pubmed_id
int64 2.9M
36.8M
| title
stringlengths 1
390
⌀ | abstract
stringlengths 2
11.6k
⌀ |
|---|---|---|
36,721,393 |
Proceedings from the Albert Charitable Trust Inaugural Workshop on Understanding the Acute Effects of Exercise on the Brain.
|
An inaugural workshop supported by The Leo and Anne Albert Charitable Trust, was held October 4-7, 2019 in Scottsdale, Arizona, to focus on the effects of exercise on the brain and to discuss how physical activity may prevent or delay the onset of aging-related neurodegenerative conditions. The Scientific Program Committee (led by Dr. Jeff Burns) assembled translational, clinical, and basic scientists who research various aspects of the effects of exercise on the body and brain, with the overall goal of gaining a better understanding as to how to delay or prevent neurodegenerative diseases. In particular, research topics included the links between cardiorespiratory fitness, the cerebrovasculature, energy metabolism, peripheral organs, and cognitive function, which are all highly relevant to understanding the effects of acute and chronic exercise on the brain. The Albert Trust workshop participants addressed these and related topics, as well as how other lifestyle interventions, such as diet, affect age-related cognitive decline associated with Alzheimers and other neurodegenerative diseases. This report provides a synopsis of the presentations and discussions by the participants, and a delineation of the next steps towards advancing our understanding of the effects of exercise on the aging brain.
|
36,721,391 |
Professors Henriette van Praag and David Gems give the 2022 Nansen Neuroscience Lectures on Is ageing inevitable in the Norwegian Academy of Science and Letters, Norway.
|
This is a summary of the 2022 Nansen Neuroscience Lectures. On 10 October 2022, Professors Henriette van Praag and David Gems gave the 2022 Nansen Neuroscience Lectures on the theme Is ageing inevitable in the Norwegian Academy of Science and Letters, Oslo, Norway. While van Praag gave a lecture entitled The benefits of exercise for brain function, Gems gave the 2
|
36,721,205 |
Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology.
|
The rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimers disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies. We generated a novel Trem2 H157Y knock-in mouse model through CRISPRCas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, immunofluorescent staining, in vivo micro-dialysis, and cortical bulk RNA sequencing. Consistent with previous in vitro findings, Trem2 H157Y increases TREM2 shedding with elevated soluble TREM2 levels in the brain and serum. Moreover, Trem2 H157Y enhances synaptic plasticity without affecting microglial density and morphology, or TREM2 signaling. In the presence of amyloid pathology, Trem2 H157Y accelerates amyloid-β (Aβ) clearance and reduces amyloid burden, dystrophic neurites, and gliosis in two independent founder lines. Targeted mass spectrometry analysis of TREM2 revealed higher ratios of soluble to full-length TREM2-H157Y compared to wild-type TREM2, indicating that the H157Y mutation promotes TREM2 shedding in the presence of Aβ. TREM2 signaling was further found reduced in Trem2 H157Y homozygous mice. Transcriptomic profiling revealed that Trem2 H157Y downregulates neuroinflammation-related genes and an immune module correlated with the amyloid pathology. Taken together, our findings suggest beneficial effects of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD risk, we speculate TREM2 H157Y in humans might increase AD risk through an amyloid-independent pathway, such as its effects on tauopathy and neurodegeneration which merit further investigation.
|
36,721,182 |
Peripheral administration of nanomicelle-encapsulated anti-Aβ oligomer fragment antibody reduces various toxic Aβ species in the brain.
|
Although a large amount of evidence has revealed that amyloid β (Aβ), especially Aβ oligomers, protofibrils, and pyroglutamated Aβs, participate primarily in the pathophysiological processes of Alzheimers disease, most clinical trials of anti-Aβ antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood-brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to Aβ oligomers encapsulated in polymeric nanomicelles on the development of Alzheimers disease pathology in Alzheimers disease model mice at the age of emergence of early Alzheimers disease pathology. During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic Aβ species, such as Aβ oligomers, toxic Aβ conformers, and pyroglutamated Aβs in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of Aβ plaques, Aβ-antibody immunoreactive areas, and also plaque core formation. Behavioral analysis of the mice model revealed that the 6H4 fragments-polymeric nanomicelle group was significantly better at maintaining long-term spatial reference memory in the probe and platform tests of the water maze, thereby indicating inhibition of the pathophysiological process of Alzheimers disease. The results indicated that the strategy of reducing toxic Aβ species in early dementia owing to Alzheimers disease by providing sufficient antibodies in the brain may modify Alzheimers disease progression.
|
36,721,148 |
The gut microbiome in Alzheimers disease what we know and what remains to be explored.
|
Alzheimers disease (AD), the most common cause of dementia, results in a sustained decline in cognition. There are currently few effective disease modifying therapies for AD, but insights into the mechanisms that mediate the onset and progression of disease may lead to new, effective therapeutic strategies. Amyloid beta oligomers and plaques, tau aggregates, and neuroinflammation play a critical role in neurodegeneration and impact clinical AD progression. The upstream modulators of these pathological features have not been fully clarified, but recent evidence indicates that the gut microbiome (GMB) may have an influence on these features and therefore may influence AD progression in human patients. In this review, we summarize studies that have identified alterations in the GMB that correlate with pathophysiology in AD patients and AD mouse models. Additionally, we discuss findings with GMB manipulations in AD models and potential GMB-targeted therapeutics for AD. Lastly, we discuss diet, sleep, and exercise as potential modifiers of the relationship between the GMB and AD and conclude with future directions and recommendations for further studies of this topic.
|
36,721,026 |
ADAMTS4 is involved in the production of the Alzheimer disease amyloid biomarker APP669-711.
|
Amyloid-β (Aβ) deposition in the brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD). We have previously identified amyloid precursor protein (APP)669-711 (a.k.a. Aβ(-3)-40) in human plasma using immunoprecipitation combined with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (IP-MALDI-MS). Furthermore, we found that the level of a composite biomarker, i.e., a combination of APP669-711Aβ1-42 ratio and Aβ1-40Aβ1-42 ratio in human plasma, correlates with the amyloid PET status of AD patients. However, the production mechanism of APP669-711 has remained unclear. Using in vitro and in vivo assays, we identified A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) as a responsible enzyme for APP669-711 production. ADAMTS4 cleaves APP directly to generate the C-terminal stub c102, which is subsequently proteolyzed by γ-secretase to release APP669-711. Genetic knockout of ADAMTS4 reduced the production of endogenous APP669-711 by 30% to 40% in cultured cells as well as mouse plasma, irrespectively of Aβ levels. Finally, we found that the endogenous murine APP669-711Aβ1-42 ratio was increased in aged AD model mice, which shows Aβ deposition as observed in human patients. These data suggest that ADAMTS4 is involved in the production of APP669-711, and a plasma biomarker determined by IP-MALDI-MS can be used to estimate the level of Aβ deposition in the brain of mouse models.
|
36,720,957 |
Behavioral and cognitive performance of humanized APOEε3ε3 liver mice in relation to plasma apolipoprotein E levels.
|
Plasma apolipoprotein E levels were previously associated with the risk of developing Alzheimers disease (AD), levels of cerebrospinal fluid AD biomarkers, cognition and imaging brain measures. Outside the brain, the liver is the primary source of apoE and liver transplantation studies have demonstrated that liver-derived apoE does not cross the blood-brain-barrier. How hepatic apoE may be implicated in behavioral and cognitive performance is not clear. In the current study, we behaviorally tested FRGN mice with humanized liver harboring the ε3ε3 genotype (E3-human liver (HL)) and compared their behavioral and cognitive performance with that of age-matched ε3ε3 targeted replacement (E3-TR) mice, the latter produces human apoE3 throughout the body whereas the E3-HL mice endogenously produce human apoE3 only in the liver. We also compared the liver weights and plasma apoE levels, and assessed whether plasma apoE levels were correlated with behavioral or cognitive measures in both models. E3-HL were more active but performed cognitively worse than E3-TR mice. E3-HL mice moved more in the open field containing objects, showed higher activity levels in the Y maze, showed higher activity levels during the baseline period in the fear conditioning test than E3-TR mice, and swam faster than E3-TR mice during training to locate the visible platform in the water maze. However, E3-HL mice showed reduced spatial memory retention in the water maze and reduced fear learning and contextual and cued fear memory than E3-TR mice. Liver weights were greater in E3-HL than E3-TR mice and sex-dependent only in the latter model. Plasma apoE3 levels were similar to those found in humans and comparable in female and male E3-TR mice but higher in female E3-HL mice. Finally, we found correlations between plasma apoE levels and behavioral and cognitive measures which were predominantly model-dependent. Our study demonstrates mouse-model dependent associations between plasma apoE levels, behavior and cognition in an AD-neutral setting and suggests that a humanized liver might be sufficient to induce mouse behavioral and cognitive phenotypes.
|
36,720,919 |
TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia.
|
Although the ε4 allele of the apolipoprotein E (ApoE4) gene has been established as a genetic risk factor for many neurodegenerative diseases, including Alzheimers disease, the mechanism of action remains poorly understood. Transient receptor potential vanilloid 1 (TRPV1) was reported to regulate autophagy to protect against foam cell formation in atherosclerosis. Here, we show that ApoE4 leads to lipid metabolism dysregulation in microglia, resulting in enhanced MHC-II-dependent antigen presentation and T-cell activation. Lipid accumulation and inflammatory reactions were accelerated in microglia isolated from TRPV1
|
36,720,893 |
Food protein-derived amyloids do not accelerate amyloid β aggregation.
|
The deposition of proteins in the form of amyloid fibrils is closely associated with several serious diseases. The events that trigger the conversion from soluble functional proteins into insoluble amyloid are not fully understood. Many proteins that are not associated with disease can form amyloid with similar structural characteristics as the disease-associated fibrils, which highlights the potential risk of cross-seeding of disease amyloid by amyloid-like structures encountered in our surrounding. Of particular interest are common food proteins that can be transformed into amyloid under conditions similar to cooking. We here investigate cross-seeding of amyloid-β (Aβ), a peptide known to form amyloid during the development of Alzheimers disease, by 16 types of amyloid fibrils derived from food proteins or peptides. Kinetic studies using thioflavin T fluorescence as output show that none of the investigated protein fibrils accelerates the aggregation of Aβ. In at least two cases (hen egg lysozyme and oat protein isolate) we observe retardation of the aggregation, which appears to originate from interactions between the food protein seeds and Aβ in aggregated form. The results support the view that food-derived amyloid is not a risk factor for development of Aβ pathology and Alzheimers disease.
|
36,720,642 |
Testing for Alzheimer Disease Biomarkers and Disclosing Results Across the Disease Continuum.
|
Three pathological processes define or are characteristic of Alzheimers disease (AD) amyloid-β, hyperphosphorylated tau, and neurodegeneration. Our understanding of AD is undergoing a transformation due to our ability to measure biomarkers of these processes across different stages of cognitive impairment. There is growing interest in using AD biomarker tests in care and research and, with this, a growing need for guidance on how to return these sensitive results to patients and participants. Here, we propose a five-step approach informed by clinical and research experience designing and implementing AD biomarker disclosure processes extant evidence describing how individuals react to AD biomarker information ethics and the literature on breaking bad news. The clinician should (1) determine the appropriateness of AD biomarker testing and return of results for the particular patient or research participant. If testing is appropriate, the next steps are to (2) provide pre-test education and seek consent for testing to the individual and their support person (3) administer testing (4) return the results to the individual and their support person and (5) follow up to promote the recipients wellbeing and to learn from their experience. We conclude by identifying open questions to guide future studies of biomarker disclosure.
|
36,720,634 |
Workers in Australian prebake aluminium smelters update on risk of mortality and cancer incidence in the Healthwise cohort.
|
To investigate mortality and the rates of incident cancer among a cohort of aluminium industry workers. Among 4507 male employees who worked in either of two Australian prebake smelters for at least 3 months, data linkage was undertaken with the Australian National Death Index and Australian Cancer Database. Standardised Mortality Ratios (SMRs) and Standardised Incidence Rates (SIRs) were estimated for the whole cohort and for production maintenance and office workers. SMRs and SIRs were calculated by time since first employment. Among production workers, there was an excess risk of mortality from mesothelioma (SMR 2.8, 95% CI 1.3 to 5.2), lung (SMR 1.4, 95% CI 1.0 to 1.8), prostate (SMR 1.9, 95% CI 1.3 to 2.7) and liver cancer (SMR 2.0, 95% CI 1.1 to 3.4) and the SIR was also increased for overall respiratory cancers, specifically lung cancers. An excess risk of death from stomach cancer (SMR 2.9, 95% CI 1.2 to 6.1) and Alzheimers disease (SMR 3.4, 95% CI 1.1 to 7.9) was seen among maintenance workers. The overall risk of death was similar to that of the Australian general population, as was mortality from cancers overall and non-malignant respiratory disease. No excess risk of death from bladder cancer or non-malignant respiratory disease was found. Excess lung cancer mortality and incidence may be explained by smoking and excess mortality from mesothelioma may be explained by asbestos exposure. An excess risk of mortality from liver and prostate cancer has been shown in production workers and requires further investigation.
|
36,720,351 |
The pollutome-connectome axis a putative mechanism to explain pollution effects on neurodegeneration.
|
The study of pollutant effects is extremely important to address the epochal challenges we are facing, where world populations are increasingly moving from rural to urban centers, revolutionizing our world into an urban world. These transformations will exacerbate pollution, thus highlighting the necessity to unravel its effect on human health. Epidemiological studies have reported that pollution increases the risk of neurological diseases, with growing evidence on the risk of neurodegenerative disorders. Air pollution and water pollutants are the main chemicals driving this risk. These chemicals can promote inflammation, acting in synergy with genotype vulnerability. However, the biological underpinnings of this association are unknown. In this review, we focus on the link between pollution and brain network connectivity at the macro-scale level. We provide an updated overview of epidemiological findings and studies investigating brain network changes associated with pollution exposure, and discuss the mechanistic insights of pollution-induced brain changes through neural networks. We explain, in detail, the pollutome-connectome axis that might provide the functional substrate for pollution-induced processes leading to cognitive impairment and neurodegeneration. We describe this model within the framework of two pollutants, air pollution, a widely recognized threat, and polyfluoroalkyl substances, a large class of synthetic chemicals which are currently emerging as new neurotoxic source.
|
36,719,948 |
Dry Chemistry-Based Bipolar Electrochemiluminescence Immunoassay Device for Point-of-Care Testing of Alzheimer-Associated Neuronal Thread Protein.
|
In this study, we developed, for the first time, a novel dry chemistry-based bipolar electrochemiluminescence (ECL) immunoassay device for point-of-care testing (POCT) of Alzheimer-associated neuronal thread protein (AD7c-NTP), where the ECL signals were automatically collected and analyzed after the sample and buffer solutions were manually added onto the immunosensor. The proposed immunoassay device contains an automatic ECL analyzer and a dry chemistry-based ECL immunosensor fabricated with a screen-printed fiber material-based chip and a three-dimensional (3D)-printed shell. Each pad of the fiber material-based chip was premodified with certain reagents for immunoreaction and then assembled to form the ECL immunosensor. The self-enhanced ECL of the Ru(II)-poly-l-lysine complex and the lateral flow fiber material-based chip make the addition of coreactants and repeated flushing unnecessary. Only the sample and buffer solutions are added to the ECL immunosensor, and the process of ECL detection can be completed in about 6 min using the proposed automatic ECL analyzer. Under optimized conditions, the linear detection range for AD7c-NTP was 1 to 10
|
36,719,834 |
Effect of neurotropin on Alzheimers disease-like changes and cognitive function in rats with chronic cerebral hypoperfusion.
|
Chronic cerebral hypoperfusion (CCH) is a main mechanism of cerebrovascular disease and is associated with various cerebrovascular and neurodegenerative diseases, including Alzheimers disease. However, treatment of CCH in clinical practice is not ideal, but neurotropin (NTP) has been shown to have a neuroprotective effect. Therefore, this study examined the effect and possible mechanism of NTP in nerve injury caused by CCH. A rat CCH model was established by bilateral common carotid artery occlusion (2VO), and rats were treated with intragastric administration of NTP (200 nukgday) for 28 consecutive days. After treatment, rats were subjected to the Morris water maze and novel object recognition test. Subsequently, an ELISA was applied to detect amyloid-β (Aβ) 1-40 and Aβ1-42 levels in rat hippocampal tissues, quantitative reverse transcription PCR assays were used to detect the mRNA expression levels of brain-derived neurotrophic factor (BDNF) and Trk B, and Western blots were used to detect the protein expression levels of BACE1, tau, p-tau, and protein kinase B (Akt)glycogen synthase kinase 3β (GSK3β) pathway-related proteins. The rat model of CCH was successfully established by 2VO. Behavioral tests indicated that the cognitive ability of 2VO rats was severely impaired. NTP treatment greatly ameliorated the cognitive disability, reduced Aβ1-40 and Aβ1-42 levels and tau phosphorylation, and upregulated BACE1, Trk B, and BDNF expression in the hippocampus of 2VO rats. Finally, we found that NTP markedly activated AktGSK3β pathway activity. NTP can ameliorate cognitive disability in CCH rats possibly by reducing Aβ accumulation and tau phosphorylation in the hippocampus. These effects of NTP may be related to the AktGSK3β pathway activation. NTP may be a promising new drug candidate for CCH patients.
|
36,719,832 |
Profiling microRNA from peripheral blood mononuclear cells in early-onset familial Alzheimers disease.
|
MicroRNAs (miRNAs) refer to short in-length, noncoding RNAs that regulate numerous cellular functions by targeting mRNA, and numerous types of research have shown that miRNA is vitalin Alzheimers disease. For identifying differentially expressed miRNAs in the peripheral blood mononuclear cell (PBMC) of early-onset familial Alzheimers disease (EOFAD), we conducted this study which might give a reference for potential therapeutic targets or biomarkers for this disease. On the basis of high-throughput sequencing, we screened the miRNAs expression profiles in PBMC regarding both EOFAD patients and healthy controls, and the biological information was analyzed. Compared with the PBMC of healthy controls, 142 miRNAs were differentially expressed in EOFAD patients ( P < 0.05), including 48 significantly differentially expressed miRNAs, 37 of which were significantly upregulated, including miR-3614-5p, miR-193A-5p, miR-2115-5p, miR-143-3p, etc. and 11 were significantly downregulated, including miR-484, miR-708-5p, miR-205-5p, miR-31-5p, etc. According to biological information analysis, 768 miRNA target genes were differentially expressed, which may be involved in multiple gene functions and cell cycle, cell senescence, and several signaling pathways, including FoxO, MAPK, Ras, mTOR, neurotrophin, etc. There are differential expressions of miRNAs in PBMC of EOFAD patients and controls, revealing their importance in Alzheimers disease as indicated by co-expression network analysis this may support basic information for new biomarkers or treatment exploring.
|
36,719,791 |
Classification of neuroimaging data in Alzheimers disease using particle swarm optimization A systematic review.
|
Particle swarm optimization (PSO) is an algorithm that involves the optimization of Non-linear and Multidimensional problems to reach the best solutions with minimal parameterization. This metaheuristic model has frequently been used in the Pathological domain. This optimization model has been used in diverse forms while predicting Alzheimers disease. It is a robust algorithm that works on linear and multi-modal data while predicting Alzheimers disease. PSO techniques have been in action for quite some time for detecting various diseases and this paper systematically reviews the papers on various kinds of PSO techniques. To perform the systematic review, PRISMA guidelines were followed and a Boolean search (particle swarm optimization OR PSO) AND Neuroimaging AND (Alzheimers disease prediction OR classification OR diagnosis) were performed. The query was run in 4-reputed databases Google Scholar, Scopus, Science Direct, and Wiley publications. For the final analysis, 10 papers were incorporated for qualitative and quantitative synthesis. PSO has shown a dominant character while handling the uni-modal as well as the multi-modal data while predicting the conversion from MCI to Alzheimers. It can be seen from the table that almost all the 10 reviewed papers had MRI-driven data. The accuracy rate was accentuated while adding other modalities or Neurocognitive measures. Through this algorithm, we are providing an opportunity to other researchers to compare this algorithm with other state-of-the-art algorithms, while seeing the classification accuracy, with the aim of early prediction and progression of MCI into Alzheimers disease.
|
36,719,785 |
European Working Group on SARS-CoV-2 Current Understanding, Unknowns, and Recommendations on the Neurological Complications of COVID-19.
|
The emergence of COVID-19 was rapidly followed by infection and the deaths of millions of people across the globe. With much of the research and scientific advancement rightly focused on reducing the burden of severe and critical acute COVID-19 infection, the long-term effects endured by those who survived the acute infection has been previously overlooked. Now, an appreciation for the post-COVID-19 condition, including its neurological manifestations, is growing, although there remain many unknowns regarding the aetiology and risk factors of the condition, as well as how to effectively diagnose and treat it. Here, drawing upon the experiences and expertise of the clinicians and academics of the European working group on COVID-19, we have reviewed the current literature to provide a comprehensive overview of the neurological sequalae of the post-COVID-19 condition. In this review, we provide a summary of the neurological symptoms associated with the post-COVID-19 condition, before discussing the possible mechanisms which may underly and manifest these symptoms. Following this, we explore the risk factors for developing neurological symptoms as a result of COVID-19 and the post-COVID-19 condition, as well as how COVID-19 infection may itself be a risk factor for the development of neurological disease in the future. Lastly, we evaluate how the post-COVID condition could be accurately diagnosed and effectively treated, including examples of the current guidelines, clinical outcomes and tools that have been developed to aid in this process, as well as addressing the protection provided by COVID-19 vaccines against post-COVID-19 condition. Overall, this review provides a comprehensive overview of the neurological sequalae of the post-COVID-19 condition.
|
36,719,721 |
A Web-Based Decision Aid for Caregivers of Persons With Dementia With Firearm Access (Safe at Home Study) Protocol for a Randomized Controlled Trial.
|
Firearm safety among individuals with Alzheimer disease and related dementias (ADRD) is an underdiscussed and underresearched concern in the United States, especially given the growing population of community-dwelling adults with ADRD. The Safety in Dementia (SiD) web-based decision aid was developed to support caregivers in addressing firearm access the efficacy of SiD is unknown. Through the SiD decision aid, the Safe at Home (SH) study aims to support caregivers in making decisions about home safety that align with their goals and values, and behaviors regarding firearm access for persons with ADRD and firearm access. The SH study is a 2-armed randomized controlled trial to test the effect of the SiD decision aid on caregivers of community-dwelling adults with ADRD who have firearm access. SH aims to recruit 500 ADRD caregivers (age ≥18 years, fluent in English or Spanish, and in the United States) through online or social media advertisements and through relevant organizations. Participants are randomized to view SiD or a control website at their own pace all participants complete web-based questionnaires at baseline, 2 weeks, 2 months, and 6 months. The primary outcome is immediate preparation for decision-making secondary outcomes include longitudinal decision outcomes and self-reported modifications to firearm access. The relative reach and effectiveness of each recruitment method (onlinesocial media and through relevant organizations) will be assessed by examining differences in caregiver participation, retention rates, and relative cost. The study enrollment began in May 2022. As of December 2022, a total of 117 participants had enrolled. The SH study is the first randomized trial of a firearm safety decision aid for ADRD caregivers. The results from this study will inform how best to support caregivers in decision-making regarding firearm safety. Further, results may guide approaches for recruiting caregivers and for dissemination of resources. ClinicalTrials.gov NCT05173922 httpsclinicaltrials.govct2showNCT05173922. DERR1-10.219643702.
|
36,719,634 |
Alterations of ATG4A and LC3B in neurons derived from Alzheimers disease patients.
|
We investigated the alterations in autophagy-related molecules in neurons differentiated from induced pluripotent stem cells obtained from patients with Alzheimers disease (AD). Consistent with our previous microarray data, ATG4A protein was upregulated in the neurons derived from a familial AD patient with an APP-E693Δ mutation who showed accumulation of intracellular amyloid β peptide (Aβ). This upregulation was reversed by inhibiting Aβ production, suggesting that the intracellular Aβ may be responsible for the upregulation of ATG4A. The LC3B-IILC3B-I ratio, an index of autophagosome formation, was lower in the neurons derived from the AD patient with APP-E693Δ as well as the neurons derived from other familial and sporadic AD patients. These findings indicate that dysregulation of autophagy-related molecules may accelerate the pathogenesis of AD.
|
36,719,337 |
Pharmacologic treatment of depression in Alzheimers disease.
|
Major depressive disorder and Alzheimers disease are common among older people, frequently co-occur and severely impact the quality of life. Unfortunately, data on the efficacy of pharmacologic treatment of depressive symptoms in patients with the neurodegenerative disease remain inconclusive. The heterogeneity of treatment study designs, from varying diagnostic specificity to diverse outcome measures, contributes to conflicting evidence across single trials and meta-analyses. In this literature review, we focus on commercially available products for antidepressant treatment in demented individuals and show how insights from randomized controlled trials could still guide and be aligned with common clinical practice.
|
36,719,290 |
Focused Ultrasound-mediated Liquid Biopsy in a Tauopathy Mouse Model.
|
Background Neurodegenerative disorders (such as Alzheimer disease) characterized by the deposition of various pathogenic forms of tau protein in the brain are collectively referred to as tauopathies. Identification of the molecular drivers and pathways of neurodegeneration is critical to individualized targeted treatment of these disorders. However, despite important advances in fluid biomarker detection, characterization of these molecular subtypes is limited by the blood-brain barrier. Purpose To evaluate the feasibility and safety of focused ultrasound-mediated liquid biopsy (sonobiopsy) in the detection of brain-derived protein biomarkers in a transgenic mouse model of tauopathy (PS19 mice). Materials and Methods Sonobiopsy was performed by sonicating the cerebral hemisphere in 2-month-old PS19 and wild-type mice, followed by measurement of plasma phosphorylated tau (p-tau) species (30 minutes after sonication in the sonobiopsy group). Next, spatially targeted sonobiopsy was performed by sonicating either the cerebral cortex or the hippocampus in 6-month-old PS19 mice. To detect changes in plasma neurofilament light chain (a biomarker of neurodegeneration) levels, blood samples were collected before and after sonication (15 and 45-60 minutes after sonication). Histologic staining was performed to evaluate tissue damage after sonobiopsy. The Shapiro-Wilk test, unpaired and paired
|
36,719,168 |
A Quantitative LC-MSMS Method for Distinguishing the Tau Protein Forms Phosphorylated and Nonphosphorylated at Serine-396.
|
Hyperphosphorylated tau protein is well-known to be involved in the formation of neurofibrillary tangles and the progression of age-related neurodegenerative diseases (tauopathies), including Alzheimers Disease (AD). Tau protein phosphorylated at serine-396 (pS396-tau) is often linked to disease progression, and we therefore developed an analytical method to measure pS396-tau in cerebrospinal fluid (CSF) in humans and animal models of AD. In the S396-region, multiple phosphorylation sites are present, causing structural complexity and sensitivity challenges for conventional bottom-up mass spectrometry approaches. Here, we present an indirect LC-MSMS method for quantification of pS396-tau. We take advantage of the reproducible miscleavage caused by S396 being preceded by a lysine (K395) and the proteolytic enzyme trypsin not cleaving when the following amino acid is phosphorylated. Therefore, treatment with trypsin discriminates between the forms of tau with and without phosphorylation at S396 and pS396-tau can be quantified as the difference between total S396-tau and nonphosphorylated S396-tau. To qualify the method, it was successfully applied for quantification of pS396-tau in human CSF from healthy controls and patients with Mild Cognitive Impairment and AD. In addition, the method was applied for rTg4510 mice where a clear dose dependent decrease in pS396-tau was observed in CSF following intravenous administration of a monoclonal antibody (Lu AF87908, hC10.2) targeting the tau epitope containing pS396. Finally, a formal validation of the method was conducted. In conclusion, this sensitive LC-MSMS-based method for measurement of pS396-tau in CSF allows for quantitative translational biomarker applications for tauopathies including investigations of potential drug induced effects.
|
36,718,490 |
Semantic dementia a complex and culturally influenced presentation.
|
The variants of frontotemporal dementia (FTD) require careful differentiation from primary psychiatric disorders as the neuropsychiatric manifestations can overshadow the unique cognitive deficits. The language variants of FTD are less readily recognised by trainees despite making up around 43% of cases. This educational article presents an anonymised case of one of the language variants semantic dementia. The cognitive deficits and neuropsychiatric manifestations (delusions and hyperreligiosity) are explored in terms of aetiology and management. By the end of the article, readers should be able to differentiate FTD from Alzheimers disease, understand the principles of management and associated risks, and develop a multifaceted approach to hyperreligiosity in dementia.
|
36,718,278 |
Dietary High-Fat Promotes Cognitive Impairment by Suppressing Mitophagy.
|
Dietary habits contribute to the characteristics of Alzheimers disease (AD) and cognitive impairment, which are partly induced by the accumulation of hyperphosphorylated Tau, a microtubule-associated protein. In mice, a fat-rich diet facilitates cognitive dysfunction. However, the mechanism by which dietary fat damages the brain remains unclear. In this study, 13-month-old C57BL6 mice were fed a normal or high-fat diet (HFD) for 6 months. Neuro-2a cells were incubated with the normal medium or palmitic acid (200
|
36,718,094 |
In silico approaches to develop new phenyl-pyrimidines as glycogen synthase kinase 3 (GSK-3) inhibitors with halogen-bonding capabilities 3D-QSAR CoMFACoMSIA, molecular docking and molecular dynamics studies.
|
Glycogen synthase kinase 3 (GSK-3) is involved in different diseases, such as manic-depressive illness, Alzheimers disease and cancer. Studies have shown that insulin inhibits GSK-3 to keep glycogen synthase active. Inhibiting GSK-3 may have an indirect pro-insulin effect by favouring glycogen synthesis. Therefore, the development of GSK-3 inhibitors can be a useful alternative for the treatment of type II diabetes. Aminopyrimidine derivatives already proved to be interesting GSK-3 inhibitors. In the current study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) have been performed on a series of 122 aminopyrimidine derivatives in order to generate a robust model for the rational design of new compounds with promising antidiabetic activity. The
|
36,718,002 |
In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimers disease.
|
Synapse loss has been considered as a major pathological change in Alzheimers disease (AD). It remains unclear about whether and how synapse loss relates to functional and structural connectivity dysfunction in AD. We measured synaptic vesicle glycoprotein 2 A (SV2A) binding using
|
36,717,922 |
Patchouli alcohol attenuates the cognitive deficits in a transgenic mouse model of Alzheimers disease via modulating neuropathology and gut microbiota through suppressing CEBPβAEP pathway.
|
Alzheimers disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive dysfunctions and behavioral impairments. Patchouli alcohol (PA), isolated from Pogostemonis Herba, exhibits multiple pharmacological properties, including neuroprotective effects. This study aimed to investigate the therapeutic effects of PA against AD using the TgCRND8 transgenic AD mouse model, and to explore the underlying mechanisms targeting CCAATenhancer-binding protein βasparagine endopeptidase (CEBPβAEP) signaling pathway. After genotyping to confirm the transgenicity, drug treatments were administered intragastrically once daily to 3-month-old TgCRND8 mice for 4 consecutive months. Several behavioral tests were applied to assess different aspects of neurological functions. Then the brain and colon tissues were harvested for in-depth mechanistic studies. To further verify whether PA exerts anti-AD effects via modulating CEBPβAEP signaling pathway in TgCRND8 mice, adeno-associated virus (AAV) vectors encoding CEBPβ were bilaterally injected into the hippocampal CA1 region in TgCRND8 mice to overexpress CEBPβ. Additionally, the fecal microbiota transplantation (FMT) experiment was performed to verify the potential role of gut microbiota on the anti-AD effects of PA. Our results showed that PA treatment significantly improved activities of daily living (ADL), ameliorated the anxiety-related behavioral deficits and cognitive impairments in TgCRND8 mice. PA modulated the amyloid precursor protein (APP) processing. PA also markedly reduced the levels of beta-amyloid (Aβ) All these findings amply demonstrated that PA could ameliorate the cognitive deficits in TgCRND8 mice via suppressing Aβ plaques deposition, hyperphosphorylation of tau protein, neuroinflammation and gut dysbiosis through inhibiting the activation of CEBPβAEP pathway, suggesting that PA is a promising naturally occurring chemical worthy of further development into the pharmaceutical treatment of AD.
|
36,717,893 |
Impact of the gut microbiota and associated metabolites on cardiometabolic traits, chronic diseases and human longevity a Mendelian randomization study.
|
Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to determine whether the gut microbiota influences cardiometabolic traits as well as the risk of chronic diseases and human longevity using a comprehensive 2-Sample Mendelian randomization approach. We included as exposures 10 gut-associated metabolites and pathways and 57 microbial taxa abundance. We included as outcomes nine cardiometabolic traits (fasting glucose, fasting insulin, systolic blood pressure, diastolic blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, body mass index BMI), eight chronic diseases previously linked with the gut microbiota in observational studies (Alzheimers disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease), as well as parental lifespan and longevity. We found 7 associations with evidence of causality before and after sensitivity analyses, but not after multiple testing correction (1198 tests). Most effect sizes (47) were small. The two largest exposure-outcome effects were markedly attenuated towards the null upon inclusion of BMI or alcohol intake frequency in multivariable MR analyses. While finding robust genetic instruments for microbiota features is challenging hence potentially inflating type 2 errors, these results do not support a large causal impact of human gut microbita features on cardiometabolic traits, chronic diseases or longevity. These results also suggest that the previously documented associations between gut microbiota and human health outcomes may not always underly causal relations.
|
36,717,892 |
Links between COVID-19 and Parkinsons diseaseAlzheimers disease reciprocal impacts, medical care strategies and underlying mechanisms.
|
The impact of coronavirus disease 2019 (COVID-19) pandemic on patients with neurodegenerative diseases and the specific neurological manifestations of COVID-19 have aroused great interest. However, there are still many issues of concern to be clarified. Therefore, we review the current literature on the complex relationship between COVID-19 and neurodegenerative diseases with an emphasis on Parkinsons disease (PD) and Alzheimers disease (AD). We summarize the impact of COVID-19 infection on symptom severity, disease progression, and mortality rate of PD and AD, and discuss whether COVID-19 infection could trigger PD and AD. In addition, the susceptibility to and the prognosis of COVID-19 in PD patients and AD patients are also included. In order to achieve better management of PD and AD patients, modifications of care strategies, specific drug therapies, and vaccines during the pandemic are also listed. At last, mechanisms underlying the link of COVID-19 with PD and AD are reviewed.
|
36,717,446 |
SkQ1 as a Tool for Controlling Accelerated Senescence Program Experiments with OXYS Rats.
|
According to the concept suggested by V. P. Skulachev and co-authors, aging of living organisms can be considered as a special case of programmed death of an organism - phenoptosis, and mitochondrial antioxidant SkQ1 is capable of inhibiting both acute and chronic phenoptosis (aging). The authors of the concept associate effects of SkQ1 with suppression of the enhanced generation of ROS in mitochondria. Numerous studies have confirmed the ability of SkQ1 to inhibit manifestations of the healthy, or physiological, aging. According to the results of our studies, SkQ1 is especially effective in suppressing the program of genetically determined accelerated senescence in OXYS rats, which appears as an early development of a complex of age-related diseases cataracts, retinopathy (similar to the age-related macular degeneration in humans), osteoporosis, and signs of Alzheimers disease. Accelerated senescence in OXYS rats is associated with mitochondrial dysfunction, but no direct associations with oxidative stress have been identified. Nevertheless, SkQ1 is able to prevent andor suppress development of all manifestations of accelerated senescence in OXYS rats. Its effects are due to impact on the activity of many signaling pathways and processes, but first of all they are associated with restoration of the structural and functional parameters of mitochondria. It could be suggested that the use of SkQ1 could represent a promising strategy in prevention of accelerated phenoptosis - early development of a complex of age-related diseases (multimorbidity) in people predisposed to it.
|
36,717,389 |
Exercise Associated with Cognitive Function in Older Men with Prostate Cancer Undergoing Androgen Deprivation Therapy.
|
To examine associations between exercise and cognitive function in older men undergoing hormone therapy for prostate cancer. Men ≥ 65 years old with prostate cancer, currently undergoing androgen deprivation therapy for ≥ 6 months (n 50), completed the Godin-Shephard Leisure-Time Physical Activity Questionnaire, and standard neuropsychological tests. Pearsons correlations and linear regressions were used to examine associations between exercise and cognitive performance. Exercise was significantly positively correlated with performance on tests of memory, attention, and executive function. Linear regressions showed that when controlling for age and education, exercise remained a significant predictor of attention and executive function performance (p < 0.05), and showed moderate, but statistically non-significant effects on memory performance (p < 0.10). Greater exercise is associated with better functioning in multiple cognitive domains in men with prostate cancer undergoing hormone therapy, providing proof-of-concept evidence that exercise may be a feasible intervention to limit cognitive dysfunction in prostate cancer patients.
|
36,717,226 |
The amyloid precursor protein modulates the position and length of the axon initial segment.
|
The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimers disease (AD). It is the parent protein of the β-amyloid peptide, the main constituent of the amyloid plaques found in an AD brain. The pathways from APP to Aβ are intensively studied, yet the normal functions of APP itself have generated less interest. We report here that glutamate stimulation of neuronal activity leads to a rapid increase in
|
36,717,015 |
Passive immunization inhibits tau phosphorylation and improves recognition learning and memory in 3xTg-AD mice.
|
Tau pathology is essential in the pathogenesis of Alzheimers disease (AD) and related tauopathies. Tau immunotherapy aimed at reducing the progression of tau pathology provides a potential therapeutic strategy for treating these diseases. By screening monoclonal antibodies 43D, 63B, 39E10, and 77G7 that recognize epitopes ranging from taus N-terminus to C-terminus, we found the 77G7, which targets the microtubule-binding domain promoted tau clearance in a dose-dependent manner by entering neuronal cells in vitro. Intra-cerebroventricular injection of 77G7 antibody reduced tau levels in the wild-type FVB mouse brain. Without influencing the levels of detergent-insoluble and aggregated tau, intravenous injection of 77G7 reduced tau hyperphosphorylation in the brain and improved novel object recognition but not spatial learning and memory in 15-18-month-old 3xTg-AD mice. These studies suggest that epitopes recognized by tau antibodies are crucial for the efficacy of immunotherapy. Immunization with antibody 77G7 provides a novel potential opportunity for tau-directed immunotherapy of AD and related tauopathies.
|
36,716,987 |
Emotion recognition and baseline cortisol levels relationship in early Alzheimer disease.
|
Emotion recognition is often impaired in early Alzheimers disease (AD) and can be evaluated using the Reading the Mind in the Eyes Test (RMET). Similarly, cortisol levels can affect cognition and could be considered a biomarker of AD. The aim of this study was to analyse the relationship between the emotion recognition task and cortisol levels in participants with early Alzheimer Disease (AD). Complex emotion recognition was assessed with RMET, and plasma cortisol levels were determined by mass spectrometry in participants classified into mild cognitive impairment (MCI) due to AD (n 25), mild dementia (MD) due to AD (n 20), MCI non-AD (n 34), MD non-AD (n 13) and healthy controls (HC) (n 16) groups. Significantly lower positive emotion recognition was found in the MCI non-AD group (p 0.02) and lower emotion recognition in MD (AD and non-AD) groups (p < 0.01) compared to the healthy group. In addition, significant differences were observed between cortisol and all RMET scores among the MCI and MD groups (p < 0.01). A significant correlation was also obtained between total and neutral RMET scores and cortisol levels in MD groups (p 0.01). These outcomes suggest that detection of positive emotion dysfunction could help to identify MCI non-AD patients. Furthermore, general impaired emotion recognition and high cortisol levels may be associated with cognitive impairment at mild dementia level.
|
36,716,975 |
The hippocampus associated GABAergic neural network impairment in early-stage of Alzheimers disease.
|
Alzheimers disease (AD) is the commonest neurodegenerative disease with slow progression. Pieces of evidence suggest that the GABAergic system is impaired in the early stage of AD, leading to hippocampal neuron over-activity and further leading to memory and cognitive impairment in patients with AD. However, the precise impairment mechanism of the GABAergic system on the pathogenesis of AD is still unclear. The impairment of neural networks associated with the GABAergic system is tightly associated with AD. Therefore, we describe the roles played by hippocampus-related GABAergic circuits and their impairments in AD neuropathology. In addition, we give our understand on the process from GABAergic circuit impairment to cognitive and memory impairment, since recent studies on astrocyte in AD plays an important role behind cognition dysfunction caused by GABAergic circuit impairment, which helps better understand the GABAergic system and could open up innovative AD therapy.
|
36,716,914 |
Progressive Spread of Beta-amyloid Pathology in an Olfactory-driven Amyloid Precursor Protein Mouse Model.
|
Years before Alzheimers disease (AD) is diagnosed, patients experience an impaired sense of smell, and β-amyloid plaques accumulate within the olfactory mucosa and olfactory bulb (OB). The olfactory vector hypothesis proposes that external agents cause β-amyloid to aggregate and spread from the OB to connected downstream brain regions. To reproduce the slow accumulation of β-amyloid that occurs in human AD, we investigated the progressive accumulation of β-amyloid across the brain using a conditional mouse model that overexpresses a humanized mutant form of the amyloid precursor protein (hAPP) in olfactory sensory neurons. Using design-based stereology, we show the progressive accumulation of β-amyloid plaques within the OB and cortical olfactory regions with age. We also observe reduced OB volumes in these mice when hAPP expression begins prior-to but not post-weaning which we tracked using manganese-enhanced MRI. We therefore conclude that the reduced OB volume does not represent progressive degeneration but rather disrupted OB development. Overall, our data demonstrate that hAPP expression in the olfactory epithelium can lead to the accumulation and spread of β-amyloid through the olfactory system into the hippocampus, consistent with an olfactory system role in the early stages of β-amyloid-related AD progression.
|
36,716,837 |
Bacopa monnieri reduces Tau aggregation and Tau-mediated toxicity in cells.
|
Alzheimers disease is a neurodegenerative disease characterized by progressive memory loss and behavioral impairments. In the present study, the ethanolic extract of Bacopa monnieri was studied for its potency to inhibit Tau aggregation and rescuing of the viability of Tau-stressed cells. Bacopa monnieri was observed to inhibit the Tau aggregation in vitro. The cells exposed to Bacopa monnieri were also observed to have a low level of ROS and caspase-3 activity. The immunoblot and immunofluorescence analysis showed that Bacopa monnieri acts as an antioxidant and restored the Nrf2 levels in Neuro2a cells. Bacopa monnieri treatment to Neuro2a cells was observed to reduce the phospho-Tau load in formaldehyde-stressed cells. Furthermore, the treatment of Bacopa monnieri reduced the phosphorylation of GSK-3β in formaldehyde-stressed cells. Ran and NUP358 are the key proteins involved in nuclear transport. It was observed that formaldehyde treatment impaired the nuclear transport by missorting the NUP358 arrangement in Neuro2a cells. On the contrary, Bacopa monnieri treatment restored the NUP358 arrangement in cells. The overall results of the present study suggested that Bacopa monnieri could be considered a potent herb against Tau phosphorylation and Tau aggregation, which projects it as a promising formulation for Alzheimers disease.
|
36,716,365 |
Bias in machine learning models can be significantly mitigated by careful training Evidence from neuroimaging studies.
|
Despite the great promise that machine learning has offered in many fields of medicine, it has also raised concerns about potential biases and poor generalization across genders, age distributions, races and ethnicities, hospitals, and data acquisition equipment and protocols. In the current study, and in the context of three brain diseases, we provide evidence which suggests that when properly trained, machine learning models can generalize well across diverse conditions and do not necessarily suffer from bias. Specifically, by using multistudy magnetic resonance imaging consortia for diagnosing Alzheimers disease, schizophrenia, and autism spectrum disorder, we find that well-trained models have a high area-under-the-curve (AUC) on subjects across different subgroups pertaining to attributes such as gender, age, racial groups and different clinical studies and are unbiased under multiple fairness metrics such as demographic parity difference, equalized odds difference, equal opportunity difference, etc. We find that models that incorporate multisource data from demographic, clinical, genetic factors, and cognitive scores are also unbiased. These models have a better predictive AUC across subgroups than those trained only with imaging features, but there are also situations when these additional features do not help.
|
36,716,346 |
Tissue specific LRRK2 interactomes reveal a distinct striatal functional unit.
|
Mutations in LRRK2 are the most common genetic cause of Parkinsons disease. Despite substantial research efforts, the physiological and pathological role of this multidomain protein remains poorly defined. In this study, we used a systematic approach to construct the general protein-protein interactome around LRRK2, which was then evaluated taking into consideration the differential expression patterns and the co-expression behaviours of the LRRK2 interactors in 15 different healthy tissue types. The LRRK2 interactors exhibited distinct expression features in the brain as compared to the peripheral tissues analysed. Moreover, a high degree of similarity was found for the LRRK2 interactors in putamen, caudate and nucleus accumbens, thus defining a potential LRRK2 functional cluster within the striatum. The general LRRK2 interactome paired with the expression profiles of its members constitutes a powerful tool to generate tissue-specific LRRK2 interactomes. We exemplified the generation of the tissue-specific LRRK2 interactomes and explored the functions highlighted by the core LRRK2 interactors in the striatum in comparison with the cerebellum. Finally, we illustrated how the LRRK2 general interactome reported in this manuscript paired with the expression profiles can be used to trace the relationship between LRRK2 and specific interactors of interest, here focusing on the LRRK2 interactors belonging to the Rab protein family.
|
36,716,024 |
Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries.
|
Diagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches. To assess the incidence of FTLD across Europe. The Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021. Random-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity. Based on 267 identified cases (mean SD patient age, 66.70 9.02 years 156 males 58.43%), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases 40.07%), followed by PPA (76 28.46%) and extrapyramidal phenotypes (69 25.84%). FTD-ALS was the rarest phenotype (15 cases 5.62%). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057. The findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.
|
36,715,843 |
Neuroprotective role of chloroquine via modulation of autophagy and neuroinflammation in MPTP-induced Parkinsons disease.
|
Parkinsons disease (PD) is a neuro-motor ailment that strikes adults in their older life and results in both motor and non-motor impairments. In neuronal and glial cells, PD has recently been linked to a dysregulated autophagic system and cerebral inflammation. Chloroquine (CQ), an anti-malarial drug, has been demonstrated to suppress autophagy in a variety of diseases, including cerebral ischemia, Alzheimers disease (AD), and Traumatic brain injury (TBI), while its involvement in PD is still unclear. BALBc mice were randomly allocated to one of four groups 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), CQ treatment with or without MPTP, or control. The CQ treatment group received CQ (intraperitoneally, 8 mgkg body weight) after 1 h of MPTP induction on day 1, and it lasted for 7 days. CQ therapy preserves dopamine levels stable, inhibits tyrosine hydroxylase (TH) positive dopaminergic cell death, and lowers oxidative stress. CQ reduces the behavioural, motor, and cognitive deficits caused by MPTP after injury. Furthermore, CQ therapy slowed aberrant neuronal autophagy (microtubule-associated protein-1 light chain 3B LC3B Beclin1) and lowered expression levels of the inflammatory cytokines interleukin 1 (IL-1β) and tumour necrosis factor (TNF-α) in the mice brain. In addition, CQs antioxidant and anti-inflammatory effects were also tested in MPTP-mediated cell death in PC12 cells, demonstrating that CQ has a neurorestorative impact by successfully rescuing MPTP-induced ROS generation and cell loss. Our findings show that CQs can help to prevent dopaminergic degeneration and improve neurological function after MPTP intoxication by lowering the harmful effects of neuronal autophagy and cerebral inflammation.
|
36,715,748 |
Transient epileptic amnesia a retrospective cohort study of 127 cases, including CSF amyloid and tau features.
|
Transient epileptic amnesia (TEA) is a late-onset epilepsy syndrome encompassing transient iterative amnesias and interictal cognitive impairment, two features that overlap with incipient neurodegenerative dementias. We, therefore, examined the yield of CSF amyloid and tau biomarkers in TEA. In this retrospective study, 127 TEA patients with unremarkable imaging findings were divided into 2 groups, namely, CSF (n 71) and no-CSF (n 56). Both were compared for demographics medical history baseline neurological, cognitive, and behavioral features baseline mesial temporal lobe atrophy and cognitive follow-up at a median of 13 months. CSF samples were examined for amyloid β-42 peptide as well as phospho-tau and total-tau levels. At baseline, the CSF-TEA group had significantly (p < 0.01) more frequent mild parkinsonism (42.9% vs. 20%) and cognitive concerns (31% vs. 10.7%), a more blunted sense of smell (34.3% vs. 9.4%), a lower baseline MMSE score (27 vs. 28.9), a more frequent amnestic mild cognitive impairment profile (69% vs. 42.6%), and more atrophic hippocampal changes. At follow-up, the CSF-TEA group had significantly (p < 0.01) lower MMSE scores (27.8 vs. 28.9). CSF analyses revealed amyloid andor tau changes in 27 patients (38%), including an Alzheimers disease (AD) profile in 17 (24%). This study shows a good diagnostic value of CSF sampling in a specific population of TEA with characteristics suggestive of incipient degenerative diseases (i.e., red flags). It argues for TEA being the inaugurating feature in some cases of AD. More broadly, our results suggest an etiological heterogeneity in TEA.
|
36,715,553 |
Anesthetic-loaded nanodroplets with focused ultrasound reduces agitation in Alzheimers mice.
|
Alzheimers disease (AD) is often associated with neuropsychiatric symptoms, including agitation and aggressive behavior. These symptoms increase with disease severity, ranging from 10% in mild cognitive impairment to 50% in patients with moderate-to-severe AD, pose a great risk for self-injury and injury to caregivers, result in high rates of institutionalization and great suffering for patients and families. Current pharmacological therapies have limited efficacy and a high potential for severe side effects. Thus, there is a growing need to develop novel therapeutics tailored to safely and effectively reduce agitation and aggressive behavior in AD. Here, we investigate for the first time the use of focused ultrasound combined with anesthetic-loaded nanodroplets (nanoFUS) targeting the amygdala (key structure in the neurocircuitry of agitation) as a novel minimally invasive tool to modulate local neural activity and reduce agitation and aggressive behavior in the TgCRND8 AD transgenic mice. Male and female animals were tested in the resident-intruder (i.e., aggressive behavior) and open-field tests (i.e., motor agitation) for baseline measures, followed by treatment with active- or sham-nanoFUS. Behavioral testing was then repeated after treatment. Active-nanoFUS neuromodulation reduced aggressive behavior and agitation in male mice, as compared to sham-treated controls. Treatment with active-nanoFUS increased the time male mice spent in social-non-aggressive behaviors. Our results show that neuromodulation with active-nanoFUS may be a potential therapeutic tool for the treatment of neuropsychiatric symptoms, with special focus on agitation and aggressive behaviors. Further studies are necessary to establish cellular, molecular and long-term behavioral changes following treatment with nanoFUS.
|
36,715,191 |
Mapping cerebral atrophy and hypometabolism on
|
Studies are lacking in evaluating brain atrophy patterns in the Malaysian population. This study aimed to compare the patterns of cerebral atrophy and impaired glucose metabolism on One-way ANOVA indicated that the means were equal for TIV, F(2,11) 1.310, p0.309, GMV, F(2,11) 0.923, p0.426, WMV, F(2,11) 0.158, p0.856 and CSF, F(2,11) 1.495 p0.266. Pearson correlations of GM, WM and CSF volume between HC and AD groups indicated the presence of brain atrophy in GM (p-0.610, p<0.0001), WM (p-0.178, p0.034) and TIV (p-0.374, p0.042) but showed increased CSF volume (p0.602, p<0.0001). Voxels analysis of the 18FFDG PET template revealed that GM atrophy differs significantly between healthy control and AD (p<0.0001). Zscore comparisons in the region of GM WM were shown to distinguish AD patients from healthy controls at the prefrontal cortex and parahippocampal gyrus. The atrophy rate within each ROI is significantly different between groups (c We recommend a reliable method in measuring the brain atrophy and locating the patterns of hypometabolism using a group-specific template registered to a quantitatively validated KNE96 group-specific template. The studied regions together with neuropsychological test approach is an effective method for the determination of AD severity in a Malaysian population.
|
36,715,085 |
Neuropathology of microbleeds in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
|
Cerebral microbleeds (CMBs) detected on magnetic resonance imaging are common in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The neuropathologic correlates of CMBs are unclear. In this study, we characterized findings relevant to CMBs in autopsy brain tissue of 8 patients with genetically confirmed CADASIL and 10 controls within the age range of the CADASIL patients by assessing the distribution and extent of hemosideriniron deposits including perivascular hemosiderin leakage (PVH), capillary hemosiderin deposits, and parenchymal iron deposits (PID) in the frontal cortex and white matter, basal ganglia and cerebellum. We also characterized infarcts, vessel wall thickening, and severity of vascular smooth muscle cell degeneration. CADASIL subjects had a significant increase in hemosideriniron deposits compared with controls. This increase was principally seen with PID. Hemosideriniron deposits were seen in the majority of CADASIL subjects in all brain areas. PVH was most pronounced in the frontal white matter and basal ganglia around small to medium sized arterioles, with no predilection for the vicinity of vessels with severe vascular changes or infarcts. CADASIL subjects have increased brain hemosideriniron deposits but these do not occur in a periarteriolar distribution. Pathogenesis of these lesions remains uncertain.
|
36,715,000 |
Apathy and depression in mild cognitive impairment distinct longitudinal trajectories and clinical outcomes.
|
Apathy is a common symptom in mild cognitive impairment (MCI) and may predict progression to dementia. Little research, however, has investigated the longitudinal trajectory of apathy in patients with MCI or controlled for depression, which can mimic apathy, when examining its clinical correlates. The current study sought to address these issues. A prospective longitudinal study was conducted over 3 years. Nine memory clinics around Australia. One hundred and eighty-five patients with MCI at baseline. Measures of cognition, function, neuropsychiatric symptoms, caregiver burden, and medication use were completed annually with additional assessments at 3 and 6 months. Patients were also assessed for dementia by expert clinicians at these time points. Of 164 patients who completed measures of neuropsychiatric symptoms, 59 (36.0%) had apathy and 61 (37.2%) had depression. The proportion affected by apathy and overall apathy scores increased over time, in contrast to measures of depression, which remained relatively stable. Apathy was associated with incident dementia and worse cognition, function, neuropsychiatric symptoms, and caregiver burden independent of both depression and incident dementia. Depression was associated with worse function, albeit to lesser degree than apathy, and neuropsychiatric symptoms. Apathy increases in MCI and is associated with worse clinical outcomes. These findings provide further evidence for apathy as a marker of clinical decline in older people and poorer outcomes across neurocognitive disorders.
|
36,714,996 |
Characteristics of very late-onset schizophrenia-like psychosis classified with the biomarkers for Alzheimers disease a retrospective cross-sectional study.
|
We aimed to investigate the association between very late-onset schizophrenia-like psychosis (VLOSLP), a schizophrenia spectrum disorder with an onset of ≥60 years, and Alzheimers disease (AD) using biomarkers. Retrospective cross-sectional study. Neuropsychology clinic of Osaka University Hospital in Japan. Thirty-three participants were classified into three groups eight AD biomarker-negative VLOSLP (VLOSLP-AD), nine AD biomarker-positive VLOSLP (VLOSLPAD), and sixteen amnestic mild cognitive impairment due to AD without psychosis (aMCI-PAD) participants. Phosphorylated tau levels in the cerebrospinal fluid and Those in both VLOSLP-AD and AD groups scored higher than those in aMCI-PAD in WMS-R LM I. On the other hand, VLOSLPAD participants scored in between the other two groups in the WMS-R LM II, with only VLOSLP-AD participants scoring significantly higher than aMCI-PAD participants. There were no significant differences in sex distribution and MMSE scores among the three groups or in the subtype of psychotic symptoms between VLOSLP-AD and AD participants. Four VLOSLP-AD and five VLOSLPAD participants harbored partition delusions. Delusion of theft was shown in two VLOSLP-AD patients and five VLOSLPAD patients. Some VLOSLP patients had AD pathology. Clinical characteristics were different between AD biomarker-positive and AD biomarker-negative VLOSLP, which may be helpful for detecting AD pathology in VLOSLP patients.
|
36,714,990 |
Neuropsychiatric symptoms and their neural correlates in individuals with mild cognitive impairment.
|
Neuropsychiatric symptoms are common in subjects with MCI and associated with higher risk of progression to AD. The cognitive and neuroanatomical correlates of neuropsychiatric symptoms in MCI have not been fully elucidated. In this study, we sought to evaluate the association between neuropsychiatric symptoms, cognitive function, regional tau deposition, and brain volumes in MCI subjects. A total of 233 MCI and 305 healthy comparisons were selected from the ADNI-3 cohort. All the subjects underwent a comprehensive neuropsychological assessment, volumetric MR brain scan, and Flortaucipir PET for in vivo assessment of regional tau deposition. Prevalence of neuropsychiatric symptoms was evaluated by means of the NPI questionnaire. Multivariate analyses of variance were used to detect differences in cognitive and imaging markers in MCI subjects with and without neuropsychiatric symptoms. 61.4% MCI subjects showed at least one neuropsychiatric symptom, with the most prevalent ones being depression (26.1%), irritability (23.6%), and sleep disturbances (23.6%). There was a significant effect of neuropsychiatric symptoms on cognitive tests of frontal and executive functions. MCI subjects with neuropsychiatric symptoms showed reduced brain volumes in the orbitofrontal and posterior cingulate cortices, while no effects were detected on regional tau deposition. Posterior cingulate cortex volume was the only predictor of global neuropsychiatric burden in this MCI population. Neuropsychiatric symptoms occur early in the AD trajectory and are mainly related to defects of control executive abilities and to the reduction of gray matter volume in the orbitofrontal and posterior cingulate cortices. A better understanding of the cognitive and neuroanatomical mechanisms of neuropsychiatric symptoms in MCI could help develop more targeted and efficacious treatment alternatives.
|
36,714,789 |
Transcranial Color-Coded Doppler Cerebral Hemodynamics Following Aerobic Exercise Training Outcomes From a Pilot Randomized Clinical Trial.
|
An active lifestyle with regular exercise is thought to decrease or delay the onset of Alzheimer dementia through increasing blood flow to the brain. We examined the mean flow velocity (MFV) and pulsatility index (PI) in the middle cerebral arteries of individuals randomized into two groups-a Usual Physical Activity (UPA) group and an Enhanced Physical Activity (EPA) exercise intervention group-to determine if exercise training is related to changes in cerebral blood flow. We examined 23 participants, randomized into a UPA group (n12) and an EPA group (n11), with transcranial color-coded Doppler (TCCD) and cardiorespiratory fitness (VO There was no significant change in MFV or PI in the UPA group or the EPA group (p-values >0.05) between baseline and 26 weeks the change between the UPA and EPA groups was also not significant (p0.603). There was no evidence of an association between change in VO This study did not demonstrate evidence of a significant change in the MFV in the middle cerebral arteries or evidence of a significant change in the PI between UPA and EPA groups. Future studies should be performed in larger cohorts and should consider use of personalized exercise programs to maximize understanding of how cerebrovascular hemodynamics change in structure and function with exercise for adults at risk for Alzheimer dementia.
|
36,714,670 |
Clinical profile of dermatitis neglecta with special emphasis on psychiatric comorbidities A case series of 22 patients from Eastern India.
|
Dermatitis neglecta (DN), first described by Poskitt
|
36,714,419 |
Retracted Inhibiting Autophagy Pathway of PI3KAKTmTOR Promotes Apoptosis in SK-N-SH Cell Model of Alzheimers Disease.
|
This retracts the article DOI 10.115520226069682..
|
36,713,928 |
Cell-type-specific synaptic modulation of mAChR on SST and PV interneurons.
|
The muscarinic acetylcholine receptor (mAChR) antagonist, scopolamine, has been shown to have a rapid antidepressant effect. And it is believed that GABAergic interneurons play a crucial role in this action. Therefore, characterizing the modulation effects of mAChR on GABAergic interneurons is crucial for understanding the mechanisms underlying scopolamines antidepressant effects. In this study, we examined the effect of mAChR activation on the excitatory synaptic transmissions in two major subtypes of GABAergic interneurons, somatostatin (SST)- and parvalbumin (PV)-expressing interneurons, in the anterior cingulate cortex (ACC). We found that muscarine, a mAChR agonist, non-specifically facilitated the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both SST and PV interneurons. Scopolamine completely blocked the effects of muscarine, as demonstrated by recovery of sESPCs and mEPSCs in these two types of interneurons. Additionally, individual application of scopolamine did not affect the EPSCs of these interneurons. In inhibitory transmission, we further observed that muscarine suppressed the frequency of both spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in SST interneurons, but not PV interneurons. Interestingly, scopolamine directly enhanced the frequency of both sIPSCs and mIPSCs mainly in SST interneurons, but not PV interneurons. Overall, our results indicate that mAChR modulates excitatory and inhibitory synaptic transmission to SST and PV interneurons within the ACC in a cell-type-specific manner, which may contribute to its role in the antidepressant effects of scopolamine.
|
36,713,907 |
Performance evaluation of automated white matter hyperintensity segmentation algorithms in a multicenter cohort on cognitive impairment and dementia.
|
White matter hyperintensities (WMH), a biomarker of small vessel disease, are often found in Alzheimers disease (AD) and their advanced detection and quantification can be beneficial for research and clinical applications. To investigate WMH in large-scale multicenter studies on cognitive impairment and AD, appropriate automated WMH segmentation algorithms are required. This study aimed to compare the performance of segmentation tools and provide information on their application in multicenter research. We used a pseudo-randomly selected dataset ( Across tools, segmentation performance was moderate for global WMH volume and number of detected lesions. After retraining on a DELCODE subset, the deep learning algorithm sysumedia showed the highest performances with an average Dices coefficient of 0.702 (±0.109 SD) for volume and a mean F1-score of 0.642 (±0.109 SD) for the number of lesions. The intra-class correlation was excellent for all algorithms (>0.9) but BIANCA (0.835). Performance improved with high WMH burden and varied across brain regions. To conclude, the deep learning algorithm, when retrained, performed well in the multicenter context. Nevertheless, the performance was close to traditional methods. We provide methodological recommendations for future studies using automated WMH segmentation to quantify and assess WMH along the continuum of cognitive impairment and AD dementia.
|
36,712,694 |
Research trends and hotspots of neurodegenerative diseases employing network pharmacology A bibliometric analysis.
| null |
36,712,678 |
Integrated untargeted and targeted metabolomics to reveal therapeutic effect and mechanism of
| null |
36,712,676 |
Miracle fruit seed as a potential supplement for the treatment of learning and memory disorders in Alzheimers disease.
|
Currently, the treatment of Alzheimers disease (AD) is still at the stage of symptomatic treatment due to lack of effective drugs. The research on miracle fruit seeds (MFSs) has focused on lipid-lowering and antidiabetic effects, but no therapeutic effects have been reported in AD. The purpose of this study was to provide data resources and a potential drug for treatment of AD. An AD mouse model was established and treated with MFSs for 1 month. The Morris water maze test was used to assess learning memory function in mice. Nissl staining was used to demonstrate histopathological changes. MFSs were found to have therapeutic implications in the AD mouse model, as evidenced by improved learning memory function and an increase in surviving neurons. To explore the mechanism of MFSs in treating AD, network pharmacological approaches, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking studies were carried out. Based on the network pharmacology strategy, 74 components from MFS corresponded to 293 targets related to the AD pathology. Among these targets, AKT1, MAPK3, ESR1, PPARG, PTGS2, EGFR, PPARA, CNR1, ABCB1, and MAPT were identified as the core targets. According to the relevant number of core targets, cis-8-octadecenoic acid, cis-10-octadecenoic acid, 2-dodecenal, and tetradecane are likely to be highly correlated with MFS for AD. Enrichment analysis indicated the common targets mainly enriched in AD and the neurodegeneration-multiple disease signaling pathway. The molecular docking predictions showed that MFSs were stably bound to core targets, specifically AKT1, EGFR, ESR1, PPARA, and PPARG. MFSs may play a therapeutic role in AD by affecting the insulin signaling pathway and the Wnt pathway. The findings of this study provide potential possibilities and drug candidates for the treatment of AD.
|
36,712,655 |
Corrigendum R-carvedilol, a potential new therapy for Alzheimers disease.
|
This corrects the article DOI 10.3389fphar.2022.1062495..
|
36,712,573 |
Trait Mindfulness Is Associated With Less Amyloid, Tau, and Cognitive Decline in Individuals at Risk for Alzheimers Disease.
|
Mindfulness, defined as nonjudgmental awareness of the present moment, has been associated with an array of mental and physical health benefits. Mindfulness may also represent a protective factor for Alzheimers disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in older adults at risk for AD dementia. Measures of trait mindfulness, longitudinal cognitive assessments, and amyloid-β (Aβ) and tau positron emission tomography scans were collected in 261 nondemented older adults with a family history of AD dementia from the PREVENT-AD (Pre-symptomatic Evaluation of Experimental or Novel Treatments for AD) observational cohort study. Multivariate partial least squares analyses were used to examine relationships between combinations of different facets of trait mindfulness and 1) cognitive decline, 2) Aβ, and 3) tau. Higher levels of mindful nonjudgment, describing, and nonreactivity were associated with less cognitive decline in attention, global cognition, and immediate and delayed memory. Higher levels of mindful nonjudgment and nonreactivity were related to less Aβ positron emission tomography signal in bilateral medial and lateral temporoparietal and frontal regions. Higher levels of mindful acting with awareness, describing, nonjudgment, and nonreactivity were associated with less tau positron emission tomography signal in bilateral medial and lateral temporal regions. Trait mindfulness was associated with less cognitive decline and less Aβ and tau in the brain in older adults at risk for AD dementia. Longitudinal studies examining the temporal relationship between trait mindfulness and AD markers, along with mindfulness intervention studies, will be important for further clarifying the potential protective benefits of mindfulness on AD risk.
|
36,712,428 |
Blood pressure and Alzheimers disease A review of meta-analysis.
|
Alzheimers disease (AD) is a neurological disorder of unknown cause, resulting in the death of brain cells. Identifying some of the modifiable risk factors for AD could be crucial for primary prevention and could lead to a reduction in the incidence of AD. This study aimed to perform a meta-meta-analysis of studies in order to assess the effect of blood pressure (BP) on the diagnosis of AD. The search was restricted to meta-analyses assessing high systolic BP (SBP) and diastolic BP (DBP) and AD. We applied the PRISMA guidelines. A total of 214 studies were identified from major databases. Finally, five meta-analyses (52 studies) were analyzed in this review. Results confirm that high SBP is associated with AD. The exploration of parameters (sex, age, study design, region, and BP measurements) shows that only region significantly moderates the relationship between BP and AD. Asian people are those whose SBP levels >140 mmHg are associated with AD. BP is associated with AD in both people aged ≤65 years and those aged ≥65 years and in cross-sectional and longitudinal studies. In the case of DBP, only women are at a higher risk of AD, particularly when its levels are >90. SBP is associated with both cerebrovascular disease and AD. Therefore, future studies should use other uncontrolled factors, such as cardiovascular diseases, diabetes, and stroke, to explain the relationship between SBP and AD.
|
36,712,184 |
Sterubin protects against chemically-induced Alzheimers disease by reducing biomarkers of inflammation- IL-6 IL-β TNF-α and oxidative stress- SODMDA in rats.
|
Sterubin, a flavanone is an active chemical compound that possesses neuroprotective activity. The current investigation was intended to assess the sterubin effect in scopolamine-activated Alzheimers disease. The rats were induced with scopolamine (1.5 mgkg) followed by treatment with sterubin (10 mgkg) for 14 days. Behavioural analysis was predictable by the Y-maze test and Morris water test. Biochemical variables like nitric oxide acetylcholinesterase, Choline acetyltransferase, antioxidant markers like superoxide dismutase, glutathione transferase, malondialdehyde, catalase, and myeloperoxidase activity, neuroinflammatory markers such as tumor necrosis factor-alpha, nuclear factor kappa B, interferon-gamma, interleukin (IL-1β), and IL-6 were measured. The result stated that sterubin reversed the oxidative stress parameters, increased motor performance, and lowered the inflammatory markers in scopolamine-induced rats. The study demonstrated that sterubin possesses neuroprotective, anti-inflammatory, and antioxidant properties which can be used as a beneficial medication in AD.
|
36,712,104 |
Applying joint graph embedding to study Alzheimers neurodegeneration patterns in volumetric data.
|
Neurodegeneration measured through volumetry in MRI is recognized as a potential Alzheimers Disease (AD) biomarker, but its utility is limited by lack of specificity. Quantifying spatial patterns of neurodegeneration on a whole brain scale rather than locally may help address this. In this work, we turn to network based analyses and extend a graph embedding algorithm to study morphometric connectivity from volume-change correlations measured with structural MRI on the timescale of years. We model our data with the multiple random eigengraphs framework, as well as modify and implement a multigraph embedding algorithm proposed earlier to estimate a low dimensional embedding of the networks. Our version of the algorithm guarantees meaningful finite-sample results and estimates maximum likelihood edge probabilities from population-specific network modes and subject-specific loadings. Furthermore, we propose and implement a novel statistical testing procedure to analyze group differences after accounting for confounders and locate significant structures during AD neurodegeneration. Family-wise error rate is controlled at 5% using permutation testing on the maximum statistic. We show that results from our analysis reveal networks dominated by known structures associated to AD neurodegeneration, indicating the framework has promise for studying AD. Furthermore, we find network-structure tuples that are not found with traditional methods in the field.
|
36,712,054 |
Functional connectivity favors hyperactivity leading to synapse loss in amyloidosis.
|
Hyperactivity is observed in early Alzheimers disease (AD) in multiple brain regions, including the visual cortex. We recently found that the postsynaptic structures favor visual cortex hyperactivity, which disrupts functional connectivity and leads to visual recognition memory deficits in a mouse AD model. It is unclear whether presynaptic structures also favor hyperactivity and whether hyperactivity depends on the target or source of presynaptic terminals. In addition, it is not well understood whether the functional connectivity of brain regions under nonpathological conditions predicts their hyperactivity in amyloid pathology. We used c-Fos immunolabeling under resting state conditions to map brain-wide neural activity and performed network analysis. We also quantified excitatory and inhibitory presynaptic terminals in hyperactive and non-hyperactive brain regions.We found that hyperactivity in the visual network originates in the cortex, and brain regions highly connected to the primary visual cortex in nonpathological conditions tend to be hyperactive in amyloid pathology. Immunolabeling presynaptic terminals from subcortical and cortical neurons show that the source rather than the target brain regions determine the vulnerability of synapses. Furthermore, we observed a reduction in presynaptic structures selectively in the hyperactive region, indicating presynaptic changes are unfavorable to hyperactivity. Brain regions with higher functional connectivity under nonpathological conditions are vulnerable to hyperactivity in amyloid pathology. Furthermore, presynapse loss may serve as an adaptation to maintain neuronal activity homeostasis.
|
36,712,026 | null |
Alzheimers disease (AD) is the most common cause of dementia among older adults.
|
36,711,965 |
Chronic seizure-induced serotonin pathway dysregulation coincides with mortality in Alzheimers disease mouse models.
|
People with early-onset Alzheimers disease (AD) with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants are at elevated seizure risk within 5 years of diagnosis. Further, seizures in AD may increase neuropsychiatric comorbidity burden. We thus hypothesized that disruptions in serotonin pathway-related protein expression was impacted by 60 Hz corneal kindled seizures in an AD-genotype-related manner. Male and female 2-3-month-old APPPS1, PSEN2-N141I, and respective transgenic (Tg) control mice underwent corneal or sham kindling for 2 weeks until reaching kindling criterion defined as five consecutive Racine stage 5 seizures. Chronic seizure-induced changes in serotonin pathway protein expression in hippocampus were then quantified by western blot. Young female APPPS1 mice kindled significantly faster than Tg-controls, whereas PSEN2-N141I mice kindled no differently versus their Tg controls. APPPS1 mice subjected to corneal kindling were at extremely elevated mortality risk relative to kindled Tg-controls, as well as sham-kindled APPPS1 and Tg-control mice, whereas PSEN2-N141I mice were not adversely affected by kindling. Kindled APPPS1 mice demonstrated a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression versus kindled Tg- and sham-kindled APPPS1 groups. Serotonin pathway protein expression in PSEN2-N141I mice was unchanged from Tg. Importantly, all changes in serotonin pathway protein expression in kindled APPPS1 mice occurred in the absence of amyloid β (Aβ) deposition. The co-occurrence of seizures in the APPPS1 mouse is sufficient to evoke unexpected mortality well ahead of pathological Aβ deposition synonymous with a symptomatic AD model. The presence of another AD-associated variant (PSEN2-N141) does not lead to seizure-induced mortality, suggesting that AD-associated risk genes differentially influence vulnerability to chronic seizure-associated mortality. Further, disruptions in serotonin pathway synthesis coincide with heightened mortality risk exclusively in adult APPPS1 mice, suggesting a possible non-canonical sudden unexpected death in epilepsy (SUDEP)-related phenotype. Sudden unexpected death is a devasting consequence of uncontrolled epilepsySerotonin pathway dysfunction may increase risk of premature mortality in epilepsyAPPPS1 mice are at higher risk of seizure-induced mortality versus other AD modelsSeizures downregulate hippocampal serotonin pathway proteins solely in APPPS1 miceSeizure-induced mortality in APPPS1 mice does not require amyloid β accumulation.
|
36,711,924 |
Defective phagocytosis leads to neurodegeneration through systemic increased innate immune signaling.
|
In nervous system development, disease and injury, neurons undergo programmed cell death, leaving behind cell corpses that are removed by phagocytic glia. Altered glial phagocytosis has been implicated in several neurological diseases including Alzheimers disease, Parkinsons disease, and traumatic brain injury. To untangle the links between glial phagocytosis and neurodegeneration, we investigated
|
36,711,875 |
Oleoylethanolamide facilitates PPARa and TFEB signaling and attenuates Ab pathology in a mouse model of Alzheimers disease.
|
Emerging evidence implicates impaired microglia function and dysregulation of lipid metabolism in Alzheimers disease (AD). Oleoylethanolamide (OEA), an endogenous lipid and PPARα agonist, has been shown to promote longevity in
|
36,711,847 |
Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimers Disease.
|
Cerebrovascular damage coexists with Alzheimers disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34CD133 co-expressions had a dose-dependent association with decreased AD risk (HR 0.67, 95% CI 0.46-0.96, p 0.03) after adjusting for age, sex, years of education, and
|
36,711,782 |
Aging and Alzheimers Disease Have Dissociable Effects on Medial Temporal Lobe Connectivity.
|
Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimers disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimers disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimers and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighborhood - the Anterior-Temporal and Posterior-Medial brain networks - in normal agers, individuals with preclinical Alzheimers disease, and patients with Mild Cognitive Impairment or mild dementia due to Alzheimers disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted U-shaped relationship between functional connectivity and Alzheimers stage. According to our results, the preclinical phase of Alzheimers disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbors in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimers disease. Instead, patients with symptomatic Alzheimers disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions (1) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age (2) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age and, (3) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimers disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging vs. Alzheimers disease.
|
36,711,777 |
Sex difference in the associations of socioeconomic status, cognitive function and brain volume with dementia in old adults Findings from the OASIS study.
|
Sex differences in the association of cognitive function and imaging measures with dementia have not been fully investigated while sex-based investigation of dementia has been discussed. Understanding sex differences in the dementia-related socioeconomic, cognitive, and imaging measurements is important for uncovering sex-related pathways to dementia and facilitating early diagnosis, family planning, and cost control. We selected data from the Open Access Series of Imaging Studies with longitudinal measurements of brain volumes on 150 individuals aged 60 to 96 years. Dementia status was determined using the Clinical Dementia Rating (CDR) scale, and Alzheimers disease was diagnosed as a CDR of ≥ 0.5. Generalized estimating equation models were used to estimate the associations of socioeconomic, cognitive and imaging factors with dementia in men and women. Lower education affected dementia more in women than in men. Age, education, Mini-Mental State Examination (MMSE), and normalized whole-brain volume (nWBV) were associated with dementia in women whereas only MMSE and nWBV were associated with dementia in men. Lower socioeconomic status was associated with a reduced estimated total intracranial volume in men, but not in women. Ageing and lower MMSE scores were associated with reduced nWBV in both men and women. The association between education and prevalence of dementia differs in men and women. Women may have more risk factors for dementia than men.
|
36,711,772 |
Unique Transcriptional Signatures Correlate with Behavioral and Psychological Symptom Domains in Alzheimers Disease.
|
Despite the significant burden, cost, and worse prognosis of Alzheimers Disease (AD) with Behavioral and Psychological Symptoms of Dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our sample Affective, Apathy, Agitation, and Psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem Anterior Cingulate Cortex (ACC) tissue. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of DEGs, most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted Gene Co-Expression Network Analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly correlated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.
|
36,711,734 |
Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimers disease.
|
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimers disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients. In this study, we investigated the levels of Angiotensin I Converting Enzyme 2 (ACE2), the main entry receptor of SARS-COV-2 in cells, in
|
36,711,721 |
The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus.
|
Background The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases. Methods Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66-104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ANOVA was used to test the effect of major dementia risk alleles in the
|
36,711,717 |
Automatic analysis of skull thickness, scalp-to-cortex distance and association with age and sex in cognitively normal elderly.
|
Personalized neurostimulation has been a potential treatment for many brain diseases, which requires insights into brainskull geometry. Here, we developed an open source efficient pipeline BrainCalculator for automatically computing the skull thickness map, scalp-to-cortex distance (SCD), and brain volume based on T
|
36,711,310 |
Revealing genetic links of Type 2 diabetes that lead to the development of Alzheimers disease.
|
A factor leading to Alzheimers Disease (AD), portrayed by peripheral insulin resistance, is Type 2 diabetes mellitus (T2D). The likelihood of T2D cases would be at boosted danger in alternating AD cases has severe social consequences. Several genes have been detected via gene expression profiling or different techniques despite the consideration of the utility of numerous of these genes stays insufficient. This project is designed to uncover the mutual genomics motifs between AD and T2D via non-negative matrix factorization (NMF) of differentially expressed genes (DEGs) of T2D Mellitus of human cortical neurons of the neurovascular unit gene expression data. A rank factorization value is calculated by employing the combination of the NMF model with the unit invariant knee (UIK) point method. The metagenes are further determined by remarking the enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) enrichment tools. In this study, the most highly expressed genes of metagenes are subjected to protein-protein interaction (PPI) network study to discover the most significant biomarkers of T2D Mellitus in the ageing brain. We screened the most important shared genes (CDKN1A, COL22A1, EIF4A, GFAP, SLC1A1, and VIM) and essential human molecular pathways that motivate these diseases. The study aimed to validate the most significant hub genes using network-based methods which detected the corresponding relationship between AD and T2D. Using in silico tools, the computational pipeline has broadly examined transformed pathways and discovered promising biomarkers and drug targets. We validated the most significant hub genes using network-based methods which detected the corresponding relationship between AD and T2D. These consequences on brain cells hypothetically reserve to diabetic Alzheimers so-called type 3 diabetes (T3D) and may offer promising methodologies for curative intrusion.
|
36,711,212 |
Task aftereffect reorganization of resting state functional brain networks in healthy aging and mild cognitive impairment.
|
The view of the human brain as a complex network has led to considerable advances in understanding the brains network organization during rest and task, in both health and disease. Here, we propose that examining brain networks within the task aftereffect model, in which we compare resting-state networks immediately before and after a cognitive engagement task, may enhance differentiation between those with normal cognition and those with increased risk for cognitive decline. We validated this model by comparing the pre- and post-task resting-state functional network organization of neurologically intact elderly and those with mild cognitive impairment (MCI) derived from electroencephalography recordings. We have demonstrated that a cognitive task among MCI patients induced, compared to healthy controls, a significantly higher increment in global network integration with an increased number of vertices taking a more central role within the network from the pre- to post-task resting state. Such modified network organization may aid cognitive performance by increasing the flow of information through the most central vertices among MCI patients who seem to require more communication and recruitment across brain areas to maintain or improve task performance. This could indicate that MCI patients are engaged in compensatory activation, especially as both groups did not differ in their task performance. In addition, no significant group differences were observed in network topology during the pre-task resting state. Our findings thus emphasize that the task aftereffect model is relevant for enhancing the identification of network topology abnormalities related to cognitive decline, and also for improving our understanding of inherent differences in brain network organization for MCI patients, and could therefore represent a valid marker of cortical capacity andor cortical health.
|
36,711,209 |
Hippocampal functional connectivity across age in an
|
Alzheimers disease (AD) is a progressive neurodegenerative disease. The early processes of AD, however, are not fully understood and likely begin years before symptoms manifest. Importantly, disruption of the default mode network, including the hippocampus, has been implicated in AD. To examine the role of functional network connectivity changes in the early stages of AD, we performed resting-state functional magnetic resonance imaging (rs-fMRI) using a mouse model harboring three familial AD mutations ( We observed higher interhemispheric functional connectivity (FC) in the hippocampus across age. This was reduced, however, in APPKI mice in later age. Further, we observed loss of hemispheric asymmetry in FC in APPKI mice. Together, this suggests that there are early changes in hippocampal FC prior to heavy onset of amyloid β plaques, and which may be clinically relevant as an early biomarker of AD.
|
36,711,203 |
Association of inflammatory bowel disease and related medication exposure with risk of Alzheimers disease An updated meta-analysis.
|
Chronic systemic inflammation may be associated with neurocognitive decline, but the relationships between inflammatory bowel disease and related medications and the risk of Alzheimers disease remain unclear. We performed a meta-analysis to evaluate the associations of ulcerative colitis, Crohns disease and related medications with risk of Alzheimers disease. We identified cohort and case-control studies by searching PubMed, Embase and Web of Science up to August 2022. Seven eligible studies with 20,174 cases of Alzheimers disease were included in the meta-analysis. Six studies reported the association between ulcerative colitis and risk of Alzheimers disease five studies reported the association between Crohns disease and risk of Alzheimers disease. Meta-analysis combining these studies did not reveal any significant association of ulcerative colitis or Crohns disease with risk of Alzheimers disease. The pooled relative risks were 1.16 (95%CI 0.96, 1.41) and 1.17 (95%CI 0.84, 1.62) for ulcerative colitis and Crohns disease, respectively. High heterogeneity was detected across the studies. Of note, there was an inverse association between inflammatory bowel disease related medication exposure and risk of Alzheimers disease. The pooled relative risk of three studies for Alzheimers disease was 0.86 (95%CI 0.75, 0.99). No publication bias was detected. This study does not support the association of ulcerative colitis and Crohns disease with the risk of Alzheimers disease. However, medications for the treatment of inflammatory bowel disease might be associated with a lower risk of Alzheimers disease.
|
36,711,200 |
Differences in structural MRI and diffusion tensor imaging underlie visuomotor performance declines in older adults with an increased risk for Alzheimers disease.
|
Visuomotor impairments have been demonstrated in preclinical AD in individuals with a positive family history of dementia and APOE e4 carriers. Previous behavioral findings have also reported sex-differences in performance of visuomotor tasks involving a visual feedback reversal. The current study investigated the relationship between grey and white matter changes and non-standard visuomotor performance, as well as the effects of APOE status, family history of dementia, and sex on these brain-behavior relationships. Older adults ( In APOE e4 carriers, grey and white matter structural measures were associated with visuomotor performance. Regression analyses showed that visuomotor deficits were predicted by lower grey matter thickness and volume in areas of the medial temporal lobe previously implicated in visuomotor control (entorhinal and parahippocampal cortices). This finding was replicated in the diffusion data, where regression analyses revealed that lower white matter integrity (lower FA, higher MD, higher RD, higher AxD) was a significant predictor of worse visuomotor performance in the forceps minor, forceps major, cingulum, inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and uncinate fasciculus (UF). Some of these tracts overlap with those important for visuomotor integration, namely the forceps minor, forceps major, SLF, IFOF, and ILF. These findings suggest that measuring the dysfunction of brain networks underlying visuomotor control in early-stage AD may provide a novel behavioral target for dementia risk detection that is easily accessible, non-invasive, and cost-effective. The results also provide insight into the structural differences in inferior parietal lobule that may underlie previously reported sex-differences in performance of the visual feedback reversal task.
|
36,710,967 |
Effects of Qi-Fu-Yin on aging of APPPS1 transgenic mice by regulating the intestinal microbiome.
|
Alzheimers disease is the most common form of dementia and closely related to aging. Qi-Fu-Yin is widely used to treat dementia, but its anti-aging effects is unknown. We used 11-month-old APPPS1 transgenic mice for behavioral tests to observe the changes in cognitive function and age-related symptoms after Qi-Fu-Yin treatment. Fecal samples were collected for 16sRNA sequencing and metagenomic sequencing. Differences among the groups of intestinal microbiota and the associations with aging and intestinal microbiota were analyzed based on the results. Here we found that Qi-Fu-Yin improved the ability of motor coordination, raised survival rate and prolonged the survival days under cold stress stimulation in aged APP PS1 transgenic mice. Our data from 16sRNA and metagenomic sequencing showed that at the Family level, the intestinal microbiota was significantly different among wild-type mice, APPPS1 transgenic mice and the Qi-Fu-Yin group by PCA analysis. Importantly, Qi-Fu-Yin improved the functional diversity of the major KEGG pathways, carbohydrate-active enzymes, and major virulence factors in the intestinal flora of APPPS1 transgenic mice. Among them, the functions of eight carbohydrate-active enzymes (GT2Glycostransf2, GT4, GT41, GH2, CE1, CE10, CE3, and GH24) and the functions of top three virulence factors (defensive virulence factors, offensive virulence factors and nonspecific virulence factors) were significantly and positively correlated with the level of grasping ability. We further indicated that the Qi-Fu-Yin significantly reduced the plasma levels of IL-6. Our results indicated that the effects of Qi-Fu-Yin anti-aging of APPPS1 transgenic mice might be through the regulation of intestinal flora diversity, species richness and the function of major active enzymes.
|
36,710,956 |
Spatial memory deficits in Alzheimers disease and their connection to cognitive maps formation by place cells and grid cells.
|
Whenever we navigate through different contexts, we build a cognitive map an internal representation of the territory. Spatial navigation is a complex skill that involves multiple types of information processing and integration. Place cells and grid cells, collectively with other hippocampal and medial entorhinal cortex neurons (MEC), form a neural network whose activity is critical for the representation of self-position and orientation along with spatial memory retrieval. Furthermore, this activity generates new representations adapting to changes in the environment. Though there is a normal decline in spatial memory related to aging, this is dramatically increased in pathological conditions such as Alzheimers disease (AD). AD is a multi-factorial neurodegenerative disorder affecting mainly the hippocampus-entorhinal cortex (HP-EC) circuit. Consequently, the initial stages of the disease have disorientation and wandering behavior as two of its hallmarks. Recent electrophysiological studies have linked spatial memory deficits to difficulties in spatial information encoding. Here we will discuss map impairment and remapping disruption in the HP-EC network, as a possible circuit mechanism involved in the spatial memory and navigation deficits observed in AD, pointing out the benefits of virtual reality as a tool for early diagnosis and rehabilitation.
|
36,710,684 |
Moral Emotions and Their Brain Structural Correlates Across Neurodegenerative Disorders.
|
Although social cognition is compromised in patients with neurodegenerative disorders such as behavioral variant frontotemporal dementia (bvFTD) and Alzheimers disease (AD), research on moral emotions and their neural correlates in these populations is scarce. No previous study has explored the utility of moral emotions, compared to and in combination with classical general cognitive state tools, to discriminate bvFTD from AD patients. To examine self-conscious (guilt and embarrassment) and other-oriented (pity and indignation) moral emotions, their subjective experience, and their structural brain underpinnings in bvFTD (n 31) and AD (n 30) patients, compared to healthy controls (n 37). We also explored the potential utility of moral emotions measures to discriminate bvFTD from AD. We used a modified version of the Moral Sentiment Task measuring the participants accuracy scores and their emotional subjective experiences. bvFTD patients exhibited greater impairments in self-conscious and other-oriented moral emotions as compared with AD patients and healthy controls. Moral emotions combined with general cognitive state tools emerged as useful measures to discriminate bvFTD from AD patients. In bvFTD patients, lower moral emotions scores were associated with lower gray matter volumes in caudate nucleus and inferior and middle temporal gyri. In AD, these scores were associated with lower gray matter volumes in superior and middle frontal gyri, middle temporal gyrus, inferior parietal lobule and supramarginal gyrus. These findings contribute to a better understanding of moral emotion deficits across neurodegenerative disorders, highlighting the potential benefits of integrating this domain into the clinical assessment.
|
36,710,683 |
Evaluation of Blood-Based Plasma Biomarkers as Potential Markers of Amyloid Burden in Preclinical Alzheimers Disease.
|
Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials. To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial. In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan (18Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants were processed within 2 h after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2 N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n 100) was processed within 24 h after phlebotomy and analyzed by C2 N. Plasma Aβ 42Aβ40 demonstrated the highest association for Aβ accumulation in the brain with an AUC 0.76 (95%CI 0.69, 0.82) at C2 N and 0.80 (95%CI 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64 p < 0.001). Age, sex, and APOE ɛ4 carrier status did not the diagnostic performance of plasma Aβ 42Aβ 40 to predict amyloid PET positivity in A4 Study participants. Plasma Aβ 42Aβ40 may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials.
|
36,710,682 |
Brain Gray Matter Volume Mediated the Correlation Between Plasma P-Tau and Cognitive Function of Early Alzheimers Disease in China A Cross-Sectional Observational Study.
|
The primary manifestations of Alzheimers disease (AD) include cognitive decline and brain gray matter volume (GMV) atrophy. Recent studies have found that plasma phosphorylated-tau (p-tau) concentrations perform better in diagnosing, differentiating, and monitoring the progression of AD. However, the correlation between plasma p-tau, GMV, and cognition remains unclear. To investigate whether GMV plays a mediating role in the association between plasma p-tau concentrations and cognition. In total, 99 participants (47 patients with AD and 52 cognitively unimpaired CU individuals) were included. All participants underwent neuropsychological assessments, laboratory examinations, and magnetic resonance imaging scans. Plasma p-tau217 and p-tau181 concentrations were measured using an enzyme-linked immunosorbent assay kit. Voxel-based morphometry was performed to assess participants brain GMV. Partial correlation and mediation analyses were conducted in AD group. Plasma p-tau concentrations were significantly higher in the AD group than in the CU group. Patients with AD had significant brain GMV atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus. In the AD group, there were significant correlations between plasma p-tau217 concentrations, GMV, and Mini-Mental State Examination (MMSE) scores. Brain GMV of the right hippocampus mediated the association between plasma p-tau217 concentrations and MMSE scores. A significant correlation between plasma p-tau181 and MMSE scores was not identified. The findings indicate that p-tau217 is a promising biomarker for central processes affecting brain GMV and cognitive function. This may provide potential targets for future intervention and treatment of tau-targeting therapies in the early stages of AD.
|
36,710,681 |
A Function of Amyloid-β in Mediating Activity-Dependent AxonSynapse Competition May Unify Its Roles in Brain Physiology and Pathology.
|
Amyloid-β protein precursor (AβPP) gives rise to amyloid-β (Aβ), a peptide at the center of Alzheimers disease (AD). AβPP, however, is also an ancient molecule dating back in evolution to some of the earliest forms of metazoans. This suggests a possible ancestral function that may have been obscured by those that evolve later. Based on literature from the functions of AβAβPP in nervous system development, plasticity, and disease, to those of anti-microbial peptides (AMPs) in bacterial competition as well as mechanisms of cell competition uncovered first by Drosophila genetics, I propose that AβAβPP may be part of an ancient mechanism employed in cell competition, which is subsequently co-opted during evolution for the regulation of activity-dependent neural circuit development and plasticity. This hypothesis is supported by foremost the high similarities of Aβ to AMPs, both of which possess unique, opposite (i.e., trophic versus toxic) activities as monomers and oligomers. A large body of data further suggests that the different Aβ oligomeric isoforms may serve as the protective and punishment signals long predicted to mediate activity-dependent axonalsynaptic competition in the developing nervous system and that the imbalance in their opposite regulation of innate immune and glial cells in the brain may ultimately underpin AD pathogenesis. This hypothesis can not only explain the diverse roles observed of Aβ and AβPP family molecules, but also provide a conceptual framework that can unify current hypotheses on AD. Furthermore, it may explain major clinical observations not accounted for and identify approaches for overcoming shortfalls in AD animal modeling.
|
36,710,680 |
Etiology and Clinical Significance of Network Hyperexcitability in Alzheimers Disease Unanswered Questions and Next Steps.
|
Cortical network hyperexcitability related to synaptic dysfunction in Alzheimers disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed subclinical epileptiform activity (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we review key unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention.
|
36,710,678 |
Luteolin and Exercise Combination Therapy Ameliorates Amyloid-β1-42 Oligomers-Induced Cognitive Impairment in Alzheimers Disease Mice by Mediating Neuroinflammation and Autophagy.
|
Alzheimers disease (AD) disturbs many patients and family. However, little progress has been made in finding effective treatments. Given AD is a multifactorial disease, luteolin and exercise combination therapy may be more effective than monotherapy. To explore the therapeutic effect and underlying mechanisms of luteolin and exercise combination therapy in AD treatment. This study utilized a validated mouse model of AD by bilateral injection of amyloid-β (Aβ)1-42 oligomers into the CA1 region of the hippocampus. By combining with animal behavioral test, thioflavin T detection, immunofluorescence and western blot test, the cognitive-enhancing effects of luteolin and exercise combination therapy and the underlying mechanisms were investigated. Luteolin (100 mgkgd) combined with exercise could significantly improve the performance of AD model mice in novel object recognition test, and the improvement was greater than that of monotherapy. Further experiments showed that luteolin and exercise alone or in combination could reverse the increase of Aβ content, the activation of astrocytes and microglia, and the decrease of the level of autophagy in hippocampus and cortex in AD model induced by Aβ 1-42 oligomers. While the combination therapy involved more intact hippocampal and cortical areas, with greater degree of changes. Luteolin and exercise combination therapy prevented Aβ 1-42 oligomers-induced cognitive impairment, possibly by decreasing neuroinflammation and enhancing autophagy. The luteolin and exercise combination therapy may be a useful therapeutic option for preventing andor delaying the progression of memory dysfunction of AD.
|
36,710,677 |
Effect of Cognitive Reserve on Physiological Measures of Cognitive Workload in Older Adults with Cognitive Impairments.
|
Cognitive reserve may protect against cognitive decline. This cross-sectional study investigated the association between cognitive reserve and physiological measures of cognitive workload in older adults with cognitive impairment. 29 older adults with cognitive impairment (age 75±6, 11 (38%) women, MoCA 20±7) and 19 with normal cognition (age 74±6 11 (58%) women MoCA 28±2) completed a working memory test of increasing task demand (0-, 1-, 2-back). Cognitive workload was indexed using amplitude and latency of the P3 event-related potential (ERP) at electrode sites Fz, Cz, and Pz, and changes in pupillary size, converted to an index of cognitive activity (ICA). The Cognitive Reserve Index questionnaire (CRIq) evaluated Education, Work Activity, and Leisure Time as a proxy of cognitive reserve. Linear mixed models evaluated the main effects of cognitive status, CRIq, and the interaction effect of CRIq by cognitive status on ERP and ICA. The interaction effect of CRIq total score by cognitive status on P3 ERP and ICA was not significant. However, higher CRIq total scores were associated with lower ICA (p 0.03). The interaction effects of CRIq subscores showed that Work Activity affected P3 amplitude (p 0.03) and ICA (p 0.03) differently between older adults with and without cognitive impairments. Similarly, Education affected ICA (p 0.02) differently between the two groups. No associations were observed between CRIq and P3 latency. Specific components of cognitive reserve affect cognitive workload and neural efficiency differently in older adults with and without cognitive impairments.
|
36,710,674 |
Apathy as a Predictor of Conversion from Mild Cognitive Impairment to Alzheimers Disease A Texas Alzheimers Research and Care Consortium (TARCC) Cohort-Based Analysis.
|
Apathy is among the neuropsychiatric symptoms frequently observed in people with cognitive impairment. It has been postulated to be a potential predictor of conversion from mild cognitive impairment (MCI) to Alzheimers disease (AD). To detect conversion rates from MCI to AD, and to determine the effect of apathy on the progression to AD in patients with MCI enrolled in the Texas Alzheimers Research and Care Consortium (TARCC) cohort. Apathy was determined by a positive response to the respective item in the Neuropsychiatric Inventory -Questionnaire (NPI-Q) completed by family members or caregivers. The final dataset included 2,897 observations from 1,092 individuals with MCI at the baseline. Kaplan-Meier survival curves were estimated to provide indices of the probability of conversion to AD over time across all individuals as well as between those with and without apathy. Cox proportional hazards regression measured the hazard associated with apathy and several other predictors of interest. Over a period of 8.21 years, 17.3% of individuals had conversion from MCI to AD (n 190 of 1,092 total individuals) across observations. The median time-to-conversion across all participants was 6.41 years. Comparing individuals with apathy (n 158) versus without apathy (n 934), 36.1% and 14.2% had conversion to AD, respectively. The median time-to-conversion was 3.79 years for individuals with apathy and 6.83 years for individuals without apathy. Cox proportional hazards regression found significant effects of several predictors, including apathy, on time-to-conversion. Age and cognitive performance were found to moderate the relationship between apathy and time-to-conversion. Apathy is associated with progression from MCI to AD, suggesting that it might improve risk prediction and aid targeted intervention delivery.
|
36,710,672 |
How Traumatic Brain Injury History Relates to Brain Health MRI Markers and Dementia Risk Findings from the 3C Dijon Cohort.
|
The long-term effects of traumatic brain injury (TBI) with loss of consciousness (LOC) on magnetic resonance imaging (MRI) markers of brain health and on dementia risk are still debated. To investigate the associations of history of TBI with LOC with incident dementia and neuroimaging markers of brain structure and small vessel disease lesions. The analytical sample consisted in 4,144 participants aged 65 and older who were dementia-free at baseline from the Three City -Dijon study. History of TBI with LOC was self-reported at baseline. Clinical Dementia was assessed every two to three years, up to 12 years of follow-up. A subsample of 1,675 participants <80 years old underwent a brain MRI at baseline. We investigated the associations between history of TBI with LOC and 1) incident all cause and Alzheimers disease (AD) dementia using illness-death models, and 2) neuroimaging markers at baseline. At baseline, 8.3% of the participants reported a history of TBI with LOC. In fully-adjusted models, participants with a history of TBI with LOC had no statistically significant differences in dementia risk (HR 0.90, 95% CI 0.60-1.36) or AD risk (HR 1.03, 95% CI 0.69-1.52), compared to participants without TBI history. History of TBI with LOC was associated with lower white matter volume (β -4.58, p 0.048), but not with other brain volumes, white matter hyperintensities volume, nor covert brain infarct. This study did not find evidence of an association between history of TBI with LOC and dementia or AD dementia risks over 12-year follow-up, brain atrophy, or markers of small vessel disease.
|
36,710,671 |
Associations Between Insulin-Like Growth Factor-1 and Resting-State Functional Connectivity in Cognitively Unimpaired Midlife Adults.
|
Insulin-like growth factor (IGF)-1 plays an important role in Alzheimers disease (AD) pathogenesis and increases disease risk. However, prior research examining IGF-1 levels and brain neural network activity is mixed. The present study investigated the relationship between IGF-1 levels and 21 neural networks, as measured by functional magnetic resonance imaging (fMRI) in 13,235 UK Biobank participants. Linear mixed models were used to regress IGF-1 against the intrinsic functional connectivity (i.e., degree of network activity) for each neural network. Interactions between IGF-1 and AD risk factors such as Apolipoprotein E4 (APOE4) genotype, sex, AD family history, and age were also tested. Higher IGF-1 was associated with more network activity in the right Executive Function neural network. IGF-1 interactions with APOE4 or sex implicated motor, primaryextrastriate visual, and executive function related neural networks. Neural network activity trends with increasing IGF-1 were different in different age groups. Higher IGF-1 levels relate to much more network activity in the Sensorimotor Network and Cerebellum Network in early-life participants (40-52 years old), compared with mid-life (52-59 years old) and late-life (59-70 years old) participants. These findings suggest that sex and APOE4 genotype may modify the relationship between IGF-1 and brain network activities related to visual, motor, and cognitive processing. Additionally, IGF-1 may have an age-dependent effect on neural network connectivity.
|
36,710,670 |
Fully Connected Multi-Kernel Convolutional Neural Network Based on Alzheimers Disease Diagnosis.
|
There is a shortage of clinicians with sufficient expertise in the diagnosis of Alzheimers disease (AD), and cerebrospinal fluid biometric collection and positron emission tomography diagnosis are invasive. Therefore, it is of potential significance to obtain high-precision automatic diagnosis results from diffusion tensor imaging (DTI) through deep learning, and simultaneously output feature probability maps to provide clinical auxiliary diagnosis. We proposed a factorization machine combined neural network (FMCNN) model combining a multi-function convolutional neural network (MCNN) with a fully convolutional network (FCN), while accurately diagnosing AD and mild cognitive impairment (MCI) corresponding fiber bundle visualization results are generated to describe their status. First, the DTI data is preprocessed to eliminate the influence of external factors. The fiber bundles of the corpus callosum (CC), cingulum (CG), uncinate fasciculus (UNC), and white matter (WM) were then tracked based on deterministic fiber tracking. Then the streamlines are input into CNN, MCNN, and FMCNN as one-dimensional features for classification, and the models are evaluated by performance evaluation indicators. Finally, the fiber risk probability map is output through FMCNN. After comparing the model performance indicators of CNN, MCNN, and FMCNN, it was found that FMCNN showed the best performance in the indicators of accuracy, specificity, sensitivity, and area under the curve. By inputting the fiber bundles of the 10 regions of interest (UNCL, UNCR, UNC, CC, CG, CGUNC, CGCC, CCUNC, CGCCUNC, and WM into CNN, MCNN, and FMCNN, respectively), WM shows the highest accuracy in CNN, MCNN, and FMCNN, which are 88.41%, 92.07%, and 96.95%, respectively. The FMCNN proposed here can accurately diagnose AD and MCI, and the generated fiber probability map can represent the risk status of AD and MCI.
|
36,710,669 |
Cognitive Aging with Dementia, Mild Cognitive Impairment, or No Impairment A Comparison of Same- and Mixed-Sex Couples.
|
Lesbian and gay older adults have health disparities that are risk factors for Alzheimers disease, yet little is known about the neurocognitive aging of sexual minority groups. To explore cross-sectional and longitudinal dementia outcomes for adults in same-sex relationships (SSR) and those in mixed-sex relationships (MSR). This prospective observational study utilized data from the National Alzheimers Coordinating Center Uniform Data Set (NACC UDS) collected from contributing Alzheimers Disease Research Centers. Participants were adults aged 55 years at baseline with at least two visits in NACC UDS (from September 2005 to March 2021) who had a spouse, partner, or companion as a co-participant. Outcome measures included CDR ® Dementia Staging Instrument, NACC UDS neuropsychological testing, and the Functional Activities Questionnaire. Multivariable linear mixed-effects models accounted for center clustering and repeated measures by individual. Both MSR and SSR groups experienced cognitive decline regardless of baseline diagnosis. In general, MSR and SSR groups did not differ statistically on cross-sectional or longitudinal estimates of functioning, dementia severity, or neuropsychological testing, with two primary exceptions. People in SSR with mild cognitive impairment showed less functional impairment at baseline (FAQ M 2.61, SD 3.18 vs. M 3.97, SD 4.53, respectively p < 0.01). The SSR group with dementia had less steep decline in attentionworking memory (β estimates -0.10 versus -0.18 p < 0.01). Participants in SSR did not show cognitive health disparities consistent with a minority stress model. Additional research into protective factors is warranted.
|
36,710,380 |
Net benefit of diagnostic tests for multistate diseases an indicator variables approach.
|
A limitation of the common measures of diagnostic test performance, such as sensitivity and specificity, is that they do not consider the relative importance of false negative and false positive test results, which are likely to have different clinical consequences. Therefore, the use of classification or prediction measures alone to compare diagnostic tests or biomarkers can be inconclusive for clinicians. Comparing tests on net benefit can be more conclusive because clinical consequences of misdiagnoses are considered. The literature suggested evaluating the binary diagnostic tests based on net benefit, but did not consider diagnostic tests that classify more than two disease states, e.g., stroke subtype (large-artery atherosclerosis, cardioembolism, small-vessel occlusion, stroke of other determined etiology, stroke of undetermined etiology), skin lesion subtype, breast cancer subtypes (benign, mass, calcification, architectural distortion, etc.), METAVIR liver fibrosis state (F0- F4), histopathological classification of cervical intraepithelial neoplasia (CIN), prostate Gleason grade, brain injury (intracranial hemorrhage, mass effect, midline shift, cranial fracture) . Other diseases have more than two stages, such as Alzheimers disease (dementia due to Alzheimers disease, mild cognitive disability (MCI) due to Alzheimers disease, and preclinical presymptomatics due to Alzheimers disease). In diseases with more than two states, the benefits and risks may vary between states. This paper extends the net-benefit approach of evaluating binary diagnostic tests to multi-state clinical conditions to rule-in or rule-out a clinical condition based on adverse consequences of work-up delay (due to false negative test result) and unnecessary workup (due to false positive test result). We demonstrate our approach with numerical examples and real data.
|
36,710,361 |
Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus.
|
Mutations in the Presenilin genes (PSEN1 and PSEN2) are the major cause of familial Alzheimers disease (AD), highlighting the importance of Presenilin (PS) in AD pathogenesis. Previous studies of PS function in the hippocampus demonstrated that loss of PS results in the impairment of short- and long-term synaptic plasticity and neurotransmitter release at hippocampal Schaffer collateral (SC) and mossy fiber (MF) synapses. Cortical input to the hippocampus through the lateral perforant pathway (LPP) and the medial perforant pathway (MPP) is critical for normal cognitive functions and is particularly vulnerable during aging and early stages of AD. Whether PS regulates synaptic function in the perforant pathways, however, remained unknown. In the current study, we investigate PS function in the LPP and MPP by performing whole-cell and field-potential electrophysiological recordings using acute hippocampal slices from postnatal forebrain-restricted excitatory neuron-specific PS conditional double knockout (cDKO) mice. We found that paired-pulse ratio (PPR) is reduced in the LPP and MPP of PS cDKO mice. Moreover, synaptic frequency facilitation or depression in the LPP or MPP, respectively, is impaired in PS cDKO mice. Notably, depletion of intracellular Ca
|
36,710,283 |
Serum inflammation markers associated with altered brain white matter microstructure in people with HIV on antiretroviral treatment.
|
Many studies have reported reduced brain white matter fractional anisotropy (FA) and increased mean diffusivity (MD) on diffusion tensor imaging (DTI) of people with HIV (PWH). Few, however, have linked individual blood inflammatory markers with white matter tract-specific FA and MD. PWH 50 years old or older from New York, NY, USA, were invited to a cross-sectional study. Demographic data, blood samples, and brain DTI were obtained. Least absolute shrinkage and selection operator (LASSO) regression was used to examine associations between biomarkers and white matter tract-specific FA and MD. All models included age, sex, race, ethnicity, diabetes, hypertension, smoking, and viral load as control variables. Seventy-two cases were analyzed. Mean age was 60 ± 6 years, 47% were women, 21% were Hispanic, and 78% were black. All had asymptomatic HIV infection and were on antiretroviral therapy. Eighty-nine percent had CD4 count >200 cellmm Elevated serum VEGF, MIP-1α, and MIP-1β were associated with altered white matter microstructure. These blood biomarkers may help predict HIV-associated white matter damage.
|
36,709,989 |
m
|
N6-methyladenosine modification of RNA (m
|
36,709,886 |
Impact of dysexecutive syndrome in quality of life in Alzheimer disease What we know now and where we are headed.
|
Alzheimers disease (AD) is a common form of dementia that leads to multiple repercussions in the patients life. This conditions clinical characteristics include loss of memory, temporal and spatial disorientation, language or executive dysfunction, and subsequent decline of social function. Dysexecutive syndrome (DS), the second most frequent neuropsychological dysfunction in AD, affects multiple brain areas and causes cognitive, behavioral, and emotional difficulties. We aimed to analyze the association between DS and AD and elucidate possible lack of evidence that may urge further research on this theme. Especially when dealing with such a disabling disease, where new findings can directly imply a better prognosis.
|
36,709,697 |
Analysis of Aβ-induced neurotoxicity and microglial responses in simple two- and three-dimensional human iPSC-derived cortical culture systems.
|
The extracellular accumulation of amyloid-β (Aβ) in plaques and associated neurodegeneration are the pathological hallmarks of Alzheimers disease (AD). These plaques are surrounded by microglia-the resident tissue macrophages of the brain parenchyma that originate from primitive macrophages from the embryonic yolk sac. Microglia, including a unique subpopulation called disease-associated microglia (DAM), are strongly implicated in AD pathology however, their exact function and physiology remain largely unknown. Notably, simple cell and tissue culture systems that adequately recreate the brain microenvironment and can simulate critical aspects of AD pathology could fundamentally contribute to elucidating microglial function in disease development and progression. Thus, we added human-induced pluripotent stem cell (hiPSC)-induced primitive macrophages (hiMacs) to hiPSC-induced cortical neurons (cell model) and cortical organoids (tissue model). The treatment of these culture systems with the O-acyl isopeptide of Aβ
|
36,709,611 |
Association between anxiety symptoms and Alzheimers disease biomarkers in cognitively healthy adults A systematic review and meta-analysis.
|
Anxiety has been identified as both a risk factor and prodromal symptom for Alzheimers disease (AD) and related dementias, however, the underlying neurobiological correlates remain unknown. The aim of this systematic review and meta-analysis was to examine the association between anxiety symptoms and two defining markers of AD neuropathology amyloid-beta (Aβ) and tau. Systematic literature searches were conducted across 5 databases. Studies investigating the relationship between anxiety and AD neuropathology (i.e., Aβ andor tau) in cognitively healthy adults were eligible. Where possible, effect sizes were combined across studies, for Aβ and tau separately, using random-effects meta-analyses. Sensitivity analyses were performed to assess whether results differed according to anxiety type (i.e., state and trait) and biomarker assessment modality (i.e., positron emission tomography and cerebrospinal fluid). Twenty-seven studies reporting data from 14 unique cohorts met eligibility criteria. Random-effects meta-analyses revealed no associations between self-reported anxiety symptoms and either Aβ (13 studies, Fishers z 0.02, 95% confidence interval CI -0.01-0.05, p 0.194) or tau (4 studies, Fishers z 0.04, 95% CI -0.02-0.09, p 0.235). Results remained unchanged across sensitivity analyses. In cognitively healthy adults, meta-analytic syntheses revealed no associations between anxiety symptoms and either Aβ or tau. There is a critical need, however, for larger studies with follow-up periods to examine the effect of anxiety symptom onset, severity, and chronicity on AD neuropathology. Additionally, further research investigating other potential neurobiological correlates is crucial to advance scientific understanding of the relationship between anxiety and dementia.
|
36,709,597 |
Brain temperature in healthy and diseased conditions A review on the special implications of MRS for monitoring brain temperature.
|
Brain temperature determines not only an individuals cognitive functionality but also the prognosis and mortality rates of many brain diseases. More specifically, brain temperature not only changes in response to different physiological events like yawning and stretching, but also plays a significant pathophysiological role in a number of neurological and neuropsychiatric illnesses. Here, we have outlined the function of brain hyperthermia in both diseased and healthy states, focusing particularly on the amyloid beta aggregation in Alzheimers disease.
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.