Progressive Cognitive Impairment Research Articles

Efficacy of a non-pharmaceutical multimodal intervention program in a group setting for patients with mild cognitive impairment: A single-arm interventional study with pre-post and external control analyses

AimThis study aimed to evaluate the efficacy of a non-pharmaceutical multimodal intervention program consisting of physical exercise, cognitive stimulation, and health education in a group setting to slow the progression of mild cognitive impairment (MCI). MethodsA single-arm interventional study was conducted on 27 patients with MCI. To evaluate the efficacy of the intervention program, a pre-post analysis was performed using EuroQol-5 Dimension (EQ-5D), Mini-Mental State Examination (MMSE), Cognitive Function Instrument (CFI), 5 Cog test, depression, and physical performance before and after the 8-month intervention. Additionally, propensity score and the semi-Bayes analyses were performed to compare the intervention program with standard medical care, using the external control patients’ data for MMSE scores. ResultsTwenty-four patients completed the intervention program. During the study period, although EQ-5D and MMSE scores remained unchanged (mean change 0.02 [95 % confidence interval (CI): −0.004, 0.04], 0.5 [-0.2, 1.3]), CFI and the subcategories of 5Cog (attention and reasoning) improved (mean change −1.23 [-2.24, −0.21], 4.3 [0.9, 7.7], 3.0 [0.4, 5.6]). In the additional analysis comparing changes in MMSE scores, patients who underwent the intervention program had less decline than the external control patients (mean change −1.7 [-2.1, −1.3]) with an observed mean difference of 2.25 [1.46, 3.03], and propensity score-adjusted difference of 2.26 [1.46, 3.05]. The semi-Bayesian approach also suggested that the intervention slowed the progression of MCI. ConclusionA non-pharmaceutical multimodal intervention program could contribute to slowing cognitive decline in patients with MCI.

Investigating the effects of chiropractic care on resting-state EEG of MCI patients.

Mild cognitive impairment (MCI) is a stage between health and dementia, with various symptoms including memory, language, and visuospatial impairment. Chiropractic, a manual therapy that seeks to improve the function of the body and spine, has been shown to affect sensorimotor processing, multimodal sensory processing, and mental processing tasks. In this paper, the effect of chiropractic intervention on Electroencephalogram (EEG) signals in patients with mild cognitive impairment was investigated. EEG signals from two groups of patients with mild cognitive impairment (n = 13 people in each group) were recorded pre- and post-control and chiropractic intervention. A comparison of relative power was done with the support vector machine (SVM) method and non-parametric cluster-based permutation test showing the two groups could be separately identified with high accuracy. The highest accuracy was obtained in beta2 (25-35 Hz) and theta (4-8 Hz) bands. A comparison of different brain areas with the SVM method showed that the intervention had a greater effect on frontal areas. Also, interhemispheric coherence in all regions increased significantly after the intervention. The results of the Wilcoxon test showed that intrahemispheric coherence changes in frontal-occipital, frontal-temporal and right temporal-occipital regions were significantly different in two groups. Comparison of the results obtained from chiropractic intervention and previous studies shows that chiropractic intervention can have a positive effect on MCI disease and using this method may slow down the progression of mild cognitive impairment to Alzheimer's disease.

Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: a randomized, controlled clinical trial

BackgroundEvidence links lifestyle factors with Alzheimer’s disease (AD). We report the first randomized, controlled clinical trial to determine if intensive lifestyle changes may beneficially affect the progression of mild cognitive impairment (MCI) or early dementia due to AD.MethodsA 1:1 multicenter randomized controlled phase 2 trial, ages 45-90 with MCI or early dementia due to AD and a Montreal Cognitive Assessment (MoCA) score of 18 or higher. The primary outcome measures were changes in cognition and function tests: Clinical Global Impression of Change (CGIC), Alzheimer’s Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating–Sum of Boxes (CDR-SB), and Clinical Dementia Rating Global (CDR-G) after 20 weeks of an intensive multidomain lifestyle intervention compared to a wait-list usual care control group. ADAS-Cog, CDR-SB, and CDR-Global scales were compared using a Mann-Whitney-Wilcoxon rank-sum test, and CGIC was compared using Fisher’s exact test. Secondary outcomes included plasma Aβ42/40 ratio, other biomarkers, and correlating lifestyle with the degree of change in these measures.ResultsFifty-one AD patients enrolled, mean age 73.5. No significant differences in any measures at baseline. Only two patients withdrew. All patients had plasma Aβ42/40 ratios <0.0672 at baseline, strongly supporting AD diagnosis. After 20 weeks, significant between-group differences in the CGIC (p= 0.001), CDR-SB (p= 0.032), and CDR Global (p= 0.037) tests and borderline significance in the ADAS-Cog test (p= 0.053). CGIC, CDR Global, and ADAS-Cog showed improvement in cognition and function and CDR-SB showed significantly less progression, compared to the control group which worsened in all four measures. Aβ42/40 ratio increased in the intervention group and decreased in the control group (p = 0.003). There was a significant correlation between lifestyle and both cognitive function and the plasma Aβ42/40 ratio. The microbiome improved only in the intervention group (p <0.0001).ConclusionsComprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in many patients with MCI or early dementia due to AD.Trial registrationApproved by Western Institutional Review Board on 12/31/2017 (#20172897) and by Institutional Review Boards of all sites. This study was registered retrospectively with clinicaltrials.gov on October 8, 2020 (NCT04606420, ID: 20172897).

Estimating individual trajectories of structural and cognitive decline in mild cognitive impairment for early prediction of progression to dementia of the Alzheimer’s type

Only a third of individuals with mild cognitive impairment (MCI) progress to dementia of the Alzheimer’s type (DAT). Identifying biomarkers that distinguish individuals with MCI who will progress to DAT (MCI-Converters) from those who will not (MCI-Non-Converters) remains a key challenge in the field. In our study, we evaluate whether the individual rates of loss of volumes of the Hippocampus and entorhinal cortex (EC) with age in the MCI stage can predict progression to DAT. Using data from 758 MCI patients in the Alzheimer’s Disease Neuroimaging Database, we employ Linear Mixed Effects (LME) models to estimate individual trajectories of regional brain volume loss over 12 years on average. Our approach involves three key analyses: (1) mapping age-related volume loss trajectories in MCI-Converters and Non-Converters, (2) using logistic regression to predict progression to DAT based on individual rates of hippocampal and EC volume loss, and (3) examining the relationship between individual estimates of these volumetric changes and cognitive decline across different cognitive functions—episodic memory, visuospatial processing, and executive function. We find that the loss of Hippocampal volume is significantly more rapid in MCI-Converters than Non-Converters, but find no such difference in EC volumes. We also find that the rate of hippocampal volume loss in the MCI stage is a significant predictor of conversion to DAT, while the rate of volume loss in the EC and other additional regions is not. Finally, individual estimates of rates of regional volume loss in both the Hippocampus and EC, and other additional regions, correlate strongly with individual rates of cognitive decline. Across all analyses, we find significant individual variation in the initial volumes and the rates of changes in volume with age in individuals with MCI. This study highlights the importance of personalized approaches in predicting AD progression, offering insights for future research and intervention strategies.

The progression of cognitive impairment and its influencing factors in older adults based on longitudinal item response theory.

Understanding the development of cognitive impairment and its influencing factors in older adults is crucial for formulating early intervention strategies. To identify the early dimensions of cognitive impairment and provide a comprehensive description of the trajectories of cognitive decline in older adults prior to death. Based on the data of 9883 older adults in the Chinese Longitudinal Healthy Longevity Survey from 2002 to 2018, a longitudinal item response theory (Longitudinal IRT) model including covariates was applied to estimate the following parameters. The items in which older adults encountered obstacles first had the least difficulty parameters (δ). The earlier the information curve of an item is lifted, the more information it provides in the early stages of cognitive impairment. Regression coefficient (β) represents the relative rate of cognitive decline. The cognitive impairment values estimated from the Longitudinal IRT were fitted to a mixed-effects model to examine cognitive impairment trajectories. 'Draw the figure on B Card' (δ = -0.816) was the most challenging item, followed by 'recalling 'clothes" (δ = 0.348) and 'recalling 'apples" (δ = 0.419), while 'name the 'pen" (δ = 4.402) was the simplest instruction for the old adults. The curves of the items in the recall dimension began to rise in the early stages of cognitive impairment. Cognitive impairment of older adults who were women (β = 0.061), elder (β = 0.111), smokers (β = 0.060), living in rural areas (β = 0.052), not participating in organised social activities (β = 0.092), suffering from hypertension (β = 0.022), hyperglycaemia (β = 0.035), dyslipidaemia (β = 0.314), low education levels (β = 0.128), manual labourers (β = 0.027), and eventual development of dementia (β = 0.212) exhibited a more accelerated progression. These individuals also had poorer cognitive trajectories. Recall is the earliest dimension of cognitive impairment. The subjects who were women, elder, smokers, living in rural areas, not participating in organised social activities, suffering from hypertension, hyperglycaemia, dyslipidaemia, low education, manual labourers, and eventually development of dementia, had a faster descending speed and poorer trajectories.

Rapidly progressive cognitive impairment resulting in heavy psychosocial burden in a patient with Fabry disease undergoing hemodialysis: a case report

BackgroundLong-term enzyme replacement therapy (ERT) may improve prognosis in the patients with Fabry disease (FD), however, detail psychosocial burden has not been focused on long life expectancy. We experienced a male case of FD under ERT, he was placed on hemodialysis and presented rapidly progressive cognitive function.Case presentationA 51-year-old male patient with FD has been receiving ERT from age of 38 years. Hemodialysis was initiated at the age of 47 years. The patient experienced several attacks of cerebral infarction, and brain images demonstrated wide-spread asymptomatic ischemic lesions. His behavior became problematic at the age of 51 years. He often exhibited restlessness during hemodialysis sessions and failure to communicate effectively. The patient experienced impairment of attention and executive function, topographical disorientation, and amnesia. Consequently, it was necessary for medical staff and family members to monitor his behavior for safe extracorporeal circulation and daily life activities. Annual standardized neuropsychiatric testing revealed worsening of cognitive performance.ConclusionsDespite treating with long-term ERT, it is necessary to determine the psychosocial burden derived from the progression of cognitive impairment in patients with FD undergoing hemodialysis.

Assessment of Cognitive Function in European Adults Aged 50+in Relation to Their Handgrip Strength and Physical Inactivity: The SHARE Study During 2019-2020.

Cognitive function is crucial during aging. This study assessed the cognitive function of European adults aged 50 and over in relation to handgrip strength and physical inactivity. Study Design: This was a cross-sectional survey. Data were collected from 41,395 adults from 27 European countries participating in the Survey of Health, Ageing, and Retirement in Europe (SHARE) during 2019-2020. Cognitive function was assessed based on five tests, and cognitive impairment was defined using 3+tests. Handgrip strength and physical inactivity were also correlated through the analysis of covariance using a complex study design. The majority of participants were female (56.6%), with a mean age of 70.9 years, and 22.6% presented multimorbidity. Furthermore, 51.1% had a normal cognitive function, while 13.3% had cognitive impairment (The estimated population was 21,944,722). Moreover, cognitive impairment was more prevalent in females than in males (14.4% vs. 12.0%, P<0.001) in patients with no years of education (P<0.001) and origin from southern European countries (P<0.001). Additionally, participants with cognitive impairment had lower mean handgrip strength compared to those with cognitive impairment in 1-2 criteria or with normal cognitive function (29.3 vs. 33.4 and 35.1 kg, respectively, P<0.001). Physically inactive participants had higher odds ratio (OR) of cognitive impairment than those engaging in moderate/vigorous physical activity, both in 1-2 tests (OR:1.73, 95% confidence interval (CI): 1.32-2.26) and in 3+tests (OR: 3.36, 95% CI: 2.57-4.40). Cognitive impairment presented low prevalence and was associated with low levels of handgrip strength and physical inactivity. These specific factors may play a special role in early detection, diagnosis, and treatment or may slow down the progression of cognitive impairment.

Molecular and functional alterations in the cerebral microvasculature in an optimized mouse model of sepsis-associated cognitive dysfunction.

The limited knowledge of how systemic inflammation contributes to cognitive decline is a major obstacle to the development of novel therapies for dementia and other neurodegenerative diseases. Clinical evidence supports a role for the cerebral microvasculature in sepsis-induced neurocognitive dysfunction, but the investigation of the underlying mechanisms has been limited by the lack of standardized experimental models. Herein, we optimized a mouse model that recapitulates important pathophysiological aspects of systemic inflammation-induced cognitive decline and identified key alterations in the cerebral microvasculature associated with cognitive dysfunction. Our study provides a reliable experimental model for mechanistic studies and therapeutic discovery of the impact of systemic inflammation on cerebral microvascular function and the development and progression of cognitive impairment.

Effect of Treatment of the Cholinergic Precursor Choline Alphoscerate in Mild Cognitive Dysfunction: A Randomized Controlled Trial.

Background and Objectives: The focus on mild cognitive dysfunction in adults is of great interest, given the risk of worsening and conversion to dementia. Cognitive dysfunctions are characterized by a decrease in the weight and volume of the brain, due to cortical atrophy, with a widening of the grooves and flattening of the convolutions. Brain atrophy that mainly involves the hippocampus is related to the progression of cognitive impairment and the conversion from mild cognitive dysfunction to dementia. Currently, there is no treatment for MCI. Results from a trial on Alzheimer's disease (ASCOMALVA trial) suggest that a sustained cholinergic challenge can slow the progression of brain atrophy typical of Alzheimer's disease associated with vascular damage. This study intends to evaluate the efficacy of choline alphoscerate in patients with mild cognitive impairment (MCI) and associated vascular damage, in stabilizing and/or slowing brain atrophy typical of adult-onset cognitive dysfunction, and in improving and/or slowing the progression of cognitive and behavioral symptoms associated with MCI. Materials and Methods: This randomized controlled trial will recruit 60 patients that will be evaluated and randomized in a 1:1 ratio to receive choline alphoscerate (1200 mg/day) or placebo, for 12 months. Analyses will be carried out using SPSS vesion No 26 the Statistician in charge of this study, with the statistical significance level chosen as 0.05. Discussion: This trial may provide evidence about the efficacy of treatment with the cholinergic precursor choline alphoscerate in patients with mild cognitive dysfunction. The results of this study will be published in peer-reviewed journals. Registration: EudraCT number: 2020-000576-38.

Role of PIM Kinase Inhibitor in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a neurodegenerative disorder, is the most prevalent form of senile dementia, causing progressive deterioration of cognition, behavior, and rational skills. Neuropathologically, AD is characterized by two hallmark proteinaceous aggregates: amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) formed of hyperphosphorylated tau. A significant study has been done to understand how Aβ and/or tau accumulation can alter signaling pathways that affect neuronal function. A conserved protein kinase known as the mammalian target of rapamycin (mTOR) is essential for maintaining the proper balance between protein synthesis and degradation. Overwhelming evidence shows mTOR signaling's primary role in age-dependent cognitive decline and the pathogenesis of AD. Postmortem human AD brains consistently show an upregulation of mTOR signaling. Confocal microscopy findings demonstrated a direct connection between mTOR and intraneuronal Aβ42 through molecular processes of PRAS40 phosphorylation. By attaching to the mTORC1 complex, PRAS40 inhibits the activity of mTOR. Furthermore, inhibiting PRAS40 phosphorylation can stop the Aβ-mediated increase in mTOR activity, indicating that the accumulation of Aβ may aid in PRAS40 phosphorylation. Physiologically, PRAS40 is phosphorylated by PIM1 which is a serine/threonine kinase of proto-oncogene PIM kinase family. Pharmacological inhibition of PIM1 activity prevents the Aβ-induced mTOR hyperactivity in vivo by blocking PRAS40 phosphorylation and restores cognitive impairments by enhancing proteasome function. Recently identified small-molecule PIM1 inhibitors have been developed as potential therapeutic to reduce AD-neuropathology. This comprehensive study aims to address the activity of PIM1 inhibitor that has been tested for the treatment of AD, in addition to the pharmacological and structural aspects of PIM1.

Data-driven sequence of cognitive decline in people with Parkinson’s disease

BackgroundUnderstanding the sequential progression of cognitive impairments in Parkinson’s disease (PD) is crucial for elucidating neuropathological underpinnings, refining the assessment of PD-related cognitive decline stages and enhancing early identification for...

The relationship and pathways between resting-state EEG, physical function, and cognitive function in older adults

ObjectiveBased on resting-state electroencephalography (EEG) evidence, this study aimed to explore the relationship and pathways between EEG-mediated physical function and cognitive function in older adults with cognitive impairment.MethodsA total of 140 older adults with cognitive impairment were recruited, and data on their physical function, cognitive function, and EEG were collected. Pearson correlation analysis, one-way analysis of variance, linear regression analysis, and structural equation modeling analysis were conducted to explore the relationships and pathways among variables.ResultsFP1 theta (effect size = 0.136, 95% CI: 0.025–0.251) and T4 alpha2 (effect size = 0.140, 95% CI: 0.057–0.249) were found to significantly mediate the relationship. The direct effect (effect size = 0.866, 95% CI: 0.574–1.158) and total effect (effect size = 1.142, 95% CI: 0.848–1.435) of SPPB on MoCA were both significant.ConclusionHigher physical function scores in older adults with cognitive impairment were associated with higher cognitive function scores. Left frontal theta and right temporal alpha2, as key observed indicators, may mediate the relationship between physical function and cognitive function. It is suggested to implement personalized exercise interventions based on the specific physical function of older adults, which may delay the occurrence and progression of cognitive impairment in older adults with cognitive impairment.

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.

Early cognitive dysfunction development immunological predictors in the ischemic stroke acute period

The purpose of the study is activity identification CXC family cytokines in patients with cognitive impairments in the acute period of ischemic stroke.Material and methods. 78 patients with diagnosis “Ischemic stroke” were examined. Depending on cognitive impairment (Montreal Cognitive Assessment (MoCA)) patients were divided into two groups: the 1st group — 58 patients with cognitive decline (MoCA ≤ 25 points); the 2nd group — 20 patients without cognitive decline. Neuropsychologic testing was performed on the second day of hospitalisation and included episodic memory, executive function, speech, gnosis, praxis and IQCODE parameters examination. Laboratory diagnosis consisted of level assessing of CXC family chemokines (CXCL10, CXCL11, CXCL9, CXCL1, CXCL8) and TNF-α cytokine in patients’ plasma on the second day of hospitalisation. Statistical analysis was employed using the Python programing language and its libraries Pandas and SciPy.Results. Statistical analysis revealed the highest level of IP-10/CXCL10 chemokines (p = 0.002) and Gro-a/CXCL1 (p = 0.044) in patients of the 1st group, statistically significant correlations of MoCA and IQCODE with IP-10/CXCL10 and Gro-a/CXCL1 concentrations, correlations of IP-10/CXCL10 concentrations with semantic information processing functions (r = –0.512), subject gnosis (r = –0.211), memory (r = 0.275), speech (r = –0.400), and Gro-a/ CXCL1 level with semantic information processing (r = –0.418).Conclusion. The study of chemokines of the CXC cluster represents a relevant and promising direction in the diagnosis and assessment of progression of early post-stroke cognitive impairment of mixed genesis due to minimal invasiveness and high specificity. Further studies are needed to verify CXCL chemokines, particularly IP-10/CXCL10 and Gro-a/CXCL1 as potential molecular markers of neurological damage in neurodegenerative and inflammatory diseases of the central nervous system.

#3031 Cell free DNA methylation analysis reveals cerebral cell death during hemodialysis

Abstract Background and Aims Patients treated with hemodialysis demonstrate a significant cognitive decline, likely explained by cerebrovascular disease and hypoperfusion. Despite the significant morbidity and mortality associated, no method exists to detect subclinical cerebral injury. This prevents early diagnosis and precludes mitigation strategies. Following cell death, cell free DNA (cfDNA) is released into the peripheral blood. Since DNA methylation is cell-type specific, cfDNA methylation analysis can reveal the cellular origin of cfDNA and cell-type specific changes in cell death. Here, we evaluate if subclinical cerebral ischemia during hemodialysis is detectable through cfDNA methylome analyses. Method Chronic hemodialysis patients with a high cardiovascular risk profile were studied during a single hemodialysis session. Brain tissue oxygenation was measured continuously by near-infrared spectroscopy using two sensors on the forehead. Plasma samples were taken immediately before and after hemodialysis. cfDNA was extracted from the blood plasma and converted into whole genome bisulfite sequencing libraries using tailored protocols. Next, in-solution target enrichment was applied to analyze 4,989 genomic loci, selected for showing specific methylation in one of 15 tissues or cell types. After sequencing, reads were aligned to the hg38 reference genome using BisMark, and deconvoluted using EMeth-Laplace to disclose the relative contribution of the 15 selected tissues or cell types. Results 41 hemodialysis patients participated in the study, with a mean age of 75 ± 8 years (46% male). The median ultrafiltration volume was 2.3 L (IQR 1.6-3.0 L). After targeted bisulfite sequencing and QC-based filtering, 35 patients remained for cfDNA methylation analysis. In 30 patients, cfDNA concentrations were increased following dialysis. Deconvolution analysis revealed a relative increase in granulocyte-derived cfDNA from 36.7% to 55% before versus after dialysis. Consequently, for most other tissues and cell types we observed a relative decrease in their cfDNA contribution. Interestingly, a subset of patients (n = 13) showed an increase in neuron-derived cfDNA from 0% to 0.26%, while no neuron-derived cfDNA was detectable in the remaining 22 patients. Near-infrared spectroscopy showed a significantly reduced cerebral oxygenation in these 13 patients (P &amp;lt; 0.0001) at 2 separate time windows during hemodialysis treatment (at 20-60 and 207-251 minutes into the session) (Fig.). Conclusion In patients with a high cardiovascular risk profile, cfDNA in peripheral blood increased after hemodialysis. cfDNA methylome analyses suggested this to be due to an increased contribution of granulocytes, indicating elevated levels of NETosis. In addition, we observed more neuron-derived cfDNA after dialysis in about 1 in 3 patients. This was most apparent in patients with a reduced brain tissue oxygenation during hemodialysis. Together, these findings suggest that hypoperfusion during hemodialysis can evoke neuronal cell death, detectable through methylome analyses of cfDNA isolated from a minimally invasively obtainable bodily fluid. Follow-up studies are ongoing to assess if this translates to progressive cognitive impairment.

Relationship between Social Participation and Cognitive Impairment in Low-Educated Older Adults Based on Indonesian Family Life Survey-5.

The increasing older adult population requires attention in terms of education and health, as higher education levels contribute to cognitive reserve and may protect against age-related cognitive impairment. Cognitive reserve is an individual's cognitive flexibility in using cognitive functions affected by brain aging, neurological diseases, and injury. Indonesia has a high prevalence of low-educated older adults, which strongly correlates with progressive cognitive impairment. Identifying risk factors for cognitive decline in this population is crucial. This study determines the factors affecting cognitive impairment in low-educated older adults using cross-sectional data from the Indonesian Family Life Survey-5. This descriptive study analyzed 2,313 low-educated older adults ≥60 years old. Univariate and bivariate analyses were used to describe the sample and identify the relationships between categorical variables. Logistic regression identified the most significant factor affecting cognitive impairment. The prevalence of cognitive impairment in low-educated older adults is 22.6%. The chi-square test revealed significant relationships between those who are aged 75 years, a status other than married, female, living in rural areas, and not participating in social activities. Age is the most prominent factor affecting cognitive impairment in such adults (P<0.001; adjusted odds ratio, 3.232; 95% confidence interval, 2.500-4.180). Cognitive impairment in the aforementioned adults is associated with being ≥75 years old, being a status other than married, being female, living in rural areas, and not participating in social activities. After controlling other variables, low-educated older adults who participated in at least ≥1 social activity in the last 12 months experienced cognitive impairment 0.64 times compared to those who did not participate in social activities.

Latest advances on new promising molecular-based therapeutic approaches for Huntington's disease.

Huntington's disease (HD) is a devastating, autosomal-dominant inherited, neurodegenerative disorder characterized by progressive motor deficits, cognitive impairments, and neuropsychiatric symptoms. It is caused by excessive cytosine-adenine-guanine (CAG) trinucleotide repeats within the huntingtin gene (HTT). Presently, therapeutic interventions capable of altering the trajectory of HD are lacking, while medications for abnormal movement and psychiatric symptoms are limited. Numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. In this review, we update the latest advances on new promising molecular-based therapeutic strategies for this disorder, including DNA-targeting techniques such as zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9; post-transcriptional huntingtin-lowering approaches such as RNAi, antisense oligonucleotides, and small-molecule splicing modulators; and novel methods to clear the mHTT protein, such as proteolysis-targeting chimeras. We mainly focus on the ongoing clinical trials and the latest pre-clinical studies to explore the progress of emerging potential HD therapeutics.

MST1 selective inhibitor Xmu-mp-1 ameliorates neuropathological changes in a rat model of sporadic Alzheimer's Disease by modulating Hippo-Wnt signaling crosstalk.

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive impairment accompanied by aberrant neuronal apoptosis. Reports suggest that the pro-apoptotic mammalian set20-like kinase 1/2 (MST1/2) instigates neuronal apoptosis via activating the Hippo signaling pathway under various stress conditions, including AD. However, whether inhibiting MST1/2 has any therapeutic benefits in AD remains unknown. Thus, we tested the therapeutic effects of intervening MST1/2 activation via the pharmacological inhibitor Xmu-mp-1 in a sporadic AD rat model. Sporadic AD was established in adult rats by intracerebroventricular streptozotocin (ICV-STZ) injection (3mg/kg body weight). Xmu-mp-1 (0.5mg/kg/body weight) was administered once every 48h for two weeks, and Donepezil (5mg/kg body weight) was used as a reference standard drug. The therapeutic effects of Xmu-mp-1 on ICV-STZ rats were determined through various behavioral, biochemical, histopathological, and molecular tests. At the behavioral level, Xmu-mp-1 improved cognitive deficits in sporadic AD rats. Further, Xmu-mp-1 treatment reduced STZ-associated tau phosphorylation, amyloid-beta deposition, oxidative stress, neurotoxicity, neuroinflammation, synaptic dysfunction, neuronal apoptosis, and neurodegeneration. Mechanistically, Xmu-mp-1 exerted these neuroprotective actions by inactivating the Hippo signaling while potentiating the Wnt/β-Catenin signaling in the AD rats. Together, the results of the present study provide compelling support that Xmu-mp-1 negated the neuronal dysregulation in the rat model of sporadic AD. Therefore, inhibiting MST/Hippo signaling and modulating its crosstalk with the Wnt/β-Catenin pathway can be a promising alternative treatment strategy against AD pathology. This is the first study providing novel mechanistic insights into the therapeutic use of Xmu-mp-1 in sporadic AD.

Genetic deletion of zinc transporter ZnT3 induces progressive cognitive deficits in mice by impairing dendritic spine plasticity and glucose metabolism.

Zinc transporter 3 (ZnT3) is abundantly expressed in the brain, residing in synaptic vesicles, where it plays important roles in controlling the luminal zinc levels. In this study, we found that ZnT3 knockout in mice decreased zinc levels in the hippocampus and cortex, and was associated with progressive cognitive impairments, assessed at 2, 6, and 9-month of age. The results of Golgi-Cox staining demonstrated that ZnT3 deficiency was associated with an increase in dendritic complexity and a decrease in the density of mature dendritic spines, indicating potential synaptic plasticity deficit. Since ZnT3 deficiency was previously linked to glucose metabolism abnormalities, we tested the expression levels of genes related to insulin signaling pathway in the hippocampus and cortex. We found that the Expression of glucose transporters, GLUT3, GLUT4, and the insulin receptor in the whole tissue and synaptosome fraction of the hippocampus of the ZnT3 knockout mice were significantly reduced, as compared to wild-type controls. Expression of AKT (A serine/threonine protein kinase) and insulin-induced AKT phosphorylation was also reduced in the hippocampus of ZnT3 knockout mice. We hypothesize that the ZnT3 deficiency and reduced brain zinc levels may cause cognitive impairment by negatively affecting glycose metabolism via decreased expression of key components of insulin signaling, as well as via changes in synaptic plasticity. These finding may provide new therapeutic target for treatments of neurodegenerative disorders.

Microcephaly and Its Related Syndromes: Classification, Genetic, Clinical, and Rehabilitative Considerations

AbstractMicrocephaly, a form of cortical cortex malformation, results from abnormal cellular production and proliferation, identified when the occipital frontal head circumference (OFC) falls two or more standard deviations (SDs) below the expected average for age, gender, and population. Severity is classified based on SD: mild (OFC &lt; 2 SD) or severe (OFC &lt; 3 SD). While microcephaly can lead to developmental delay, intellectual disability, epilepsy, and cerebral palsy, not all cases exhibit these issues. Classified as primary/congenital or secondary/postnatal, microcephaly can stem from genetic or acquired factors in both types. Congenital microcephaly origins vary, while secondary microcephaly is characterized by normal OFC at birth, followed by a decrease within the first year, often associated with progressive cognitive and motor impairments. Primary hereditary microcephaly (MCPH), or microcephaly vera, is genetically diverse, with 28 related genes (MCPH1 to MCPH28) encoding proteins linked to centrosomes and progenitor cell mitosis in the brain ventricle's neuroepithelium. Defects in deoxyribonucleic acid (DNA) repair pathways (e.g., NBN, FANCA, ATR, ATM genes) can lead to microcephaly by impairing DNA repair. Enzyme deficiencies in metabolic pathways may also contribute, causing toxic metabolite accumulation or essential metabolite loss (microcephaly of metabolic origin). Acquired congenital microcephaly may result from ischemic or infectious processes, drugs, radiation, maternal diseases during pregnancy, with damage influenced by fetal genetics, environmental interactions, developmental stage, and exposure intensity/duration. Diagnostic workup includes electroencephalogram, ophthalmological, auditory, magnetic resonance imaging, metabolic, echocardiogram, and infection screening tests, alongside genetic evaluations like cytogenetic studies, fluorescence in situ hybridization, comparative genomic microarray-hybridization, single-nucleotide microarray-polymorphism, and exome sequencing. Symptomatic treatment is available, and genetic counseling is crucial for affected families.