Common Dementia Research Articles

Neuropsychiatric presentations of common dementia syndromes: A concise review for primary care team members.

Dementia is a syndrome characterized by cognitive changes which interfere with daily functioning. Neuropsychiatric symptoms (NPS) are also pervasive and may even occur prior to any noticeable cognitive decline. Still, NPS are less associated with the early stages of the disease course, despite mounting research evidence that NPS present early and often in several dementia syndromes, even in the absence of cognitive decline (i.e., mild behavioral impairment [MBI]). Primary care teams are at the forefront of dementia care, yet they frequently report insufficient training in dementia diagnosis and management. This poses a serious problem considering that timely diagnosis of dementia is critical for optimal outcomes and maximum efficacy of intervention. We provide a concise narrative review of four dementia syndromes (Alzheimer's disease, vascular dementia, dementia with Lewy bodies, and behavioral variant frontotemporal dementia) and their associated neuropsychiatric presentations, as well as at-a-glance clinical guides, to help primary care team members recognize possible prodromal neurodegenerative disease and to prompt further workup. We also review next steps in the management of dementia and symptoms of MBI for primary care team members. As evidenced by the NPS profiles of these dementia syndromes, subacute new onset of psychiatric symptoms in an older adult should prompt consideration of an emerging dementia process and possible further workup of such, even in the absence of cognitive decline.

Trimethylamine N-Oxide Aggravates Neuro-Inflammation via lncRNA Fendrr/miR-145-5p/PXN Axis in Vascular Dementia Rats.

Vascular dementia (VaD) is the second most common dementia in the world. An increasing number of studies have demonstrated the important role of long non-coding RNAs (lncRNAs) in VaD. Our previous investigation demonstrated that Trimethylamine-N-oxide (TMAO) exacerbates cognitive impairment and neuropathological alterations in VaD rats. Thus, we hypothesized that TMAO could play an injury role in VaD by regulating lncRNAs. The rats using the bilateral common carotid artery (2VO) model were administered TMAO (120 mg/kg) for 8 consecutive weeks, 4weeks preoperatively and 4weeks postoperatively. High-throughput sequencing was conducted to investigate the effects of TMAO treatment on lncRNA expression in rat hippocampus and bioinformatics analysis was performed to identify potential downstream targets. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of lncRNA fetal-lethal noncoding developmental regulatory RNA (Fendrr), miR-145-5p, and paxillin (PXN). Learning and spatial memory capacities were measured, as well as inflammatory factors. Nissl staining was used to observe neuronal injury in the CA1 area of the hippocampus. Furthermore, we used the Fendrr loss-of-function assay, miR-145-5p gain-of-function assays and PXN loss-of-function assay to explore the mechanisms by which TMAO acts on VaD. TMAO administration upregulated lncRNA Fendrr expression in the rat hippocampus, while the damaging effects of TMAO were counteracted after knockdown of Fendrr. Fendrr exhibits highly expressed in 2VO rats and sponged miR-145-5p, which targets PXN. Silencing of Fendrr or PXN, or promotion of miR-145-5p improved neurological function injury, reduced neuronal damage, as well as repressed inflammation response. Inhibition of miR-145-5p abrogated up Fendrr knockdown mediated influence on 2VO rats. The results of this study indicated that TMAO inhibits the miR-145-5p/PXN axis by increasing the Fendrr expression, thus exacerbating the development of VaD.

A mixed methods evaluation of the music and psychology and social connections (MAPS) pilot - A dyadic intervention for couples affected by young-onset dementia.

People living with young-onset dementia and their care-partners are at risk of a range of adverse mental health outcomes and social isolation. There are few interventions aimed at supporting couples affected by young-onset dementia, which poses unique psychosocial challenges for younger people. This pre-post interventional mixed methods pilot study aimed to assess the feasibility and acceptability of an online group program for people with young-onset dementia and their care-partners living at home in Australia. The Music And Psychology and Social connections (MAPS) program aimed to address: (1) the challenges and changes associated with young-onset dementia; and (2) coping and wellbeing. The program involved six weekly two-hour sessions co-facilitated by a psychologist and music therapist, and a private Facebook group. The primary outcomes of feasibility and acceptability were assessed through a post-program focus group, separate individual feedback sessions with each couple, and a program evaluation questionnaire. Thematic analysis was conducted on the focus group transcripts and field notes from couple feedback sessions. We also examined the preliminary utility of MAPS in improving mental health and social connectedness, using quantitative pre-post-measures. Five couples completed the MAPS program. The most common dementia type was Alzheimer's Disease. Participant attendance was 87% across all sessions. Qualitative findings supported acceptability of the program with four emergent themes: being connected to others with shared experiences; reframing thoughts and feelings about dementia; music as a therapeutic tool; and benefits of MAPS. The high retention rate, qualitative findings and positive program evaluation suggest MAPS may be a promising, feasible and acceptable program for couples affected by young-onset dementia.

A computer approach to assess age-related changes of the brain white matter in Alzheimer's disease

BackgroundAge is one of the major risk factors for Alzheimer's disease (AD) which is considered the most common adult-onset dementia. There is little information about age-related changes during brain dementia. MethodsThis study observed age-related variations in the brain throughout adulthood in magnetic resonance imaging (MRI) of the AD and healthy brains. The Open Access Series of Imaging Studies (OASIS) is used as a database. The method consists of design and develop a computer approach based on artificial intelligence (AI) to segment white matter (WM) from the MRI. Then, the number of pixels within the segmented white matter (WM) of the brain was calculated. Correlation was used to investigate age relation with WM changes in the normal and AD brain. ResultsThe WM change with aging was more correlated in AD group (rAD = −0.505, p-value = 0.0007) than control group (rControl = −0.357, p-value = 0.0001). ConclusionHigher correlation of WM pixel counts with age in AD group approved that AD is characterized by the relevant involvement of the WM and age. Our approach gained additional information on the quantitative pathological changes associated with the AD as the most common brain disorder of the elderly.

Anti-amyloid Antibody Drugs as Disease-Modifying Therapies for Alzheimer's Disease

Alzheimer's disease (AD) is a common dementia disorder in the elderly individuals, accounting for approximately 60-70% of all dementia cases. Recently, significant progress has been made in developing and approving anti-amyloid antibody drugs as one of the disease-modifying therapies (DMT) that aim to slow the progression of AD by targeting amyloid-beta accumulation in the brain. Notable drugs such as aducanumab, lecanemab, and donanemab have shown potential in clinical trials, leading to the approval of aducanumab and lecanemab, and approval is also expected for donanemab. Other anti-amyloid drugs such as remternetug and trontinemab are also under development. However, challenges remain, including adverse effects like amyloid-related imaging abnormalities (ARIA) and the need for addressing healthcare preparedness to support their use. This paper outlines the current status of DMT for AD, including the clinical trial results and current applications of these drugs. It also discusses the existing challenges to improve the safety and accessibility of DMTs.

End-of-Life Healthcare Utilization in Lewy Body Dementia.

Lewy body dementia (LBD) is the second most common neurodegenerative dementia in the US, presenting unique end-of-life challenges. This study examined healthcare utilization and care continuity in the last year of life in LBD. Medicare claims for enrollees with LBD, continuously enrolled in the year preceding death, were examined from 2011-2018. We assessed hospital stays, emergency department (ED) visits, intensive care unit (ICU) admissions, life-extending procedures, medications, and care continuity. We identified 45,762 LBD decedents, predominantly female (51.8%), White (85.9%), with average age of 84.1 years (SD 7.5). There was a median of 2 ED visits (IQR 1-5) and 1 inpatient stay (IQR 0-2). Higher age was inversely associated with ICU stays (Odds Ratio [OR] 0.96; 95% Confidence Interval [CI] 0.96-0.97) and life-extending procedures (OR 0.96; 95% CI 0.95-0.96). Black and Hispanic patients experienced higher rates of ED visits, inpatient hospitalizations, ICU admissions, life-extending procedures, and in-hospital deaths relative to White patients. On average, 15 (7.5) medications were prescribed in the last year. Enhanced care continuity correlated with reduced hospital (OR 0.72; 95% CI 0.70-0.74) and ED visits (OR 0.71; 95% CI 0.69-0.87) and fewer life-extending procedures (OR 0.71; 95% CI 0.64-0.79). This study underscored the complex healthcare needs of people with LBD during their final year, which was influenced by age and race. Care continuity may reduce hospital and ED visits and life-extending procedures.

Exploring tau protein and amyloid-beta propagation: A sensitivity analysis of mathematical models based on biological data

Alzheimer’s disease is the most common dementia worldwide. Its pathological development is well known to be connected with the accumulation of two toxic proteins: tau protein and amyloid-β. Mathematical models and numerical simulations can predict the spreading patterns of misfolded proteins in this context. However, the calibration of the model parameters plays a crucial role in the final solution. In this work, we perform a sensitivity analysis of heterodimer and Fisher–Kolmogorov models to evaluate the impact of the equilibrium values of protein concentration on the solution patterns. We adopt advanced numerical methods such as the IMEX-DG method to accurately describe the propagating fronts in the propagation phenomena in a polygonal mesh of sagittal patient-specific brain geometry derived from magnetic resonance images. We calibrate the model parameters using biological measurements in the brain cortex for the tau protein and the amyloid-β in Alzheimer’s patients and controls. Finally, using the sensitivity analysis results, we discuss the applicability of both models in the correct simulation of the spreading of the two proteins.Statement of significance: Alzheimer’s disease is related to the accumulation of tau protein and amyloid-β. Mathematical models to predict the spreading patterns require accurate parameter calibration. In this work, we perform a sensitivity analysis of heterodimer and Fisher–Kolmogorov models to evaluate the impact of the equilibrium values of protein concentration on the solution patterns obtained with advanced numerical simulations on patient-specific brain geometry derived from magnetic resonance images. By using biological measurements in the brain cortex for the proteins in Alzheimer’s patients and controls, we use sensitivity analysis to discuss the applicability of models in simulating protein spreading.

Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

Notopterygium incisum roots extract (NRE) alleviates neuroinflammation pathology in Alzheimer’s disease through TLR4-NF-κB pathway

Ethnopharmacological relevanceNotopterygium incisum Ting ex H. T. Chang, also called ‘Qianghuo’, is a distinct umbelliferae plant in China. The rhizomes and roots of Notopterygium incisum have long been used to treat headaches, colds, analgesia and rheumatoid arthritis. It is a main traditional Chinese medicine in Qianghuo Yufeng Decoction, which was used to treat diseases such as liver and kidney insufficiency, mental paralysis and dementia. Aim of this studyAs the most common dementia, Alzheimer's disease (AD) has a complicated pathogenesis. So far, there is no effective drug to prevent its pathological process. Previous research has shown that Notopterygium incisum root extract (NRE) may inhibit the release of Aβ and the activation of tau in mice with AD. However, the effect of NRE on the pathological process of neuroinflammation is still unclear. Materials and methodsWe determined the pro-inflammatory cytokines levels in BV2 cells exposed to LPS/Aβ42 after treated with NRE. APP/PS1 and LPS-induced C57BL/6 neuroinflammatory mice were given NRE for 8 weeks and 5 days respectively to detect the pathological changes of neuroinflammation. ResultsThe findings showed that NRE had a notable inhibitory effect on the levels of TNF-α and IL-1β in BV2 cells induced by LPS/Aβ42. The results of in vivo experiments show that following NRE treatment, there was a notable decrease in the number of activated microglia in the hippocampus of APP/PS1 mice as indicated by immunofluorescence results. Sholl analysis showed that microglia branches increased in NRE group, indicating that M1 microglia activation was inhibited. In the mice model injected with LPS in the tail vein, PCR and Western Blot results confirmed the anti-inflammatory effect of NRE, Nissl staining showed the protective effect of NRE on neurons, and immunofluorescence results also indicated that the activation of M1 microglia was inhibited. ConclusionThese results suggest that long term oral administration of NRE may inhibit neuroinflammation in the progression of AD.

Changes of brain functional network in Alzheimer’s disease and frontotemporal dementia: a graph-theoretic analysis

BackgroundAlzheimer’s disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias, presenting with similar clinical features that challenge accurate diagnosis. Despite extensive research, the underlying pathophysiological mechanisms remain unclear, and effective treatments are limited. This study aims to investigate the alterations in brain network connectivity associated with AD and FTD to enhance our understanding of their pathophysiology and establish a scientific foundation for their diagnosis and treatment.MethodsWe analyzed preprocessed electroencephalogram (EEG) data from the OpenNeuro public dataset, comprising 36 patients with AD, 23 patients with FTD, and 29 healthy controls (HC). Participants were in a resting state with eyes closed. We estimated the average functional connectivity using the Phase Lag Index (PLI) for lower frequencies (delta and theta) and the Amplitude Envelope Correlation with leakage correction (AEC-c) for higher frequencies (alpha, beta, and gamma). Graph theory was applied to calculate topological parameters, including mean node degree, clustering coefficient, characteristic path length, global and local efficiency. A permutation test was then utilized to assess changes in brain network connectivity in AD and FTD based on these parameters.ResultsBoth AD and FTD patients showed increased mean PLI values in the theta frequency band, along with increases in average node degree, clustering coefficient, global efficiency, and local efficiency. Conversely, mean AEC-c values in the alpha frequency band were notably diminished, which was accompanied by decreases average node degree, clustering coefficient, global efficiency, and local efficiency. Furthermore, AD patients in the occipital region showed an increase in theta band node degree and decreased alpha band clustering coefficient and local efficiency, a pattern not observed in FTD.ConclusionsOur findings reveal distinct abnormalities in the functional network topology and connectivity in AD and FTD, which may contribute to a better understanding of the pathophysiological mechanisms of these diseases. Specifically, patients with AD demonstrated a more widespread change in functional connectivity, while those with FTD retained connectivity in the occipital lobe. These observations could provide valuable insights for developing electrophysiological markers to differentiate between the two diseases.

A feature-aware multimodal framework with auto-fusion for Alzheimer’s disease diagnosis

Alzheimer’s disease (AD), one of the most common dementias, has about 4.6 million new cases yearly worldwide. Due to the significant amount of suspected AD patients, early screening for the disease has become particularly important. There are diversified types of AD diagnosis data, such as cognitive tests, images, and risk factors, many prior investigations have primarily concentrated on integrating only high-dimensional features and simple fusion concatenation, resulting in less-than-optimal outcomes for AD diagnosis. Therefore, We propose an enhanced multimodal AD diagnostic framework comprising a feature-aware module and an automatic model fusion strategy (AMFS). To preserve the correlation and significance features within a low-dimensional space, the feature-aware module employs a low-dimensional SHapley Additive exPlanation (SHAP) boosting feature selection as the initial step, following this analysis, diverse tiers of low-dimensional features are extracted from patients’ biological data. Besides, in the high-dimensional stage, the feature-aware module integrates cross-modal attention mechanisms to capture subtle relationships among different cognitive domains, neuroimaging modalities, and risk factors. Subsequently, we integrate the aforementioned feature-aware module with graph convolutional networks (GCN) to address heterogeneous data in multimodal AD, while also possessing the capability to perceive relationships between different modalities. Lastly, our proposed AMFS autonomously learns optimal parameters for aligning two sub-models. The validation tests using two ADNI datasets show the high accuracies of 95.9% and 91.9% respectively, in AD diagnosis. The methods efficiently select features from multimodal AD data, optimizing model fusion for potential clinical assistance in diagnostics.

Caregiver Experiences and Burden in Moderate-Advanced Dementia With Lewy Bodies.

Dementia with Lewy bodies (DLB) is a common degenerative dementia, but research on caregiver experiences in late stages is lacking. This study aimed to investigate the caregiving experience in moderate-advanced DLB to identify opportunities for improving care and support. Dyads of individuals with moderate-advanced DLB and their primary informal caregivers were recruited from specialty clinics, advocacy organizations, and research registries. The study collected demographics, disease-related measures, and measures of the caregiver experience relating to caregiver support, burden, grief, self-efficacy, depression, quality of life, and coping. Spearman correlation coefficients and Wilcoxon rank-sum tests evaluated the relationships of caregiver measures with patient and caregiver variables with adjustments for multiple testing. Caregivers (n = 143) were mostly women (83.5%) and spouses (84.7%) (mean age 68 years; range 37-85). Almost 40% reported high burden and/or depression. Caregiver measures correlated with fluctuation and behavioral symptom severity, sleepiness, and autonomic symptoms of the person with DLB. Higher burden correlated with worse caregiver quality of life, higher depression, and grief. Greater self-efficacy, social support, and resilience correlated with lower caregiver burden. The most frequently reported caregiver concerns were being unable to plan for the future, having to put the needs of the person with DLB ahead of the caregiver's own needs, and worry that the person with DLB would become too dependent on the caregiver, but many additional concerns were endorsed. Caregivers were generally satisfied with medical team support. The lowest reported satisfaction related to information regarding disease progression and how well medical teams shared information with each other. Various patient-related and caregiver-related factors influence caregiver experiences in moderate-advanced DLB. Clinicians can target caregiver needs by providing support resources and DLB education and treating bothersome patient symptoms. Future research should investigate what interventions can modify and improve caregiver experiences in advanced DLB and identify therapeutics for patient symptoms currently without adequate treatments (e.g., fluctuations, daytime sleepiness). NCT04829656.

Energy landscape analysis of brain network dynamics in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative dementia, characterized by abnormal dynamic functional connectivity (DFC). Traditional DFC analysis, assuming linear brain dynamics, may neglect the complexity of the brain's nonlinear interactions. Energy landscape analysis offers a holistic, nonlinear perspective to investigate brain network attractor dynamics, which was applied to resting-state fMRI data for AD in this study. This study utilized resting-state fMRI data from 60 individuals, comparing 30 Alzheimer's patients with 30 controls, from the Alzheimer's Disease Neuroimaging Initiative. Energy landscape analysis was applied to the data to characterize the aberrant brain network dynamics of AD patients. The AD group stayed in the co-activation state for less time than the healthy control (HC) group, and a positive correlation was identified between the transition frequency of the co-activation state and behavior performance. Furthermore, the AD group showed a higher occurrence frequency and transition frequency of the cognitive control state and sensory integration state than the HC group. The transition between the two states was positively correlated with behavior performance. The results suggest that the co-activation state could be important to cognitive processing and that the AD group possibly raised cognitive ability by increasing the occurrence and transition between the impaired cognitive control and sensory integration states.

Epidemiology and prevalence of dementia and Alzheimer's disease in American Indians: Data from the Strong Heart Study.

Accurate epidemiologic estimates for dementia are lacking for American Indians, despite substantive social and health disparities. The Strong Heart Study, a population-based cohort of 11 American Indian tribes, conducted detailed cognitive testing and examinations over two visits approximately 7 years apart. An expert panel reviewed case materials for consensus adjudication of cognitive status (intact; mild cognitive impairment [MCI]; dementia; other impaired/not MCI) and probable etiology (Alzheimer's disease [AD], vascular bain injury [VBI], traumatic brain injury [TBI], other). American Indians aged 70-95 years had 54% cognitive impairment including 10% dementia. VBI and AD were primary etiology approximately equal proportions (>40%). Apolipoprotein (APO) Eε4 carriers were more common among those with dementia (p=0.040). Plasma pTau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were higher among those with cognitive impairment, but not amyloid beta (Aβ). Cognitive intact had mean 3MSE 92.2 (SD 6.4) and mean Montreal Cognitive Assessment (MoCA) score of 21.3 (SD 3.2). This is the first population-based study to estimate the prevalence of vascular and Alzheimer's dementias in a population-based study of American Indians. The Strong Heart Study is a population-based cohort of American Indian tribes, conducted over 30+ years and three US geographic regions (Northern Plains, Southern Plains, Southwest). Our teams conducted detailed cognitive testing, neurological examination, and brain imaging over two visits approximately 7 years apart. An expert panel reviewed collected materials for consensus-based adjudication of cognitive status (intact; MCI; dementia; other impaired/not MCI) and probable underlying etiology (AD; VBI; TBI; other). In this cohort of American Indians aged 70-95, 54% were adjudicated with cognitive impairment, including approximately 35% MCI and 10% dementia. These data expand on prior reports from studies using electronic health records, which had suggested prevalence, and incidence of dementia in American Indians to be more comparable to the majority population or non-Hispanic White individuals, perhaps due to latent case undercounts in clinical settings. Vascular and neurodegenerative injuries were approximately equally responsible for cognitive impairment, suggesting that reduction of cardiovascular disease is needed for primary prevention. Traumatic injury was more prevalent than in other populations, and common among those in the "other/not MCI" cognitive impairment category. Mean scores for common dementia screening instruments-even among those adjudicated as unimpaired-were relatively low compared to other populations (mean unimpaired 3MSE 92.2, SD 6.4; mean unimpaired MoCA 21.3, SD 3.2), suggesting the need for cultural and environmental adaptation of common screening and evaluation instruments.

Isoform-specific effects of neuronal inhibition of AMPK catalytic subunit on LTD impairments in a mouse model of Alzheimer’s disease

Synaptic dysfunction is highly correlated with cognitive impairments in Alzheimer’s disease (AD), the most common dementia syndrome in the elderly. Long-term potentiation (LTP) and long-term depression (LTD) are two primary forms of synaptic plasticity with opposite direction of synaptic efficiency change. Both LTD and LTD are considered to mediate the cellular process of learning and memory. Substantial studies demonstrate AD-associated deficiency of both LTP and LTD. Meanwhile, the molecular signaling mechanisms underlying impairment of synaptic plasticity, particularly LTD, are poorly understood. By taking advantage of the novel transgenic mouse models recently developed in our lab, here we aimed to investigate the roles of AMP-activated protein kinase (AMPK), a central molecular senor that plays a critical role in maintaining cellular energy homeostasis, in regulation of LTD phenotypes in AD. We found that brain-specific suppression of the AMPKα1 isoform (but not AMPKα2 isoform) was able to alleviate mGluR-LTD deficits in APP/PS1 AD mouse model. Moreover, suppression of either AMPKα isoform failed to alleviate AD-related NMDAR-dependent LTD deficits. Taken together with our recent studies on roles of AMPK signaling in AD pathophysiology, the data indicate isoform-specific roles of AMPK in mediating AD-associated synaptic and cognitive impairments.

Anterior insula is more vulnerable than posterior insula to TDP-43 pathology in common dementias and ALS.

Based on the anatomic proximity, connectivity, and functional similarities between the anterior insula and amygdala, we tested the hypothesis that the anterior insula is an important focus in the progression of TDP-43 pathology in LATE-NC. Blinded to clinical and neuropathologic data, phospho-TDP (pTDP) inclusion pathology was assessed in paired anterior and posterior insula samples in 105 autopsied patients with Alzheimer disease, Lewy body disease, LATE-NC and hippocampal sclerosis (HS), amyotrophic lateral sclerosis (ALS), and other conditions. Insular pTDP pathology was present in 34.3% of the study cohort, most commonly as neuronal inclusions and/or short neurites in lamina II, and less commonly as subpial processes resembling those described in the amygdala region. Among positive samples, pTDP pathology was limited to the anterior insula (41.7%), or occurred in both anterior and posterior insula (58.3%); inclusion density was greater in anterior insula across all diseases (p < .001). pTDP pathology occurred in 46.7% of ALS samples, typically without a widespread TDP-43 proteinopathy. In LATE-NC, it was seen in 30.4% of samples (mostly LATE-NC stages 2 and 3), often co-occurring with basal forebrain pathology and comorbid HS, suggesting this is an important step in the evolution of this pathology beyond the medial temporal lobe.

Neurons and Glial Cells of the Lateral Tuberal Hypothalamic Nucleus in Vascular Dementia

The aim was to study the size and density of neurons and glial cells of the hypothalamic lateral tuberal nucleus (LTN) in vascular dementia (VD), which is the second most common dementia. Material and methods. The density of neurons and glial cells, the cross-sectional area of nuclei, nucleoli and perikarya of LTN neurons were determined in patients with VD (n=10) and in the control group of individuals (n=10) who did not have any neurological or cognitive dysfunction. Comparison of indicators between groups was carried out using ANOVA and Student's t-test. Results. In VD cases all of the studied morphometric parameters of neurons and their density were decreased by within 20% (p&lt;0.02). An increase in the neuroglial index by an average of 27% (p=0.04) was also noted. Сhanges in the size of neurons and nucleoli were observed regardless of the gender of patients. However, a decrease in the neuronal density (p = 0,008) and an increase in the neuroglial index (p=0,03) were noted only in the group of female patients. Conclusion. VD leads to a decrease in the metabolic activity of neurons of the hypothalamus and of the lateral tuberal nucleus, in particular. Moreover, a part of LTN neurons dies inducing a compensatory and adaptive increase in the population of glial cells. Thus, some late manifestations of VD, such as asthenia and increased exhaustion, may be caused, at least in part by a decrease in the neuronal activity and reorganization of intercellular interactions in the LTN.

The relationship between major depressive disorder and dementia: A bidirectional two-sample Mendelian randomization study

BackgroundMajor depressive disorder (MDD) and dementia psychiatric and neurological diseases that are clinically widespread, but whether there is a causal link between them is still unclear. In this study, bidirectional two-sample Mendelian randomization (MR) was used to investigate the potential causal relationship between MDD and dementia via a genome-wide association study (GWAS) database, containing samples from the European population. MethodWe collected data on MDD and common clinical dementia subtypes from GWAS, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and vascular dementia (VaD). A series of bidirectional two-sample MR studies and correlation sensitivity analysis were carried out. ResultsIn the study of the effect of MDD on dementia subtypes, no causal relationship was found between MDD and dementia subtypes other than VaD, inverse variance weighted (IVW) method: odds ratio (OR), 2.131; 95 % confidence interval (CI), 1.249–3.639, P = 0.006; MDD-AD: OR, 1.000; 95 % CI, 0.999–1.001, P = 0.537; MDD-FTD: OR, 1.476; 95 % CI, 0.471–4.627, P = 0.505; MDD-PDD: OR, 0.592; 95 % CI, 0.204–1.718, P = 0.335; MR–Egger method: MDD-DLB: OR, 0.582; 95 % CI, 0.021–15.962, P = 0.751. In reverse MR analyses, no dementia subtype was found to be a risk factor for MDD. LimitationsThe results of this study may not be generalizable to non-European populations. ConclusionMDD was identified as a potential risk factor for VaD, but no dementia subtype was found to be a risk factor for MDD. These results suggest a new avenue for the prevention of VaD.

Ultrasensitive and Multiple Biomarker Discrimination for Alzheimer's Disease via Plasmonic & Microfluidic Sensing Technologies.

As the population ages, the worldwide prevalence of Alzheimer's disease (AD) as the most common dementia in the elderly is increasing dramatically. However, a long-term challenge is to achieve rapid and accurate early diagnosis of AD by detecting hallmarks such as amyloid beta (Aβ42). Here, a multi-channel microfluidic-based plasmonic fiber-optic biosensing platform is established for simultaneous detection and differentiation of multiple AD biomarkers. The platform is based on a gold-coated, highly-tilted fiber Bragg grating (TFBG) and a custom-developed microfluidics. TFBG excites a high-density, narrow-cladding-mode spectral comb that overlaps with the broad absorption of surface plasmons for high-precision interrogation, enabling ultrasensitive monitoring of analytes. In situ detection and in-parallel discrimination of different forms of Aβ42 in cerebrospinal fluid (CSF) are successfully demonstrated with a detection of limit in the range of ≈30-170 pg mL-1, which is one order of magnitude below the clinical cut-off level in AD onset, providing high detection sensitivity for early diagnosis of AD. The integration of the TFBG sensor with multi-channel microfluidics enables simultaneous detection of multiple biomarkers using sub-µL sample volumes, as well as combining initial binding rate and real-time response time to differentiate between multiple biomarkers in terms of binding kinetics. With the advantages of multi-parameter, low consumption, and highly sensitive detection, the sensor represents an urgently needed potentials for large-scale diagnosis of diseases at earlystage.

Targeting Lewy body dementia with neflamapimod-rasagiline hybrids.

Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38α, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of 1 and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6-dichlorophenyl ring of 1, generating neflamapimod-propargylamine hybrids 3 and 4. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The N-methyl-N-propargyl derivative 4 showed a nanomolar p38α-MAPK inhibitory activity (IC50 = 98.7 nM), which is only 2.6-fold lower compared to that of the parent compound 1, while displaying no hepato- and neurotoxicity up to 25 μM concentration. It also retained a similar immunomodulatory profile against the N9 microglial cell line. Gratifyingly, at 5 μM concentration, 4 demonstrated a neuroprotective effect against dexamethasone-induced reactive oxygen species production in neuronal cells that was higher than that of 1.