoCA) performance in Huntington's disease patients correlates with cortical and caudate atrophy.

Huntington’s Disease (HD) is an autosomal neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Cognitive impairment develops gradually in HD patients, progressing later into a severe cognitive dysfunction. The Montreal Cognitive Assessment (MoCA) is a brief screening test commonly employed to detect mild cognitive impairment, which has also been useful to assess cognitive decline in HD patients. However, the relationship between MoCA performance and brain structural integrity in HD patients remains unclear. Therefore, to explore this relationship we analyzed if cortical thinning and subcortical nuclei volume differences correlated with HD patients’ MoCA performance. Twenty-two HD patients and twenty-two healthy subjects participated in this study. T1-weighted images were acquired to analyze cortical thickness and subcortical nuclei volumes. Group comparison analysis showed a significantly lower score in the MoCA global performance of HD patients. Also, the MoCA total score correlated with cortical thinning of fronto-parietal and temporo-occipital cortices, as well as with bilateral caudate volume differences in HD patients. These results provide new insights into the effectiveness of using the MoCA test to detect cognitive impairment and the brain atrophy pattern associated with the cognitive status of prodromal/early HD patients.

DHF-7 Ameliorates Behavioral Disorders and White Matter Lesions by Regulating BDNF and Fyn in a Mouse Model of Schizophrenia Induced by Cuprizone and MK-801.

BackgroundSchizophrenia is a psychiatric disorder including multiple clinical symptoms such as severe psychosis and cognitive dysfunction. DHF-7 is a novel dihydroflavanone derivative that was designed and synthesized to treat schizophrenia. This study aimed to investigate the effects and mechanisms of DHF-7 in a mouse model of schizophrenia induced by a combination of cuprizone and MK-801.MethodsAfter intragastric administration of DHF-7 for 7 weeks, open field, Y-maze, and novel object recognition tests were performed to detect behavioral changes in the mouse model. White matter lesions and myelin loss were determined using transmission electron microscopy and oil red O staining. Western blotting and immunohistochemistry were used to detect the expression of the related proteins.ResultsThe results showed that DHF-7 treatment significantly improved cognitive impairment and positive symptoms in the model mice. Moreover, DHF-7 alleviated white matter lesions and demyelination and promoted the differentiation and maturation of oligodendrocytes for remyelination in the corpus callosum of model mice. The mechanistic study showed that DHF-7 increased the expression of brain-derived neurotrophic factor and phosphorylated Fyn, thus activating the tyrosine kinase receptor B (Trk B)/Fyn/N-methyl-D-aspartate receptor subunit 2 B (NMDAR2B) and Raf/mitogen-activated protein kinase (MEK)/ extracellular signal-related kinase (ERK) signaling pathways.ConclusionsOur results provide an experimental basis for the development of DHF-7 as a novel therapeutic agent for schizophrenia.

Prevalence and severity of cognitive dysfunction in patients referred for transcatheter aortic valve implantation (TAVI): clinical and cognitive impact at 1year.

We estimated the proportion and severity of cognitive disorders in an unselected population of patients referred for transcatheter aortic valve implantation (TAVI). Second, we describe clinical and cognitive outcomes at 1year. Eligible patients were aged ≥ 70years, with symptomatic aortic stenosis and an indication for TAVI. The Montreal Cognitive Assessment (MoCA) was used to assess cognitive dysfunction (CD), defined as no CD if score ≥ 26, mild CD if 18-25; moderate CD if 10-18, and severe CD if < 10. We assessed survival and in-hospital complications at 6months and 1year. Between June 2019 and October 2020, 105 patients were included; 21 (20%) did not undergo TAVI, and thus, 84 were analyzed; median age 85years, 53.6% females, median EuroScore 11.5%. Median MoCA score was 22 (19-25); CD was excluded in 18 (21%), mild in 50 (59.5%), moderate in 15 (19%) and severe in 1. Mean MoCA score at follow-up was 21.9(± 4.69) and did not differ significantly from baseline (21.79 (± 4.61), p = 0.73). There was no difference in success rate, in-hospital complications, or death across CD categories. The clinical course of patients with mild or moderate CD is not different at 1year after TAVI compared to those without cognitive dysfunction.

Association of Acute Respiratory Failure in Early Childhood With Long-term Neurocognitive Outcomes

Approximately 23 700 US children undergo invasive mechanical ventilation for acute respiratory failure annually, with unknown long-term effects on neurocognitive function. To evaluate neurocognitive outcomes of children who survive pediatric intensive care unit (PICU) hospitalization for acute respiratory failure compared with their biological siblings. Prospective sibling-matched cohort study conducted at 31 US PICUs and associated neuropsychology testing centers. Patients were 8 years or younger with a Pediatric Cerebral Performance Category score of 1 (normal) before PICU admission and less than or equal to 3 (no worse than moderate neurocognitive dysfunction) at PICU discharge, excluding patients with a history of neurocognitive deficits or who were readmitted and underwent mechanical ventilation. Biological siblings were aged 4 to 16 years at testing, with Pediatric Cerebral Performance Category score of 1 and no history of mechanical ventilation or general anesthesia. A total of 121 sibling pairs were enrolled from September 2, 2014, to December 13, 2017, and underwent neurocognitive testing starting March 14, 2015. The date of the final follow-up was November 6, 2018. Critical illness and PICU treatment for acute respiratory failure. The primary outcome was IQ, estimated by the age-appropriate Vocabulary and Block Design subtests of the Wechsler Intelligence Scale. Secondary outcomes included measures of attention, processing speed, learning and memory, visuospatial skills, motor skills, language, and executive function. Evaluations occurred 3 to 8 years after hospital discharge. Patients (n = 121; 55 [45%] female patients) underwent PICU care at a median (IQR) age of 1.0 (0.2-3.2) years, received a median (IQR) of 5.5 (3.1-7.7) days of invasive mechanical ventilation, and were tested at a median (IQR) age of 6.6 (5.4-9.1) years. Matched siblings (n = 121; 72 [60%] female siblings) were tested at a median (IQR) age of 8.4 (7.0-10.2) years. Patients had a lower mean estimated IQ than matched siblings (101.5 vs 104.3; mean difference, -2.8 [95% CI, -5.4 to -0.2]). Among secondary outcomes, patients had significantly lower scores than matched siblings on nonverbal memory (mean difference, -0.9 [95% CI, -1.6 to -0.3]), visuospatial skills (mean difference, -0.9 [95% CI, -1.8 to -0.1]), and fine motor control (mean difference, -3.1 [95% CI, -4.9 to -1.4]) and significantly higher scores on processing speed (mean difference, 4.4 [95% CI, 0.2-8.5]). There were no significant differences in the remaining secondary outcomes, including attention, verbal memory, expressive language, and executive function. Among children, survival of PICU hospitalization for respiratory failure and discharge without severe cognitive dysfunction was associated with significantly lower subsequent IQ scores compared with matched siblings. However, the magnitude of the difference was small and of uncertain clinical importance.

Management of Psychiatric Disorders in Patients with Respiratory Diseases.

Management of Psychiatric Disorders in Patients with Respiratory Diseases.

A novel variant in UBE3A in a family with multigenerational intellectual disability and developmental delay.

BackgroundAngelman syndrome (AS) is a rare neurodevelopmental disorder and is characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. Although the maternal chromosomal region 15q11.2‐q13 deletion is the most common mechanism of AS, ~10% of individuals with AS are caused by the intragenic variants in the maternally inherited UBE3A, which encodes an E3 ubiquitin ligase.MethodsClinical diagnoses were based on detailed clinical findings. Trio‐based exome sequencing was performed on the proband and her parents to identify the underlying genetic variants. The candidate variants were confirmed by Sanger sequencing following PCR amplification. In silico analyses were conducted to predict the effect of the identified variant on the function of UBE3A protein.ResultsWe identified a novel variant c.2029G>C (p. Gly677Arg) in UBE3A as the most promising candidate. In silico analyses showed that p.Gly677Arg in the UBE3A affects a highly conserved residue. Her mother had the variant at this locus. Sanger sequencing results showed that II‐2, II‐5, II‐7, IV‐1, III‐5, III‐7, III‐8, and III‐9 have the variant c.2029G>C, and all patients inherited maternally variant in UBE3A, while the offsprings of the male carrier were unaffected.ConclusionsWe identified a novel variant (c.2029G>C) in the UBE3A in a Chinese family with multigenerational intellectual disability and developmental delay. Our findings expanded the genotypic spectrum of AS and provided important information for genetic counseling.

Characterizing speech heterogeneity in schizophrenia-spectrum disorders.

Schizophrenia-spectrum disorders (SSD) are highly heterogeneous in risk factors, symptom characteristics, and disease course outcome. Although speech anomalies have long been recognized as a core symptom of SSD, speech markers are an unexplored source of symptom heterogeneity that may be informative in recognizing relevant subtypes. This study investigated speech heterogeneity and its relation to clinical characteristics in a large sample of patients with SSD and healthy controls. Speech samples were obtained from 142 patients with SSD and 147 healthy controls by means of open-ended interviews. Speech was analyzed using standardized open-source acoustic speech software. Hierarchical clustering was conducted using acoustic speech markers. Symptom severity was rated with the Positive and Negative Syndrome Scale, and cognition was assessed with the Brief Assessment of Cognition for Schizophrenia. Three speech clusters could be distinguished in the patient group that differed regarding speech properties, independent of medication use. One cluster was characterized by mild speech disturbances, while two severely impaired clusters were recognized (fragmented speakers and prolonged pausers). Both clusters with severely impaired speech had more severe cognitive dysfunction than the mildly impaired speakers. Prolonged pausers specifically had difficulties with memory-related tasks. Prolonged pausing, as opposed to fragmented speaking, related to chronic active psychosis and refractory psychotic symptoms. Based on speech clustering, subtypes of patients emerged with distinct disease trajectories, symptomatology, and cognitive functioning. The identification of clinically relevant subgroups within SSD may help to characterize distinct profiles and benefit the tailoring of early intervention and improvement of long-term functional outcome. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Discrepancy Between Cognitive Test and Brain Imaging Results in Alzheimer's Disease Associated with Diabetes.

Although a large number of studies have been performed on the association between Alzheimer's disease (AD) and type 2 diabetes mellitus (DM), the underlying pathophysiology of AD associated with DM has not been fully elucidated to date. We compared cognitive functions and brain imaging findings between AD patients with and without DM to characterize the association between cognition and imaging findings in AD patients with DM. Cognitive functions and brain imaging findings, including medial temporal lobe atrophy analyzed by magnetic resonance imaging, and hypoperfusion in the parietal, posterior cingulate, and frontal regions analyzed by single-photon emission computed tomography were compared between 126 AD patients without DM ([AD-DM]) and 51 AD patients with DM ([AD+DM]). Factors associated with cognitive-imaging associations, including education, occupation, leisure activity, comorbidity, frailty, and other demographics, were analyzed. The [AD+DM] group showed significantly more severe cognitive dysfunction than the [ADDM] group, despite a similar degree of brain imaging abnormalities. Among the factors associated with cognitive-imaging associations, the level of leisure activity was significantly lower in the [AD+DM] group than in the [AD-DM] group, but no significant differences in other factors were observed between the 2 groups. The cognitive-imaging discrepancy observed in AD patients with DM may be associated with their low cognitive reserve, possibly caused by their low amount of leisure activities. Our findings suggest that lifestyle interventions, including physical, cognitive, and social activities, may reduce cognitive decline in AD patients with DM.

Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective.

Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signaling pathways and transcriptional programs. Forkhead Box G1 (FOXG1) is one of the master regulators that play fundamental roles in forebrain development; from the timing of neurogenesis, to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes, ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits, with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in the neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as the increased yield of information from high throughput omics, have opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of the clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems, to highlight the prospects of research and possible clinical interventions.

Assessment of cognitive dysfunction using the Montreal Cognitive Assessment test: rate, severity and comparison with the Clock test alone in a population of patients referred for TAVI

Abstract Background Although not recommended in routine practice, the detection and quantification of Cognitive Dysfunction (CD) in older patients might have an impact on clinical decisions. We assessed the rate and severity of CD in an unselected population of patients referred for Transcatheter Aortic Valve Implantation (TAVI) using the Montreal Cognitive Assessment (MoCA) and using the Clock Drawing Test (ClockT) alone. Methods The MoCA was performed before TAVI by an experienced operator. The ClockT was scored out of 10 points according to the Rouleau rating scale. CD was defined according to the MoCA score: No CD if score ≥26, mild CD if score 18–25, moderate if 10–17 and severe if &amp;lt;10. Inter-observer reliability of scoring on the ClockT was estimated with the Bland-Altman method. Agreement between MoCA scores and the ClockT for ruling out and for detecting CD were measured with the Kappa coefficient. Results MoCA was performed in 83 consecutive patients referred for TAVI, median age 85 years. The mean time required for assessment was 11±2 min for the MoCA and 3±2 min for the ClockT. The mean MoCA score was 21±4.5: CD was excluded in 17 (20%) pts, mild CD was found in 50 (60%), moderate in 15 (18%) and severe in one (1%). The median ClockT score was 8 (interquartile 6; 9), with excellent inter-observer concordance (Kappa= 0.84). Overall, 51% of the variance of the MoCA score was explained by the ClockT alone according to multiple regression. A ClockT &amp;lt;7 detected a group with significantly lower MoCA score, compared to pts with higher ClockT scores (figure). Conclusion Among patients referred for TAVI, CD can be excluded using the MoCA test in 20%, while moderate or severe CD is observed in 18%. The ClockT alone is faster to implement, reliable to interpret and enabled detection of patients with moderate CD when Rouleau scoring was &amp;lt;7. Funding Acknowledgement Type of funding sources: None.

Perillaldehyde improves cognitive function in vivo and in vitro by inhibiting neuronal damage via blocking TRPM2/NMDAR pathway

BackgroundVascular cognitive dysfunction in patients with vascular dementia (VD) is a kind of severe cognitive dysfunction syndrome caused by cerebrovascular diseases. At present, effective drugs to improve the cognitive function of VD patients still need to be explored. Transient Receptor Potential Melastatin 2 (TRPM2) channel is a nonspecific cation channel that plays a key role in the toxic death of neurons. Perillaldehyde (PAE) has the protective effect of epilepsy and insomnia and other central nervous system diseases. The aim of this study is to explore whether PAE improves cognitive function in VD rats and to investigate the potential mechanisms in vivo and vitro.MethodsVD rats were induced by bilateral common carotid arteries occlusion (2-vessel occlusion [2VO]) and treated with PAE for 4 weeks. The neuroprotective effects of PAE was subsequently assessed by the Morris water maze, hematoxylin–eosin (HE) staining, Golgi staining, electron microscopy, Neuron-specific nuclear protein (Neu N) staining, and TdT-mediated dUTP nick end labeling (TUNEL) staining. After primary hippocampal neurons were isolated, cell viability was detected by MTT assay and intracellular Ca2+ concentration was detected by calcium imaging assay. The content of Nitriteoxide (NO), Malondialdehyde (MDA) and Superoxide dismutase (SOD) activity in serum of rats were observed by Enzyme Linked Immunosorbent Assay (ELISA). Immunohistochemistry, Western blot, and Confocal laser scanning were used to detect the expression levels of N-methyl-d-asprtate receptor-2B (NR2B) and TRPM2.ResultsThe results showed that PAE can improve the number and activity of neurons, increase the length and number of dendrites in hippocampus, decrease the Vv value and PE value of neuronal nucleus and mitochondrial structure significantly, increase the s value and L value in nucleus structure, decrease the s value and L value in mitochondrial structure, and improve the learning and memory ability of rats significantly. And PAE can strengthen the ability of antioxidant stress confirmed by increasing the activity of SOD and reducing the production of MDA. The results of western blot, immunohistochemistry and immunofluorescence showed that PAE could reduce the level of TRPM2 and increase the expression of NR2B.ConclusionsTaken together, our findings provide evidence that the neuroprotective effects of PAE in VD rats maybe through TRPM2 inhibition and subsequent activation of NMDAR signaling pathway.

Mechanisms of glycolysis and bioenergy state of cells at the stages of cardiosurgical interventions in patients with hypoxic — ischemic impairments of the brain

Objective — to study the features of bioenergetic provision of oxidative homeostasis (OH) in patients with hypoxic‑ischemic brain lesions (HIBL) before and after cardiac surgery (CS) using artificial circulation (AC).&#x0D; Methods and subjects. Clinical and biochemical studies were performed in 38 patients, including 14 with ischemic stroke, 15 with encephalopathy, and 9 with severe cognitive dysfunction.&#x0D; Results. Analysis of metabolic indicators of glycolysis activity and energy homeostasis of cells before and after CS revealed the patterns of changes in the disorganization of glycolysis mechanisms, intensification of anaerobic mechanisms while limiting the energy supply of cells. The obtained data confirm the formation of specific postoperative metabolic provision of bioenergy in patients with CS, which should be considered as one of the triggers of HIBL and individualization of antioxidant cerebroprotection in the preoperative period, taking into account the state of bioenergetic metabolism of cells and the dominant mechanisms of glycolysis.&#x0D; Conclusions. Preoperative antioxidant cerebroprotection as a means of prevention of hypoxic‑ischemic brain lesions during cardiac surgery using artificial circulation should be based on the determination of bioenergetic and metabolic reserves, the depletion of which by antioxidant drugs suppression should not be considered, as activation of anaerobic glycolysis at simultaneous metabolic suppression of mitochondrial bioenergetics is a factor of formation or aggravation of ischemic lesions of brain.&#x0D;