Patients with Alzheimer's disease (AD) often develop osteoporosis, but the role of bone remodeling in AD remains unclear. We previously showed that osteoblast-specific expression of APP induces bone loss, glial activation, and behavioral deficits, suggesting a bone-to-brain signaling axis. Here, we identify an altered skull bone marrow (SBM)-to-brain axis in AD. Early SBM changes, including reduced cellularity, increased density, and expanded vascular channels to the meninges, occur in multiple APP mouse models. These vascular changes facilitate migration of SBM-derived myeloid cells into the meninges and cortex, improving cerebral blood flow (CBF) and slowing cognitive decline. Notably, these effects are age-dependent, emerging at 6 months but diminishing by 12 months. Enhancing this axis via bone marrow transplantation improves CBF and cognitive function in aged mice, whereas disrupting it through osteoblastic deletion of ATP6AP2 impairs both. Together, these findings reveal a previously unrecognized SBM-to-brain axis that regulates immune, vascular, and cognitive functions, highlighting systemic contributions to AD pathogenesis.

INTRODUCTION: Feeling lonely defined as a subjective dissatisfaction with social relationships, is associated with an increased risk of functional and cognitive decline well-known factors for institutionalization. The objective was to evaluate the predictive role of feeling lonely on admission to nursing homes among elderly people hospitalized via emergency departments. METHODS: This was an observational, longitudinal, prospective, multicenter study. Participants were recruited over a period of ten months. Patients were eligible if they were aged 75 years or older and hospitalized in a medical ward of the same hospital as the emergency department (ED) where they were initially admitted. The assessment included the collection of sociodemographic data-age, sex, level of education, available support (particularly the presence of a primary caregiver), number of children, and living arrangements (home or institutional setting)-as well as clinical variables, including presence of dementia or delirium, mood disorders, comorbidities, nutritional status, dependence in activities of daily living (ADL), mobility, risk of falls, and risk of pressure ulcers. The assessment included the collection of sociodemographic (age, sex, level of education, available support (in particular the presence of a primary caregiver), number of children, living conditions (e.g., at home or in an institution) Loneliness was assessed using item 14 of the CES-D (Center for Epidemiologic Studies Depression) scale. Univariate and multivariate analyses were performed using a Cox model that took death into account as a competing risk, using a Fine & Gray model. RESULTS: The mean age was 84.4 ± 5.9 years, and 55% were women. In this population, 40% reported feeling lonely, 41% were at risk of depression, 78% had at least one child, 67% had at least one family caregiver, and 79% (n = 833) lived alone. Over the 36-month follow-up period, 31.46% of patients entered nursing homes. Independent risk factors for institutionalization included social determinants specifically feeling lonely, which was independently associated with an increased risk of placement at 12, 24, and 36 months. Individuals reporting loneliness showed an increased risk of functional and cognitive decline. CONCLUSION: This study regarding hospitalized elderly after admission to an Emergency Department shows that feeling lonely is not merely a marker of social vulnerability but is independently associated with of nursing home admission.

Care for a parent with dementia is often shared among multiple adult children, yet it is not always evenly distributed. Guided by the family stress process model, this study examined associations between perceptions of care equality, depressive symptoms, loneliness, and positive affect among 208 adult children caring for a parent with dementia within 110 families from the Siblings Caring for a Parent with Dementia Study (mean age = 58.36, = 9.38; 89% women), and mediating roles of caregiver burden and social support. When adult child caregivers perceived that they were contributing more to parental care than their sibling, they reported greater depressive symptoms than participants who reported equal care. Unequal care was linked to depressive symptoms, loneliness, and positive affect via caregiver burden but not social support. Perceptions of (un)equal divisions of care are associated with adult children's mental health, representing potential caregiving intervention targets.

BACKGROUND: Falls and physical inactivity are both linked to increased dementia risk, but their joint impact has not been well studied. It remains unclear whether physical activity can mitigate the elevated dementia risk after a fall and whether it also lowers the likelihood of future falls. METHODS: We used data from 44,488 adults aged ≥ 60 years in three cohorts. Falls and physical activity were self-reported. Incident dementia was tracked during follow-up. Cox proportional hazards models estimated the associations of falls with dementia and physical activity with dementia and falls, stratified by fall history. RESULTS: Over a median follow-up of 5.9-7.9 years, 3,492 dementia cases were identified. Falls were associated with a 70% higher risk of dementia (pooled HR = 1.70, 95% CI: 1.57-1.84). In the no-fall group, compared with inactivity, low, moderate, and high physical activity were progressively associated with lower risks of dementia (HRs = 0.63, 0.53, 0.43) and falls (HRs = 0.77, 0.68, 0.58). These protective effects were consistent among fallers, with similar dose-response gradients. CONCLUSIONS: Falls substantially increased dementia risk. Higher levels of physical activity were linked to lower risks of both dementia and falls, regardless of fall history.

BACKGROUND: Alterations in amine metabolism have been implicated in Alzheimer's disease (AD), but the relationships between plasma and cerebrospinal fluid (CSF) amine levels remain insufficiently understood. AIM: To investigate longitudinal changes in amines in plasma and CSF, as well as their cross-matrix correlations, in male and female TgF344-AD transgenic rats compared with wild-type (WT) controls. METHOD: LC-MS-based targeted metabolomics was used to quantify 60 plasma amines and 55 CSF amines in male and female TgF344-AD and WT rats at 12, 25, 50 and 85 weeks of age. Generalized linear models, Pearson correlations, and Fisher's r-to-z transformation were applied for statistical analysis. RESULTS: In plasma, age- and sex-associated differences were observed. At 25 weeks, three amines (4-hydroxy-proline, homocitrulline, and hydroxylysine) showed significantly increased levels in male TgF344-AD rats after multiple-testing correction. Additional trend-level changes were observed at 12, 50, and 85 weeks. In CSF, no amines passed the significance threshold after multiple-testing correction, although descriptive age- and sex-associated patterns were observed, with earlier changes in males and later-stage trends in females. CSF-plasma correlations tended to be stronger in TgF344-AD rats than in WT rats, with relatively strong correlations for alpha-aminobutyric acid, citrulline, N6,N6,N6-trimethyl-lysine, and putrescine. CONCLUSIONS: Body fluid, age- and sex-dependent amine alterations in CSF and plasma of TgF344-AD rats compared to WT controls provide important insights into AD disease processes and may aid early diagnosis and therapeutic targeting.

OBJECTIVE: To develop a nomogram that incorporating clinical data and transcranial sonography (TCS) markers for predicting Parkinson's disease patients with cognitive impairment (PD-CI). METHODS: 149 PD with normal cognition (PD-NCI), 117 PD with mild CI (PD-MCI), and 79 PD with dementia (PDD) were included as the training set, 145 PD patients and 154 age- and gender-matched volunteers were enrolled as the test set and control group, respectively. Logistic regression was utilized to screen risk factors for predicting PD-CI, and a nomogram was generated. RESULTS: A predictive model was developed using age, education level, homocysteine, substantia nigra hyperechogenicity (SNH), and third ventricle (V3) width. Receiver operating characteristic curves indicated that V3 width, homocysteine, and the model effectively distinguished between PD-NCI and PD-CI, PDD and non-PDD, as well as PDD and PD-MCI, with the predictive model yielding the highest area under the curve. Calibration curves showed that the predictions of the final model in both the training and test sets closely matched the actual probabilities, while clinical decision curves suggested that the nomogram provided a substantial clinical net benefit. CONCLUSION: A predictive model for PD-CI that incorporates age, education level, plasma homocysteine levels, SNH, and V3 width has been developed and validated.

BACKGROUND AND AIMS: Healthcare students' attitudes towards dementia are crucial to the quality of care. Experiential learning is a promising strategy; however, the comparative effectiveness of its various modalities remains unclear. This systematic review and meta-analysis aimed to evaluate the impact of experiential learning interventions on healthcare students' attitudes towards dementia. METHODS: A comprehensive literature search was conducted across eight databases (e.g., PubMed, Embase, Cochrane Library) for studies published up to August 2024. A total of 2,350 articles were initially identified using the keywords "experiential learning," "students," "attitude," and "dementia." Only studies that evaluated the impact of experiential learning on attitudes towards dementia using the Dementia Attitude Scale (DAS) were included. RESULTS: Thirteen studies involving 1,861 healthcare students were included. Experiential learning significantly improved attitudes towards dementia (WMD = 9.46, 95% CI [6.33-12.58], p < 0.001). Both short-term (single-session) and long-term programs (multiple-session) demonstrated comparable levels of improvement (p = 0.49). Artistic interventions (e.g., storytelling, visual arts) produced significantly greater effects than non-artistic interventions (WMD = 13.44 vs. 7.58, p = 0.02). Interdisciplinary interventions were associated with greater improvement in attitudes, whereas virtual learning formats showed inconsistent outcomes and lacked sufficient representation for robust subgroup analysis. CONCLUSION: Experiential learning, particularly artistic and interdisciplinary approaches, significantly enhances healthcare students' attitudes towards dementia. Even brief interventions proved effective, underscoring their applicability in resource-limited settings. However, methodological limitations, such as quasi-experimental designs, short-term follow-ups, and limited disciplinary and geographic diversity, restrict generalizability. Future studies should employ rigorous designs, explore virtual innovations, and assess long-term outcomes to inform scalable, evidence-based dementia education.

BACKGROUND: Dementia is a neurocognitive disorder that involves deterioration in cognitive and daily functioning, leading to loss of independence and reduced quality of life. While pharmacological treatments offer limited symptomatic relief, non-pharmacological approaches such as exercise have shown promise in improving cognitive and functional outcomes. However, evidence from community-based structured exercise interventions remains limited, particularly in low-resource settings. This trial aims to evaluate the effects of a community-based structured group exercise program on cognitive and physical function among older adults with dementia. METHODS: This assessor-blinded, community-based randomized controlled trial will be conducted from February to September 2026 in Bangladesh. A total of 120 older adults diagnosed with dementia will be randomly allocated (1:1) to either the experimental group (structured group exercise program with healthy lifestyle advice) or the control group (healthy lifestyle advice alone). The intervention will consist of supervised sessions three times a week for 12 weeks, followed by a 12-week follow-up period. The outcome will be measured on both cognitive and physical function bases. Cognitive function will be evaluated using the Mini-Mental State Examination (MMSE), Addenbrooke's Cognitive Examination Revised (ACE-R), Trail Making Test (TMT) A-B, and Digit Span Test (DST). Physical function will be measured using the Senior Fitness Test (SFT), Berg Balance Scale (BBS), Timed Up and Go (TUG) Test, and Instrumental Activities of Daily Living scale (IADLs). All outcomes will be measured at baseline, posttest (12 weeks), and follow-up period (12 weeks). Data will be analyzed using SPSS following the intention-to-treat principle. DISCUSSION: The findings are expected to support the integration of physiotherapist-led, community-based exercise into dementia care, offering a feasible, safe, and cost-effective approach for improving cognitive and physical function in older adults with dementia. Despite potential limitations in generalizability, the study's community implementation and follow-up design will contribute valuable insights into sustainable rehabilitation practices in resource-limited settings. TRIAL REGISTRATION: This trial is registered prospectively in the Clinical Trial Registry India; ID: CTRI/2025/10/096618; Registered on: 29/10/2025. Link: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTQ0NDg3&Enc=&userName=.

Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.

Hearing is the largest modifiable mid-life risk factor for Alzheimer's disease (AD), yet its link to dementia remains unclear. We identified a neurophysiological biomarker of AD risk using the non-invasive, rapidly acquired, and clinically translatable auditory brainstem response (ABR) in normal hearing knock-in rats (Swedish familial AD risk variant to Amyloid precursor protein, App; male and female). Human ABRs have been proposed as a biomarker for AD and related dementias. The novel metric reported here is derived from multidimensional parametric feature extraction on the distribution statistics of repeated single-trial ABR traces. We report accurate prediction of genetic risk for AD risk in young and aged rats: App separate clearly from healthy humanized (App) in sex- and age-dependent manners. Notably, auditory learning during young adulthood shifted the App ABR signature towards a healthy App-like state that maintained over time into older age. Altogether the findings support the utility of the ABR to track disease state, progression, and effects of intervention, and point to a central neural generator of auditory dysfunction related to AD risk. ABRs could provide a very early biomarker for detection of AD risk and used to test the synergy of auditory and cognitive functions in human dementia.

Synaptic dysfunction emerges early in Alzheimer's disease, often years before the appearance of clinical symptoms, and is among the most reliable predictors of subsequent cognitive decline. Despite its importance, the cellular events that trigger this early synaptic vulnerability remain poorly defined. Growing evidence points to a critical failure at the interface between neuronal energy metabolism and synaptic signalling, commonly referred to as the mitochondria-synapse axis, suggesting that its disruption may occur well before the accumulation of classical amyloid and tau pathology. In this Review, we combine findings from human neuronal models, multi-omics analyses, and in vivo studies to show how amyloid-β oligomers (Aβ oligomers) induce subtle yet consequential defects in mitochondrial trafficking, calcium handling, redox homeostasis, and local ATP supply. Together, these changes undermine the precise coordination between mitochondrial metabolism and calcium-dependent signalling that is essential for synaptic plasticity. As a result, affected neural circuits lose the capacity to meet the energetic demands of sustained information processing. We propose that this early uncoupling of energy availability from synaptic demand represents a leading contributor to neuronal vulnerability rather than a secondary consequence of protein aggregation, based on converging evidence from iPSC-derived cortical neurons, human neuronal cultures, and transgenic mouse models, with human in vivo validation still emerging. Finally, we highlight emerging therapeutic strategies aimed at restoring mitochondrial quality control, axonal transport, and metabolic communication. By re-aligning bioenergetic support with synaptic function, such approaches may open a critical window for intervention before irreversible circuit degeneration takes hold.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia in older adults. The presence of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) constitutes the two principal neuropathological features of AD. However, current therapies targeting only Aβ or tau remain suboptimal, likely due to intrinsic neuronal and glial dysfunction in affected brain regions. Urolithin A (UroA) is a widely recognized mitophagy activator with potent antioxidant and anti-inflammatory properties. Current clinical studies confirm UroA's safety in humans and its broad benefits for mitochondrial health. Preclinical data show enhanced lysosomal and mitochondrial quality in neurons and glia during AD progression. Given current AD pathology insights, UroA shows significant therapeutic promise. The AMPK/SIRT/mTOR signaling axis regulates cellular adaptation to metabolic stress and energy balance, and is significantly dysregulated in AD progression. This review comprehensively evaluates the structural and biological characteristics of UroA, with a focus on its role in enhancing mitophagy, promoting lysophagy, and mitigating neuroinflammation in the context of AD. However, current research has not clarified how UroA enhances mitochondrial and lysosomal function while suppressing neuroinflammation. This report further investigates the potential interplay between UroA and the AMPK/SIRT/mTOR signaling pathway, elucidating a plausible mechanism through which UroA regulates the autophagic-lysosomal system and mitigates neuroinflammation via modulation of this axis.

BACKGROUND: Reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 repeats 13 (ADAMTS13) is associated with an increased risk of dementia, independent of Von Willebrand Factor levels (VWF). Pathways underlying this association remain poorly understood. OBJECTIVES: Investigate the associations of VWF levels and ADAMTS13 activity with vascular cognitive impairment (VCI) and cerebral small vessel disease (CSVD). METHODS: In this cross-sectional study, we included 147 participants with VCI and 120 reference subjects (mean age:67.5 years,41% women). Using multivariable logistic regression, we determined the cross-sectional association of ADAMTS13 activity and VWF levels in plasma with VCI. Additionally, across cases and reference subjects combined, we determined the cross-sectional association of VWF and ADAMTS13 with markers of CSVD on 3T brain MRI. RESULTS: Participants with lower ADAMTS13 activity had a higher odds of VCI (OR per 1-SD decrease:1.46 [95%CI:1.04-2.04), whereas participants with higher VWF levels did not (OR per 1-SD increase:1.15 [95%CI:0.85-1.56]). Overall, lower ADAMTS13 and higher VWF were similarly associated with higher white matter hyperintensity volume (mean difference per 1-SD change in ADAMTS13:0.12 [95%CI:-0.01-0.25, and for VWF:0.13 [95%CI:0.01-0.26). For microbleeds, lacunes and microinfarcts, low ADAMTS13 and high VWF showed ORs of around 2 for the utmost quartiles, which was statistically significant only for VWF and lacunes. We found no evidence of synergistic effects of ADAMTS13 and VWF. CONCLUSIONS: Low ADAMTS13 activity is associated with VCI, independent of concurrently measured VWF. Low ADAMTS13 activity and high VWF levels are associated with markers of CSVD.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive neuronal loss, cognitive impairment, oxidative stress, neuroinflammation, and aggregation of abnormal proteins, including amyloid precursor protein (APP), amyloid-beta (Aβ), and hyper phosphorylated Tau (p-Tau). Developing therapies that simultaneously target multiple pathogenic pathways remains a major therapeutic challenge. Lawsone (LW), a naturally occurring naphthoquinone derived from the leaf of henna plant (Lawsonia inermis), was investigated for its therapeutic potential in AD. Computational studies were performed to evaluate binding affinities and stability of the compound against key AD-related molecular targets. Sprague-Dawley rats were randomly assigned to five groups: vehicle control, Scopolamine (SCP), donepezil (DNZ), and two groups treated with LW at doses of 2.5 and 5mg/kg. Morris water Maze and Y Maze tests were employed to validate the behavioral performance. Oxidative stress markers were measured biochemically, tissue histopathology was evaluated using hematoxylin-eosin and Congo red staining. Expression of the proinflamatory markers, nuclear factor kappa β (NF-κβ), c-Jun N terminal kinase (c-JNK), Tumor necrosis factor-α (TNF-α) and Alzheimer's associated proteins APP, Aβ, and Tau were assessed through real time polymerase chain reaction (qPCR), enzyme linked immunosorbent assay (ELISA). Computational evaluation showed strong binding to NF-κβ, c-JNK, acetylcholinestrase (AChE), butyrylcholinestrase (BuChE) and TNF-α, supporting its multi-target potential. LW demonstrated neuropharmacological efficacy through preservation of neuronal structure, suppression of Aβ pathology, enhancement of cognitive function, restoration of antioxidant defenses, downregulation of proinflamatory, amyloidogenic, and tauopathic markers. These findings featured its potential as a multi target therapeutic agent for the management of AD.

Alzheimer's disease (AD) and total joint arthroplasty are prevalent and often concomitant in older adults, but an etiologic link is debated. Since wear particles are an inevitable side product of total joint arthroplasty (TJA), we hypothesized that older adults with TJA agglomerate higher-than-normal concentrations of implant alloy elements caused by the dissemination of debris from the implants, resulting in a pathological reaction. A cross-sectional analysis was conducted among 701 autopsied participants of an ongoing longitudinal cohort (Memory and Aging Project (MAP)) of whom postmortem neuropathologic data was available and implant-related metals (cobalt, titanium) were quantified in four brain regions by inductively coupled mass-spectrometry. MAP participants are enrolled without known dementia at baseline and followed annually for cognitive assessments using 19-test battery. In the analytical sample, 229 had TJA (total hip arthroplasty, total knee arthroplasty, and total shoulder arthroplasty) and n=472 had no total joint. Due to a higher likelihood of cobalt release in total hip arthroplasty, the TJA group was subdivided into a hip (n=146) and a knee/shoulder (n=83) group. We used regression and linear mixed-effects models, adjusted for demographics and apolipoprotein E ε4 status, to examine associations between metals, AD pathology and cognitive decline. Cobalt content of brain tissue was 8.9% higher in the total hip arthroplasty group than in the no-TJA group (p=0.003). Cobalt-containing particles were identified within brain tissue using scanning electron microscopy. In the inferior temporal cortex, cobalt was positively associated (p=0.0004) and titanium was negatively associated (p=0.038) with amyloid-beta load, but had no association with cognition. These results warrant monitoring the potential impact of metal implant debris on brain health. STATEMENT OF SIGNIFICANCE: This study is of great clinical significance because Alzheimer's disease (AD) and total joint arthroplasty (TJA)-the end-stage treatment of osteoarthritis-affect large and overlapping groups in our aging population. There is limited knowledge about the relationship between the prominent TJA implant metals cobalt and titanium and the pathogenesis of AD. This study shows that Co28Cr6Mo and Ti6Al4V implant alloy particles-most likely from a subset of total hip replacements with accelerated wear or tribocorrosion-can disseminate to the brain and be associated with increased cobalt and titanium concentrations. Cobalt was associated with greater AD pathology in the inferior-temporal cortex, even after correction for other known AD risk factors. However, there was no correlation with cognitive decline. Titanium was negatively associated with AD pathology, but titanium oxide appeared to be abundant in the brain from sources other than joint replacements.

INTRODUCTION: Idiopathic normal pressure hydrocephalus (iNPH) is frequently underdiagnosed due to non-specific symptoms and the risks of invasive testing. While disproportionately enlarged subarachnoid space hydrocephalus (DESH) is a hallmark imaging feature, manual assessment is subjective and qualitative. We developed the Disproportionately Elevated Sulcal Index (DESI), a fully automated deep learning-based volumetric biomarker, to objectively quantify these morphological changes. METHODS: We trained a U-Net model with an EfficientNet-B0 encoder on T1-weighted MRI scans from the Baltimore Longitudinal Study of Aging and Johns Hopkins Clinic (n=1,248) to segment Sylvian fissures and superior sulcal spaces. DESI was defined as the volumetric ratio of the Sylvian fissure to superior sulci within an AC-PC aligned wedge. The model was externally validated on the multi-site PENS trial dataset (n=94), comparing NPH patients against healthy controls and participants with Alzheimer's disease and vascular dementia. RESULTS: In external validation, DESI demonstrated high diagnostic accuracy. The index distinguished NPH patients with DESH features from non-DESH NPH cases with an Area Under the Curve (AUC) of 0.97. When differentiating NPH with DESH from a pooled group of healthy controls and neurodegenerative mimics, DESI achieved an AUC of 0.99 (sensitivity 98%, specificity 100%). In a broad comparison of all NPH cases versus all non-NPH groups, DESI maintained an AUC of 0.94. CONCLUSIONS: DESI provides a robust, fully automated quantification of sulcal disproportion that effectively differentiates iNPH from normal aging and neurodegenerative mimics. This continuous, non-invasive metric offers a scalable tool for accurate iNPH screening and patient stratification in clinical settings.

Alzheimer's disease (AD) is associated with impaired connectivity in critical functional networks. This study investigated the effects of 20 Hz transcranial magnetic stimulation (TMS) on brain network mechanisms in 25 patients with AD, including 17 in the TMS group and 8 in the sham group. We analyzed resting-state functional magnetic resonance imaging data, using the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify neural activity and identify regions of interest. Subsequently, changes in static and dynamic functional connectivity were analyzed based on these regions. The results showed that: (1)In the TMS group, significant increases in ALFF/fALFF were observed specifically in the right dorsolateral superior frontal gyrus (SFGdor.R) and the left anterior cingulate gyrus (ACG.L); (2)Enhanced static functional connectivity between the SFGdor.R and the right middle temporal gyrus was positively correlated with improvements in Montreal Cognitive Assessment scores, while reduced static functional connectivity between the ACG.L and the left inferior temporal gyrus was associated with gains in Boston Naming Test scores; (3)Improvements in both Montreal Cognitive Assessment scores and Mini Mental State Examination scores were linked to decreased dynamic functional connectivity variability between the ACG.L and the middle occipital gyrus. These findings suggest that TMS improves cognitive and behavioral performance in patients with AD through multiscale regulatory effects, and that this improvement may be associated with alterations in functional integration among brain regions as well as reduced variability of abnormal network dynamics, providing new insights into the mechanism of action of TMS in AD.

Cannabinoids are traditionally recognized for their effect on the nervous system. Emerging evidence suggests that cannabinoids mitigate inflammation driven by Th1/Th17 responses, which are linked to autoimmune diseases. In addition to their symptomatic, and analgesic effects, cannabinoids suppress the immune response by modulating regulatory T-cell activity, reducing microglial activation, and help in maintaining the integrity of the epithelial barrier. These findings suggest that cannabinoids may be involved in immune, and metabolic regulatory pathways. Despite the promising preclinical data, translating these findings into effective treatments for autoimmune disorders has proven challenging. Current human studies have primarily focused on symptomatic relief such as reducing spasticity, managing pain, improving sleep quality, and boosting appetite. However, few trials have included immune profiling, i.e., assessed cytokine panels, performed immune cell phenotyping, tracked relapses, or utilized inflammation-focused imaging endpoints. Consequently, documented benefits are primarily symptomatic, while potential disease-modifying effects are not yet adequately studied. Cannabinoids interact with CB1, CB2, TRP, and PPAR-γ receptor proteins, suggesting that they may offer targeted immune modulation rather than broad immunosuppression, potentially overcoming limitations of conventional therapies. Moreover, new compounds like cannabigerol (CBG), cannabidivarin (CBV), and CB2-selective agonists with minimal psychoactivity offer expanded therapeutic options. However, challenges persist due to variability in formulations, bioavailability issues, regulatory hurdles, and a lack of long-term safety data. Future clinical development will require standardised GMP-grade preparations, robust pharmacokinetic evaluation, and trials that include immune-related endpoints such as T-cell polarisation, inflammasome markers, oxidative stress profiles, microbiome signatures, and longitudinal imaging, to clarify their therapeutic potential in autoimmune diseases.

Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous spectrum of cognitive disorders driven by cerebrovascular pathology and represents a major contributor to late-life cognitive decline. VCID is highly prevalent and frequently coexists with Alzheimer's disease pathology. Despite this, it remains poorly defined in clinical practice and lacks approved disease-modifying therapies. Therapeutic development has been hindered by biological heterogeneity, challenges in patient stratification, and a historical emphasis on neurodegenerative targets that inadequately address vascular mechanisms. Increasing evidence implicates dysfunction of the neurovascular unit-including small vessel disease, chronic hypoperfusion, blood-brain barrier disruption, and neuroinflammation-as a central driver of vascular-mediated cognitive impairment and a unifying therapeutic target across diverse VCID phenotypes. In this review, we synthesize current understanding of VCID pathobiology with a focus on neurovascular unit dysfunction and emerging mechanism-based strategies aimed at restoring vascular and neurovascular homeostasis. We further examine translational considerations for targeting neurovascular signaling pathways, including endothelial stabilization, modulation of vascular inflammation, and preservation of blood-brain barrier integrity. As an illustrative example, we discuss preclinical evidence supporting Mas receptor agonism, including the glycosylated angiotensin-(1-7) analogue PNA5, as a potential approach to address vascular-mediated cognitive impairment. Finally, we explore implications for biomarker selection, patient enrichment, and early clinical trial design. Together, this framework highlights neurovascular dysfunction as a tractable therapeutic target in VCID and underscores the need for mechanism-driven approaches to address a substantial unmet clinical need.

BACKGROUND: Bipolar disorder (BD) is a major mood disorder influenced by both genetic and environmental factors. While DNA methylation from peripheral tissues can reflect both genetic and environmental influences and reveal insights into disease biology, it remains understudied in BD. DNA methylation signatures may complement polygenic scores (PGS) and hold potential as biomarkers. Here, we conducted the largest epigenome-wide association study (EWAS) of BD to date and evaluated the predictive value of polymethylation scores (PMS) in classifying case-control status. METHODS: DNA methylation from peripheral blood of 1729 cases and 1747 controls, comprising twelve cohorts, was obtained. We performed meta-analyses for the total sample, male-only, and female-only analyses. Differentially methylated regions (DMRs) were identified using the comb-p method. Polymethylation scores for BD (BD-PMS) were tested for association with BD, and in combination with PGS. FINDINGS: We identified 47 differentially methylated CpG positions (DMPs) in the total and four in the female-only analysis. Ninety, fourteen and six DMRs were identified in the total sample, female-only, and male-only analyses, respectively. Genes annotated to the top DMPs were enriched for immune activation and phosphorylation pathways. DMRs were annotated to genes relevant to neurotransmission, including GABBR1 and CACNA2D4. BD-PMS explained 2% of the variance in BD case-control status, and improved the variance explained from 7.9 to 8.5% when combined with PGS. For bipolar I disorder, BD-PMS explained 4.9% of the variance, and improved the variance explained by PGS from 15.9 to 18.5%. Association of BD with PMS for schizophrenia and major depression suggests pleiotropic epigenetic effects. INTERPRETATION: DNA methylation signatures of BD are detectable in blood using adequately powered data and may reveal novel BD biology that is not captured by genetic studies. PMS from large cohorts have the potential to facilitate the development of prediction tools to aid clinical decision-making. FUNDING: This investigation was primarily funded by the Research Council of Norway (RCN #250299, #273446, #223273) and the University of Bergen. A complete list of funding organisations is provided in the Acknowledgements.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has several advantages compared to other interventions for neurological and psychological disorders. However, various adverse effects have been reported in rTMS research, and little is known about who is most susceptible to rTMS adverse effects, or how they can be minimized. AIMS: We aimed to identify risk factors for adverse effects reported in a recent clinical trial examining rTMS as a treatment for Alzheimer's disease (AD). We hypothesized that higher stimulation intensity would be associated with experiencing unspecified pain/discomfort, dental pain, headache, jaw pain, and muscle contractions, but not be associated with other adverse effects. METHODS: Using detailed notes from treatment sessions, 10 adverse effects were identified. Spearman correlations were conducted to assess relationships between the highest applied stimulation intensity and normalized frequency of each adverse effect amongst those who experienced that adverse effect. Demographic information, cognitive scores, and withdrawal status were compared between the binarized groups of participants who experienced adverse effects versus those who did not. Spearman correlations were also conducted on the binarized adverse effects and the highest applied stimulation intensity. Logistic regressions were conducted to identify potential risk factors. RESULTS: In both the sham and active treatment groups, unspecified pain/discomfort was the most common adverse effect, followed by muscle contractions and dizziness. In both the active and sham treatment groups, stimulation intensity was positively associated with muscle contractions, but was not significantly related to any other adverse effect. In evaluating groups with/without adverse effects, we found there was a significantly higher proportion of males reporting adverse effects in both the active treatment group and the sham treatment group compared to females. CONCLUSION: The findings of this study are a step toward understanding how researchers can minimize such adverse effects, and thereby, create a less aversive experience for rTMS participants.

Cognitive dysfunction is a major nonmotor feature of Parkinson's disease (PD) that impairs quality of life and increases caregiver burden. Its intellectual structure and thematic development remain underexplored. This bibliometric and scientometric study analyzed English-language publications on PD-related cognitive dysfunction indexed in Web of Science, Scopus, and PubMed (2000-May 2025). After screening and duplicate removal, 8721 articles were included. VOSviewer 1.6.20, Python, and Microsoft Excel were used for co-authorship, bibliographic coupling, co-word, and citation analyses. Results showed 8721 publications authored by 34,311 researchers, with the United States, China, and the United Kingdom leading in output and international collaboration (collaboration index 8.02). Four thematic clusters were identified: diagnostic criteria and staging, neurobiological mechanisms, nonmotor symptoms and quality of life, and therapeutic interventions. Findings highlight a mature but evolving research field, emphasizing multidisciplinary integration, stronger collaboration, and the need to explore biomarkers, neuroinflammation, and novel therapeutic approaches.

BACKGROUND: Community gathering places in Japan, supported by local governments, are expected to promote physical and cognitive health through physical activity and social interaction, in line with the World Health Organization's concept of age-friendly environments. However, evidence regarding their effects on dementia prevention remains inconsistent. This study aimed to assess whether habitual exercise modifies the association between participation in community gathering places and incident cognitive disability in older adults. METHODS: This retrospective cohort study used data from the Public Survey of Long-Term Care Prevention in Habikino City, Japan, and included community-dwelling adults aged ≥ 65 years without certified care needs. Participation in community gathering places was investigated at baseline and incident cognitive disability was tracked from January 2020 to January 2024. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for demographics and health status. To test the effect modification by exercise habit, product terms between participation and exercise status were included in the model. We addressed missing baseline data using multiple imputation. RESULTS: A total of 2758 eligible older adults were included in the primary analysis. We observed a potential effect modification by exercise habit status (p for interaction = 0.092). Participation in community-gathering places was associated with a lower hazard of cognitive disability among individuals without exercise habits (adjusted HR [95% CI], 0.51 [0.27, 0.97]), whereas no such association was observed among those with exercise habits (1.09 [0.57, 2.09]). CONCLUSIONS: The association between participation in community gathering places and cognitive disability may differ according to habitual exercise status. These findings suggest that municipally supported community gathering places may represent an accessible form of participation associated with a lower risk of cognitive disability among older adults without established exercise habits.

BACKGROUND: Age-associated cognitive deterioration and neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD), are predominantly influenced by oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation. Dietary phenolic acids, prevalent in plant-based foods, have demonstrated potential neuroprotective and cognitive-enhancing effects in recent studies. PURPOSE: This review seeks to thoroughly assess the neuroprotective mechanisms of phenolic acids and to consolidate existing evidence from human and preclinical studies concerning their potential efficacy in alleviating cognitive impairment and neurodegeneration. STUDY DESIGN: Narrative and evidence-based literature review. METHODS: Recent experimental, clinical, and epidemiological studies examining significant phenolic acids - such as caffeic, chlorogenic, ferulic, gallic, rosmarinic, sinapic, ellagic, protocatechuic, p-coumaric, and tannic acids - in relation to AD, PD, and cognitive functions were retrieved from electronic databases. We put together the most important information about molecular mechanisms and treatment. RESULTS: Preclinical studies show that phenolic acids have antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation effects by changing important signaling pathways like Nrf2/HO-1, NF-κB, and PI3 K/Akt. These actions protect dopaminergic neurons, lower the toxicity of amyloid-beta and α-synuclein, and make behavior better in disease models. Human studies suggest that increased dietary consumption of phenolic acids, especially hydroxycinnamic acids such as caffeic and chlorogenic acid, is associated with enhanced cognitive performance and a diminished risk of cognitive decline, although results are not uniform. CONCLUSION: Phenolic acids are secure, readily accessible neuroprotective compounds that can alter various pathological pathways associated with cognitive decline and the progression of neurodegenerative diseases.

: The genetic architecture of amyotrophic lateral sclerosis (ALS) has been predominantly characterized in populations of European ancestry, while Latin American populations remain underrepresented despite their complex admixture. : To map the molecular hypotheses explored in ALS research conducted in Latin American populations and identify key methodological and structural gaps. : A scoping review was conducted following Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. Searches were performed in Web of Science, Scopus, PubMed/MEDLINE, SciELO, and LILACS. Studies investigating genetic or molecular aspects of ALS or the ALS-FTD spectrum in Latin American populations were included. Data were extracted using a standardized matrix and synthesized descriptively. : Nineteen studies met inclusion criteria. Most were small, single-center investigations employing targeted candidate-gene approaches, predominantly focused on C9orf72 expansions and SOD1 mutations. Reported C9orf72 frequencies varied substantially across countries, indicating population-specific genetic heterogeneity. Only one study incorporated explicit ancestry inference, and no genome-wide association studies or large multicenter ALS genomic cohorts were identified. : ALS research in Latin America remains limited, fragmented, and largely candidate-gene driven, with minimal integration of ancestry-informed approaches. The absence of large-scale genomic studies, despite existing regional sequencing capacity, highlights the need for coordinated multicenter initiatives to enable equitable implementation of precision medicine.