Progressive Cognitive Impairment Research Articles

Cardiovascular Disease, Brain Glucose Metabolism, and Neurocognitive Decline in People With Human Immunodeficiency Virus.

Cardiovascular disease (CVD) and neuroinflammation are thought to exacerbate neurocognitive dysfunction in treated people with human immunodeficiency virus (PWH). Here, we longitudinally measured brain glucose metabolism as a measure of neuronal integrity in treated PWH using [18F]Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in correlation with atherosclerotic cardiovascular disease (ASCVD) scores, cerebrospinal fluid (CSF) neuroinflammatory markers, neurocognitive outcomes, and other clinical and laboratory variables (CLVs). Well-controlled PWH (n = 36) underwent baseline and follow-up FDG PET/CT obtained 3.5 years apart on average. Longitudinal changes in whole brain and regional relative FDG uptake, brain volumes, CLVs, CSF cytokines, and neuropsychological measures were measured. A variable selection model identified baseline variables related to future brain metabolic changes while multivariable models explored neuropsychological implications of brain metabolism and volumetrics. High ASCVD scores predicted future decreased thalamic uptake (slope = -0.0068, P = .027) and decreasing thalamic uptake correlated with worsening cognition (slope = 15.80, P = .020). Despite longitudinal greater than expected gray matter loss, whole brain FDG uptake did not change over the follow-up period. Most CSF cytokines decreased longitudinally but were not predictive of FDG changes. We found that high ASCVD scores in a group of treated PWH were related to thalamic hypometabolism, which in turn correlated with neurocognitive decline. Our findings support the contribution of CVD to neurocognitive dysfunction. More proactive CVD management may have a role in mitigating progression of cognitive impairment. Lack of change in global brain glucose metabolism despite documented accelerated gray matter volume loss over the same period suggests that FDG PET might underestimate neuronal injury in PWH compared to structural magnetic resonance imaging.

Cardiovascular dysautonomia and cognitive impairment in Parkinson's disease (Review).

Cognitive impairment is a prevalent non-motor symptom of Parkinson's disease (PD), which can result in significant disability and distress for patients and caregivers. There is a marked variation in the timing, characteristics and rate at which cognitive decline occurs in patients with PD. This decline can vary from normal cognition to mild cognitive impairment and dementia. Cognitive impairment is associated with several pathophysiological mechanisms, including the accumulation of β-amyloid and tau in the brain, oxidative stress and neuroinflammation. Cardiovascular autonomic dysfunctions are commonly observed in patients with PD. These dysfunctions play a role in the progression of cognitive impairment, the incidents of falls and even in mortality. The majority of symptoms of dysautonomia arise from changes in the peripheral autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. Cardiovascular changes, including orthostatic hypotension, supine hypertension and abnormal nocturnal blood pressure (BP), can occur in both the early and advanced stages of PD. These changes tend to increase as the disease advances. The present review aimed to describe the cognitive changes in the setting of cardiovascular dysautonomia and to discuss strategies through which these changes can be modified and managed. It is a multifactorial process usually involving decreased blood flow to the brain, resulting in the development of cerebral ischemic lesions, an increased presence of abnormal white matter signals in the brain, and a potential influence on the process of neurodegeneration in PD. Another possible explanation is this association being independent observations of PD progression. Patients with clinical symptoms of dysautonomia should undergo 24-h ambulatory BP monitoring, as they are frequently subtle and underdiagnosed.

Ginsenoside compound K alleviates D-galactose-induced mild cognitive impairment by modulating gut microbiota-mediated short-chain fatty acid metabolism.

The occurrence and progression of mild cognitive impairment (MCI) are closely related to dysbiosis of the gut microbiota. Ginsenoside compound K (CK), a bioactive component of ginseng, has been shown to alleviate gut microbiota dysbiosis and neural damage. However, the mechanisms by which CK regulates the gut microbiota to improve MCI remain unexplored. In this study, an MCI mouse model induced by D-galactose was used, and 16S rRNA gene sequencing, metabolomics, transcriptomics, and integrative multi-omics analyses were employed to investigate the potential mechanisms by which CK alleviates MCI through modulation of the gut microbiota. The results demonstrated that CK repaired intestinal barrier dysfunction caused by MCI, improved blood-brain barrier (BBB) integrity, inhibited activation of microglial cells and astrocytes, and significantly ameliorated MCI. Furthermore, CK enhanced gut microbiota diversity, notably enriched beneficial bacteria such as Akkermansia, and modulated the levels of short-chain fatty acids (SCFAs), particularly increasing propionate, thereby alleviating gut microbiota dysbiosis caused by MCI. Germ-free experiments confirmed that gut microbiota is a key factor for ginsenoside CK in relieving MCI. Further investigation revealed that CK regulated the TLR4-MyD88-NF-κB signaling pathway through modulation of gut microbiota-mediated propionate metabolism, significantly reducing systemic inflammation and alleviating MCI. Our findings provide a new theoretical basis for using CK as a potential means of modulating the gut microbiota for the treatment of MCI.

Exploring the Mechanisms and Therapeutic Approaches of Mitochondrial Dysfunction in Alzheimer's Disease: An Educational Literature Review.

Alzheimer's disease (AD) presents a significant challenge to global health. It is characterized by progressive cognitive deterioration and increased rates of morbidity and mortality among older adults. Among the various pathophysiologies of AD, mitochondrial dysfunction, encompassing conditions such as increased reactive oxygen production, dysregulated calcium homeostasis, and impaired mitochondrial dynamics, plays a pivotal role. This review comprehensively investigates the mechanisms of mitochondrial dysfunction in AD, focusing on aspects such as glucose metabolism impairment, mitochondrial bioenergetics, calcium signaling, protein tau and amyloid-beta-associated synapse dysfunction, mitophagy, aging, inflammation, mitochondrial DNA, mitochondria-localized microRNAs, genetics, hormones, and the electron transport chain and Krebs cycle. While lecanemab is the only FDA-approved medication to treat AD, we explore various therapeutic modalities for mitigating mitochondrial dysfunction in AD, including antioxidant drugs, antidiabetic agents, acetylcholinesterase inhibitors (FDA-approved to manage symptoms), nutritional supplements, natural products, phenylpropanoids, vaccines, exercise, and other potential treatments.

MicroRNAs: pioneering regulators in Alzheimer’s disease pathogenesis, diagnosis, and therapy

This article delves into Alzheimer’s disease (AD), a prevalent neurodegenerative condition primarily affecting the elderly. It is characterized by progressive memory and cognitive impairments, severely disrupting daily life. Recent research highlights the potential involvement of microRNAs in the pathogenesis of AD. MicroRNAs (MiRNAs), short non-coding RNAs comprising 20–24 nucleotides, significantly influence gene regulation by hindering translation or promoting degradation of target genes. This review explores the role of specific miRNAs in AD progression, focusing on their impact on β-amyloid (Aβ) peptide accumulation, intracellular aggregation of hyperphosphorylated tau proteins, mitochondrial dysfunction, neuroinflammation, oxidative stress, and the expression of the APOE4 gene. Our insights contribute to understanding AD’s pathology, offering new avenues for identifying diagnostic markers and developing novel therapeutic targets.

Anything is better than nothing’: exploring attitudes towards novel therapies in leukodystrophy clinical trials

Background/AimLeukodystrophies comprise a group of genetic white matter disorders that lead to progressive motor and cognitive impairment. Recent development of novel therapies has led to an increase in clinical trials for leukodystrophies. To enable recruitment of individuals with a leukodystrophy into clinical trials, clinical trial acceptability should be ascertained. We sought therefore, to identify the motivations for and barriers to clinical trial participation in addition to clinical trial features that may be of concern to individuals with a leukodystrophy and/or their carers.MethodsAdults with a leukodystrophy and parents/carers of individuals with a leukodystrophy were recruited through the Australian Leukodystrophy Registry and through online advertisements. Qualitative semi-structured interviews were used to explore participants views on what clinical trials involve, the perceived risks and benefits of clinical trials, their desire to participate in clinical trials and their personal experience with leukodystrophy. Thematic analysis of data was performed with co-coding of interview transcripts.Results5 interviews were held with parents of children with leukodystrophy, 4 with parents of adults with leukodystrophy and 3 with adults diagnosed with leukodystrophy. Motivations for clinical trial enrolment include access to potentially lifesaving novel treatments and improved prognostic outcomes. Participants were concerned about adverse clinical trial outcomes, including side effects and exacerbation of illness. Despite this, majority of participants were willing to try anything in clinical trials, demonstrating a high tolerance for first in human trials and trials utilising invasive treatment options.ConclusionsInterviewees communicated a strong desire to participate in interventional clinical trials involving novel therapies. To support enrolment into future leukodystrophy clinical trials we suggest the provision of transparent information regarding clinical trial treatments, consideration of alternative trial control measures, and inclusion of treating clinicians in the trial recruitment process. Clinicians play an integral role in initiating transparent conversations regarding trial risks and adverse outcomes.

Molecular and Functional Alterations in the Cerebral Microvasculature in an Optimized Mouse Model of Sepsis-Associated Cognitive Dysfunction.

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in sepsis-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammation. In the acute phase, we identified novel molecular (e.g., upregulation of plasmalemma vesicle-associated protein, PLVAP, a driver of endothelial permeability, and the procoagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small-molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small-molecule BBB permeability, elevated levels of PAI-1, intra-/perivascular fibrin/fibrinogen deposition, and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor, suggesting diffuse axonal injury, synapse degeneration, and impaired neurotrophism. Our study serves as a standardized mouse model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition.

Dynamics of Cognitive Impairment in MCI Patients over a Three-Year Period: The Informative Role of Blood Biomarkers, Neuroimaging, and Genetic Factors.

Given the high growth rates of cognitive decline among the elderly population and the lack of effective etiological treatments, early diagnosis of cognitive impairment progression is an imperative task for modern science and medicine. It is of particular interest to identify predictors of an unfavorable subsequent course of cognitive disorders, specifically, rapid progression. Our study assessed the informative role of various risk factors on the dynamics of cognitive impairment among mild cognitive impairment (MCI) patients. The study included patients with MCI (N = 338) who underwent neuropsychological assessment, magnetic resonance imaging (MRI) examination, blood sampling for general and biochemical analysis, APOE genotyping, and polygenic risk score (PRS) evaluation. The APOE ε4/ε4 genotype was found to be associated with a diminished overall cognitive scores initial assessment and negative cognitive dynamics. No associations were found between cognitive changes and the PRS. The progression of cognitive impairment was associated with the width of the third ventricle and hematological parameters, specifically, hematocrit and erythrocyte levels. The absence of significant associations between the dynamics of cognitive decline and PRS over three years can be attributed to the provided suitable medical care for the prevention of cognitive impairment. Adding other risk factors and their inclusion in panels assessing the risk of progression of cognitive impairment should be considered.

Computational Analysis of Marker Genes in Alzheimer’s Disease across Multiple Brain Regions

Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia in the elderly, which is characterized by progressive cognitive impairment. Herein, we undertake a sophisticated computational analysis by integrating single-cell RNA sequencing (scRNA-seq) data from multiple brain regions significantly affected by the disease, including the entorhinal cortex, prefrontal cortex, superior frontal gyrus, and superior parietal lobe. Our pipeline combines datasets derived from the aforementioned tissues into a unified analysis framework, facilitating cross-regional comparisons to provide a holistic view of the impact of the disease on the cellular and molecular landscape of the brain. We employed advanced computational techniques such as batch effect correction, normalization, dimensionality reduction, clustering, and visualization to explore cellular heterogeneity and gene expression patterns across these regions. Our findings suggest that enabling the integration of data from multiple batches can significantly enhance our understanding of AD complexity, thereby identifying key molecular targets for potential therapeutic intervention. This study established a precedent for future research by demonstrating how existing data can be reanalysed in a coherent manner to elucidate the systemic nature of the disease and inform the development of more effective diagnostic tools and targeted therapies.

Inhibition of Calcineurin with FK506 Reduces Tau Levels and Attenuates Synaptic Impairment Driven by Tau Oligomers in the Hippocampus of Male Mouse Models.

Alzheimer's disease (AD) is the most common age-associated neurodegenerative disorder, characterized by progressive cognitive decline, memory impairment, and structural brain changes, primarily involving Aβ plaques and neurofibrillary tangles of hyperphosphorylated tau protein. Recent research highlights the significance of smaller Aβ and Tau oligomeric aggregates (AβO and TauO, respectively) in synaptic dysfunction and disease progression. Calcineurin (CaN), a key calcium/calmodulin-dependent player in regulating synaptic function in the central nervous system (CNS) is implicated in mediating detrimental effects of AβO on synapses and memory function in AD. This study aims to investigate the specific impact of CaN on both exogenous and endogenous TauO through the acute and chronic inhibition of CaN. We previously demonstrated the protective effect against AD of the immunosuppressant CaN inhibitor, FK506, but its influence on TauO remains unclear. In this study, we explored the short-term effects of acute CaN inhibition on TauO phosphorylation and TauO-induced memory deficits and synaptic dysfunction. Mice received FK506 post-TauO intracerebroventricular injection and TauO levels and phosphorylation were assessed, examining their impact on CaN and GSK-3β. The study investigated FK506 preventive/reversal effects on TauO-induced clustering of CaN and GSK-3β. Memory and synaptic function in TauO-injected mice were evaluated with/without FK506. Chronic FK506 treatment in 3xTgAD mice explored its influence on CaN, Aβ, and Tau levels. This study underscores the significant influence of CaN inhibition on TauO and associated AD pathology, suggesting therapeutic potential in targeting CaN for addressing various aspects of AD onset and progression. These findings provide valuable insights for potential interventions in AD, emphasizing the need for further exploration of CaN-targeted strategies.

White matter structure and derived network properties are used to predict the progression from mild cognitive impairment of older adults to Alzheimer’s disease

ObjectiveTo identify white matter fiber injury and network changes that may lead to mild cognitive impairment (MCI) progression, then a joint model was constructed based on neuropsychological scales to predict high-risk individuals for Alzheimer's disease (AD) progression among older adults with MCI.MethodsA total of 173 MCI patients were included from the Alzheimer's Disease Neuroimaging Initiative(ADNI) database and randomly divided into training and testing cohorts. Forty-five progressed to AD during a 4-year follow-up period. Diffusion tensor imaging (DTI) techniques extracted relevant DTI quantitative features for each patient. In addition, brain networks were constructed based on white matter fiber bundles to extract network property features. Ensemble dimensionality reduction was applied to reduce both DTI quantitative features and network features from the training cohort, and machine learning algorithms were added to construct white matter signature. In addition, 52 patients from the National Alzheimer's Coordinating Center (NACC) database were used for external validation of white matter signature. A joint model was subsequently generated by combining with scale scores, and its performance was evaluated using data from the testing cohort.ResultsBased on multivariate logistic regression, clinical dementia rating and Alzheimer’s disease assessment scales (CDRS and ADAS, respectively) were selected as independent predictive factors. A joint model was constructed in combination with the white matter signature. The AUC, sensitivity, and specificity in the training cohort were 0.938, 0.937, and 0.91, respectively, and the AUC, sensitivity, and specificity in the test cohort were 0.905, 0.923, and 0.872, respectively. The Delong test showed a statistically significant difference between the joint model and CDRS or ADAS scores (P < 0.05), yet no significant difference between the joint model and the white matter signature (P = 0.341).ConclusionThe present results demonstrate that a joint model combining neuropsychological scales can be constructed by using machine learning and DTI technology to identify MCI patients who are at high-risk of progressing to AD.

Ferroptosis in Cognitive Impairment Associated with Diabetes and Alzheimer's Disease: Mechanistic Insights and New Therapeutic Opportunities.

Cognitive impairment associated with diabetes and Alzheimer's disease has become a major health issue affecting older individuals, with morbidity rates growing acutely each year. Ferroptosis is a novel form of cell death that is triggered by iron-dependent lipid peroxidation. A growing body of evidence suggests a strong correlation between the progression of cognitive impairment and diabetes, Alzheimer's disease, and ferroptosis. The pharmacological modulation of ferroptosis could be a promising therapeutic intervention for cognitive impairment associated with diabetes and Alzheimer's disease. In this review, we summarize evidence on ferroptosis in the context of cognitive impairment associated with diabetes and Alzheimer's disease and provide detailed insights into the function and potential action pathways of ferroptosis. Furthermore, we discuss the therapeutic importance of natural ferroptosis products in improving the cognitive impairment associated with diabetes and Alzheimer's disease and provide new insights for clinical treatment.

Impact of Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i) Therapy on Dementia and Cognitive Decline.

Dementia is an age-related syndrome characterized by the progressive deterioration of cognition and capacity for independent living. Diabetes is often associated with cognitive decline and shares similar pathophysiological mechanisms with dementia, such as systemic inflammation, oxidative stress, insulin resistance, and advanced glycation end-products formation. Therefore, adequate diabetes management may reduce the risk of cognitive decline, especially in patients with other comorbidities and risk factors. The sodium glucose cotransporter inhibitors (SGLT2i) regulate renal glucose reabsorption by blocking the SGLT2 cotransporters located in the proximal tubules, causing glycosuria and intraglomerular pressure reduction. Their use helps to lower blood pressure by modifying sodium and water homeostasis; these drugs are also commonly used in the treatment of heart failure and chronic kidney disease, while recently, a potential neuroprotective role in the central nervous system has been suggested. The aim of our scoping review is to analyze current evidence about the potential neuroprotective effects of SGLT2i in adult patients. We performed a scoping literature review to evaluate the effect of SGLT2i on dementia, mild cognitive impairment (MCI) and Alzheimer's disease incidence and progression. The screening process was performed through different searches on PubMed and EMBASE, evaluating original works published up to January 2024. In conclusion, the use of SGLT2i could be associated with a neuroprotective effect in patients with diabetes, reducing the incidence or the progression of MCI and dementia. Further prospective studies are needed to validate this hypothesis and to evaluate the effectiveness of this class of drugs in normal glycemic profile patients.

Establishment and evaluation of a clinical prediction model for cognitive impairment in patients with cerebral small vessel disease

BackgroundThere are currently no effective prediction methods for evaluating the occurrence of cognitive impairment in patients with cerebral small vessel disease (CSVD).AimsTo investigate the risk factors for cognitive dysfunction in patients with CSVD and to construct a risk prediction model.MethodsA retrospective study was conducted on 227 patients with CSVD. All patients were assessed by brain magnetic resonance imaging (MRI), and the Montreal Cognitive Assessment (MoCA) was used to assess cognitive status. In addition, the patient’s medical records were also recorded. The clinical data were divided into a normal cognitive function group and a cognitive impairment group. A MoCA score < 26 (an additional 1 point for education < 12 years) is defined as cognitive dysfunction.ResultsA total of 227 patients (mean age 66.7 ± 6.99 years) with CSVD were included in this study, of whom 68.7% were male and 100 patients (44.1%) developed cognitive impairment. Age (OR = 1.070; 95% CI = 1.015 ~ 1.128, p < 0.05), hypertension (OR = 2.863; 95% CI = 1.438 ~ 5.699, p < 0.05), homocysteine(HCY) (OR = 1.065; 95% CI = 1.005 ~ 1.127, p < 0.05), lacunar infarct score(Lac_score) (OR = 2.732; 95% CI = 1.094 ~ 6.825, P < 0.05), and CSVD total burden (CSVD_score) (OR = 3.823; 95% CI = 1.496 ~ 9.768, P < 0.05) were found to be independent risk factors for cognitive decline in the present study. The above 5 variables were used to construct a nomogram, and the model was internally validated by using bootstrapping with a C-index of 0.839. The external model validation C-index was 0.867.ConclusionsThe nomogram model based on brain MR images and clinical data helps in individualizing the probability of cognitive impairment progression in patients with CSVD.

Traumatic Brain Injury, Seizures, and Cognitive Impairment Among Older Adults

Traumatic brain injury (TBI), seizures, and dementia increase with age. There is a gap in understanding the associations of TBI, seizures, and medications such as antiseizure and antipsychotics with the progression of cognitive impairment across racial and ethnic groups. To investigate the association of TBI and seizures with the risk of cognitive impairment among cognitively normal older adults and the role of medications in moderating the association. This multicenter cohort study was a secondary analysis of the Uniform Data Set collected between June 1, 2005, and June 30, 2020, from the National Alzheimer's Coordination Center. Statistical analysis was performed from February 1 to April 3, 2024. Data were collected from participants from 36 Alzheimer's Disease Research Centers in the US who were 65 years or older at baseline, cognitively normal at baseline (Clinical Dementia Rating of 0 and no impairment based on a presumptive etiologic diagnosis of AD), and had complete information on race and ethnicity, age, sex, educational level, and apolipoprotein E genotype. Health history of TBI, seizures, or both conditions. Progression to cognitive impairment measured by a Clinical Dementia Rating greater than 0. Among the cohort of 7180 older adults (median age, 74 years [range, 65-102 years]; 4729 women [65.9%]), 1036 were African American or Black (14.4%), 21 were American Indian or Alaska Native (0.3%), 143 were Asian (2.0%), 332 were Hispanic (4.6%), and 5648 were non-Hispanic White (78.7%); the median educational level was 16.0 years (range, 1.0-29.0 years). After adjustment for selection basis using propensity score weighting, seizure was associated with a 40% higher risk of cognitive impairment (hazard ratio [HR], 1.40; 95% CI, 1.19-1.65), TBI with a 25% higher risk of cognitive impairment (HR, 1.25; 95% CI, 1.17-1.34), and both seizure and TBI were associated with a 57% higher risk (HR, 1.57; 95% CI, 1.23-2.01). The interaction models indicated that Hispanic participants with TBI and seizures had a higher risk of cognitive impairment compared with other racial and ethnic groups. The use of antiseizure medications (HR, 1.23; 95% CI, 0.99-1.53), antidepressants (HR, 1.32; 95% CI, 1.17-1.50), and antipsychotics (HR, 2.15; 95% CI, 1.18-3.89) was associated with a higher risk of cognitive impairment, while anxiolytic, sedative, or hypnotic use (HR, 0.88; 95% CI, 0.83-0.94) was associated with a lower risk. This study highlights the importance of addressing TBI and seizures as risk factors for cognitive impairment among older adults. Addressing the broader social determinants of health and bridging the health divide across various racial and ethnic groups are essential for the comprehensive management and prevention of dementia.

KARS Mutations Impair Brain Myelination by Inducing Oligodendrocyte Deficiency: One Potential Mechanism and Improvement by Melatonin.

It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl-tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock-in mouse models throughthe CRISPR-Cas9 system. Kars knock-in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes' significantly imbalanced expression of differentiation regulators and increased capase-3-mediated apoptosis were observed in the brain white matter of Kars knock-in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady-state level of mitochondrial tRNALys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock-in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock-in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of KarsR504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock-in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)-related diseases.

Omaveloxolone Ameliorates Cognitive Deficits by Inhibiting Apoptosis and Neuroinflammation in APP/PS1 Mice.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease associated with aging, characterized by progressive cognitive impairment and memory loss. However, treatments that delay AD progression or improve its symptoms remain limited. The aim of the present study was to investigate the therapeutic effects of omaveloxolone (Omav) on AD and to explore the underlying mechanisms. Thirty-week-old APP/PS1 mice were selected as an experimental model of AD. The spatial learning and memory abilities were tested using the Morris water maze. Amyloid-beta (Aβ) deposition in the brains was measured using immunohistochemistry. Network pharmacological analyses and molecular docking were conducted to gain insights into the therapeutic mechanisms of Omav. Finally, validation analyses were conducted to detect changes in the associated pathways and proteins. Our finding revealed that Omav markedly rescued cognitive dysfunction and reduced Aβ deposition in the brains of APP/PS1 mice. Network pharmacological analysis identified 112 intersecting genes, with CASP3 and MTOR emerging as the key targets. In vivo validation experiments indicated that Omav attenuated neuronal apoptosis by regulating apoptotic proteins, including caspase 3, Bax, and Bcl-2. Moreover, Omav suppressed neuroinflammation and induced autophagy by inhibiting the phosphorylation of mTOR. These findings highlight the therapeutic efficacy of Omav in AD and that its neuroprotective effects were associated with inhibiting neuronal apoptosis and regulating neuroinflammation.

Motor progression trajectories and risk of mild cognitive impairment in Parkinson's disease: A latent class trajectory model from PPMI cohort.

Rare studies have investigated the association between heterogeneity of motor progression and risk of early cognitive impairment in Parkinson's disease (PD). In this study, we aim to identify distinct trajectories of motor progression longitudinally and investigate their impact on predicting mild cognitive impairment (MCI). A 5-year cohort including 415 PD patients at baseline was collected from the Parkinson's Progression Markers Initiative. The severity of motor symptoms was evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III. The latent class trajectory model and nonlinear mixed-effects model were used to analyze and delineate the longitudinal changes in motor symptoms. Propensity score matching (PSM) was used to minimize the impact of potential confounders. Cox proportional hazard models were applied to calculate hazard ratios for MCI, and a Kaplan-Meier curve was generated using the occurrence of MCI during the follow-up as the time-to-event. Two latent trajectories were identified: a mild and remitting motor symptoms class (Class 1, 33.01%) and a severe and progressive motor symptom class (Class 2, 66.99%). Patients in Class 2 initially exhibited severe motor symptoms that worsened progressively despite receiving anti-PD medications. In comparison, patients in Class 1 exhibited milder symptoms that improved following drug therapy and a slower progression. During a 5-year follow-up, patients in Class 2 showed a higher risk of developing MCI compared to those in Class 1 before PSM (Log-Rank 28.58, p < 0.001) and after PSM (Log-Rank 8.20, p = 0.004). PD patients with severe and progressive motor symptoms are more likely to develop MCI than those with mild and stable motor symptoms.

Analysis of individual alpha frequency in a large cohort from a tertiary memory center.

Precise and timely diagnosis is crucial for the optimal use of emerging disease-modifying treatments for Alzheimer disease (AD). Electroencephalography (EEG), which is noninvasive and cost-effective, can capture neural abnormalities linked to various dementias. This study explores the use of individual alpha frequency (IAF) derived from EEG as a diagnostic and prognostic tool in cognitively impaired patients. This retrospective study included 375 patients from the tertiary Memory Clinic of IRCCS San Raffaele Hospital, Milan, Italy. Participants underwent clinical and neuropsychological assessments, brain imaging, cerebrospinal fluid biomarker analysis, and resting-state EEG. Patients were categorized by amyloid status, the AT(N) classification system, clinical diagnosis, and mild cognitive impairment (MCI) progression to AD dementia. IAF was calculated and compared among study groups. Receiver operating characteristic (ROC) analysis was used to calculate its discriminative performance. IAF was higher in amyloid-negative subjects and varied significantly across AT(N) groups. ROC analysis confirmed IAF's ability to distinguish A-T-N- from the A+T+N+ and A+T-N+ groups. IAF was lower in AD and Lewy body dementia patients compared to MCI and other dementia types, with moderate discriminatory capability. Among A+ MCI patients, IAF was significantly lower in those who converted to AD within 2 years compared to stable MCI patients and predicted time to conversion (p < 0.001, R = 0.38). IAF is a valuable tool for dementia diagnosis and prognosis, correlating with amyloid status and neurodegeneration. It effectively predicts MCI progression to AD, supporting its use in early, targeted interventions in the context of disease-modifying treatments.

Exploring galectin-3's role in predicting mild cognitive impairment in type 2 diabetes and its regulation by miRNAs.

This study aimed to investigate the role of galectin-3 (Gal-3; coded by LGALS3 gene), as a biomarker for MCI in T2DM patients and to develop and validate a predictive nomogram integrating galectin-3 with clinical risk factors for MCI prediction. Additionally, microRNA regulation of LGALS3 was explored. The study employed a cross-sectional design. A total of 329 hospitalized T2DM patients were recruited and randomly allocated into a training cohort (n = 231) and a validation cohort (n = 98) using 7:3 ratio. Demographic data and neuropsychological assessments were recorded for all participants. Plasma levels of galectin-3 were measured using ELISA assay. We employed Spearman's correlation and multivariable linear regression to analyze the relationship between galectin-3 levels and cognitive performance. Furthermore, univariate and multivariate logistic regression analyses were conducted to identify independent risk factors for MCI in T2DM patients. Based on these analyses, a predictive nomogram incorporating galectin-3 and clinical predictors was developed. The model's performance was evaluated in terms of discrimination, calibration, and clinical utility. Regulatory miRNAs were identified using bioinformatics and their interactions with LGALS3 were confirmed through qRT-PCR and luciferase reporter assays. Galectin-3 was identified as an independent risk factor for MCI, with significant correlations to cognitive decline in T2DM patients. The developed nomogram, incorporating Gal-3, age, and education levels, demonstrated excellent predictive performance with an AUC of 0.813 in the training cohort and 0.775 in the validation cohort. The model outperformed the baseline galectin-3 model and showed a higher net benefit in clinical decision-making. Hsa-miR-128-3p was significantly downregulated in MCI patients, correlating with increased Gal-3 levels, while Luciferase assays confirmed miR-128-3p's specific binding and influence on LGALS3. Our findings emphasize the utility of Gal-3 as a viable biomarker for early detection of MCI in T2DM patients. The validated nomogram offers a practical tool for clinical decision-making, facilitating early interventions to potentially delay the progression of cognitive impairment. Additionally, further research on miRNA128's regulation of Gal-3 levels is essential to substantiate our results.