Early-stage Alzheimer Research Articles

Evaluating the effect of rapamycin treatment in Alzheimer’s disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol

BackgroundRapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and preclinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer’s disease have shown beneficial effects of rapamycin, including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The “Evaluating Rapamycin Treatment in Alzheimer’s Disease using Positron Emission Tomography” (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer’s disease.MethodsERAP is a six-month-long, single-arm, open-label, phase IIa biomarker-driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer’s disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints include changes in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function.DiscussionThe ERAP study is a clinical trial using in vivo imaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer’s disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease-modifying treatment in Alzheimer’s disease.Trial registrationClinicalTrials.gov ID NCT06022068, date of registration 2023–08-30.

Fixel-Based Analysis Reveals Tau-Related White Matter Changes in Early Stages of Alzheimer's Disease.

Several studies have shown white matter (WM) abnormalities in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aβ-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aβ-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics.

Innovative Approaches Using the Arts to Support Persons with Dementia and Caregivers

There is a growing movement to explore the use of the arts to enhance the quality of life for persons with dementia (PWD) and their caregivers. Viewing art can promote well-being as well as express complex emotions during times of change and challenge. Listening to music and singing has been shown to enhance morale and reduce risk for depression and loneliness in older adults. Responsiveness to music is maintained in PWD even through later stages of the cognitive impairment. Arts-based programs appear pleasant and engaging, enhancing well-being. Looking deeper, they are based on educational theory and practice and on understanding of the neurocognitive changes with dementia. Additional benefits include increasing social interactions, promoting creativity and providing caregiver support.In this session, two geriatric psychiatrists and a decorated professional artist will discuss and demonstrate the interface between the arts and dementia in three domains: 1) art museum-based activities, 2) art creation by caregivers to process and cope with the stress of caregiving and disease progression, and 3) participation in music activities. Dr. Mary Blazek will begin the session, leading symposium participants in art-based activities. She will then discuss the growing literature on visual art museum programs for PWD and their caregivers. Dr. Mark Gilbert will discuss the use of portraiture as a research method to investigate the relationships and interactions between older patients and their partners in care. Dr. Susan Lehmann will review recent work highlighting the cognitive, social, and emotional benefits of participation in music activities for older adults and PWD.“In the Moment” Art Museum Programs for Persons with Dementia and their caregiversIn 2006, New York's Museum of Modern Art developed Meet Me at MoMA, a program for shared art experiences for (PWD) and their caregivers. Museums across the globe have developed similar programs emphasizing engaging with art “in the moment” as opposed to fostering reminiscence. Dr. Blazek will begin this session leading participants in sample activities from these programs. She will discuss the genesis of these programs and their impact on the PWD, on caregivers and on their relationships."Portrait of a Process: Exploring the experience of older adults and their partners in care through portraiture"Artist, researcher and teacher, Dr. Gilbert, will discuss artworks he created during a two-year research study in collaboration with geriatrician, Dr. Kenneth Rockwood at Geriatric Medical Research, Halifax, Nova Scotia, Canada. Memory Serves: Drawing Others Close used portraiture as a research method to investigate the relationships and interactions between older patients and their partners in care. Dr. Gilbert will also introduce a collection of drawings carried out by his late father, Scottish artist Norman Gilbert (1926-2019). The drawings were created as he sat with his wife of 65 years, Pat, as she lay dying in hospital of Alzheimer's related illness.“With a Song in My Heart”: How music can support emotional and cognitive well-being in persons with dementia and their care-partnersMusic plays a central role in human culture throughout the world and has the power to move us at every age. Aging musicians, from Bruce Springsteen to Billy Joel to Elton John, have enjoyed long performing careers, and performers such as Tony Bennett and Glen Campbell continued to perform in the early stages of Alzheimer's disease. Responsiveness to music is retained by PWD even into the later stages of cognitive impairment. There is growing evidence that listening to music, singing, or playing a musical instrument can have positive benefits for cognition as well as for emotional well-being for older adults and PWD. Dr. Lehmann will review recent studies that illuminate the relationship between brain health and music for older adults and will address interventions using music to support well-being in older adults with dementia.

Aβ oligomers peak in early stages of Alzheimer's disease preceding tau pathology.

Soluble amyloid beta (Aβ) oligomers have been suggested as initiating Aβ related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear. A total of 526 participants in early clinical stages of AD and controls from a longitudinal cohort were neurobiologically classified for amyloid and tau pathology applying the AT(N) system. Aβ and tau oligomers in the quantified cerebrospinal fluid (CSF) were measured using surface-based fluorescence intensity distribution analysis (sFIDA) technology. Across groups, highest Aβ oligomer levels were found in A+ with subjective cognitive decline and mild cognitive impairment. Aβ oligomers were significantly higher in A+T- compared to A-T- and A+T+. APOEε4 allele carriers showed significantly higher Aβ oligomer levels. No differences in tau oligomers were detected. The accumulation of Aβ oligomers in the CSF peaks early within the AD continuum, preceding tau pathology. Disease-modifying treatments targeting Aβ oligomers might have the highest therapeutic effect in these disease stages. Using surface-based fluorescence intensity distribution analysis (sFIDA) technology, we quantified Aβ oligomers in cerebrospinal fluid (CSF) samples of the DZNE-Longitudinal Cognitive Impairment and Dementia (DELCODE) cohortAβ oligomers were significantly elevated in mild cognitive impairment (MCI)Amyloid-positive subjects in the subjective cognitive decline (SCD) group increased compared to the amyloid-negative control groupInterestingly, levels of Aβ oligomers decrease at advanced stages of the disease (A+T+), which might be explained by altered clearing mechanisms.

Anti-amyloid therapies: are they effective and safe?

Abstract After numerous unsuccessful attempts to create a therapy that could alter the course of Alzheimer’s disease, first monoclonal antibodies targeting amyloid-β in the brain have finally shown consistent evidence of clinical effectiveness. These therapies not only slow the progression of the disease, but also show positive results in secondary clinical outcomes and reduced amyloid-β levels on PET scans. This presentation will examine the main features of the previous failed trials and explore possible reasons for their lack of success in developing a treatment for early-stage Alzheimer’s disease. It will also compare the safety profiles of various antibodies and point out precautions that should be taken when using them in regular clinical practice. Furthermore, it will be discussed how blood-based biomarkers can revolutionize the clinical care pathway, making it easier to adopt antibody treatments. A comprehensive model that integrates case-finding and treatment across various healthcare sectors will be proposed. In conclusion, we may have made a significant breakthrough by demonstrating that reducing amyloid-β levels leads to clinical benefits, not just changes in biomarkers. As the new generation of drugs becomes more commonly used, we will see whether their statistical effectiveness translates into meaningful clinical changes. This could mark the start of a new phase in the development of drugs for Alzheimer’s disease.Disclosure of InterestNone Declared

A Comparative Study on Feature Extraction Techniques for the Discrimination of Frontotemporal Dementia and Alzheimer's Disease with Electroencephalography in Resting-State Adults.

Early-stage Alzheimer's disease (AD) and frontotemporal dementia (FTD) share similar symptoms, complicating their diagnosis and the development of specific treatment strategies. Our study evaluated multiple feature extraction techniques for identifying AD and FTD biomarkers from electroencephalographic (EEG) signals. We developed an optimised machine learning architecture that integrates sliding windowing, feature extraction, and supervised learning to distinguish between AD and FTD patients, as well as from healthy controls (HCs). Our model, with a 90% overlap for sliding windowing, SVD entropy for feature extraction, and K-Nearest Neighbors (KNN) for supervised learning, achieved a mean F1-score and accuracy of 93% and 91%, 92.5% and 93%, and 91.5% and 91% for discriminating AD and HC, FTD and HC, and AD and FTD, respectively. The feature importance array, an explainable AI feature, highlighted the brain lobes that contributed to identifying and distinguishing AD and FTD biomarkers. This research introduces a novel framework for detecting and discriminating AD and FTD using EEG signals, addressing the need for accurate early-stage diagnostics. Furthermore, a comparative evaluation of sliding windowing, multiple feature extraction, and machine learning methods on AD/FTD detection and discrimination is documented.

Degeneration in Nucleus basalis of Meynert signals earliest stage of Alzheimer’s disease progression

Nucleus Basalis of Meynert (NbM), a crucial source of cholinergic projection to the entorhinal cortex (EC) and hippocampus (HC), has shown sensitivity to neurofibrillary degeneration in the early stages of Alzheimer’s Disease. Using deformation-based morphometry (DBM) on up-sampled MRI scans from 1447 Alzheimer’s Disease Neuroimaging Initiative participants, we aimed to quantify NbM degeneration along the disease trajectory. Results from cross-sectional analysis revealed significant differences of NbM volume between cognitively normal and early mild cognitive impairment cohorts, confirming recent studies suggesting that NbM degeneration happens before degeneration in the EC or HC. Longitudinal linear mixed-effect models were then used to compare trajectories of volume change after realigning all participants into a common timeline based on their cognitive decline. Results indicated the earliest deviations in NbM volumes from the cognitively healthy trajectory, challenging the prevailing idea that Alzheimer’s originates in the EC. Converging evidence from cross-sectional and longitudinal models suggest that the NbM may be a focal target of early AD progression, which is often obscured by normal age-related decline.

Detection of Early Stage Alzheimer's Disease in Gradient-Based MR Images Using Deep Learning Methods

Alzheimer's Disease (AD), a form of dementia prevalent in older age, is a neurodegenerative condition impacting brain nerve cells. Early-stage AD symptoms are often subtle, complicating timely diagnosis. Early detection allows for intervention, slowing disease progression and facilitating appropriate treatments. Deep learning methods, particularly gradient-based images, prove promising for early Alzheimer's detection in Magnetic Resonance (MR) imaging. Gradient-based images, highlighting details in low-intensity images and enhancing contrast, play a vital role in determining structures' location, shape, and size, notably in techniques like Magnetic Resonance Imaging (MRI). This study aims to boost model performance in early AD detection by applying the Gradient filter before training deep learning models on diverse-angle and constant-density brain MRI images. The dataset comprises three categories representing early-stage AD, including images of mild cognitive impairment and healthy individuals. Original and gradient-filtered image subsets were inputted into deep learning models. Results indicate superior performance of gradient-based images, with the Densenet201 deep learning model achieving the highest accuracy at 98.63%.

Design and Evaluation of a Comprehensive Assistance App for Early-Stage Alzheimer's Patients

This study endeavors to create and assess a specialized mobile application (app) designed to cater to the unique needs of individuals in the early stages of Alzheimer's disease (AD). The ultimate goal is to improve their daily life management. This abstract offers a comprehensive overview of the research, encompassing the research context, problem analysis, design principles, user interface development, and evaluation of the app's users. Throughout the study, rigorous scholarly standards are upheld, with the inclusion of citations from academic literature to support the assertions put forth. The research context highlights the increasing prevalence of Alzheimer's disease and the growing importance of developing supportive tools for affected individuals. The problem investigation delves into the specific challenges faced by early-stage AD patients in their daily lives, such as memory deficits and cognitive impairments, emphasizing the need for tailored solutions. In the design phase, the study outlines the principles guiding the app's development, emphasizing user-centered design and accessibility. The user interface development section provides insights into the app's visual and interactive elements, with a focus on simplicity and usability to accommodate the cognitive limitations of the target audience. Furthermore, the paper discusses the rigorous evaluation process undertaken to gauge the app's effectiveness in improving daily life management for early-stage AD patients. This evaluation includes user feedback, usability testing, and performance metrics, ensuring that the app meets its intended objectives. Throughout this research, citations from academic literature are incorporated to validate the research findings and demonstrate the scholarly rigor of the study.

Pharmacotherapy for patients with Alzheimer’s disease

Background: Alzheimer’s disease is a neurodegenerative condition characterized by the accumulation of amyloid and tau proteins, leading to neuronal loss, cognitive decline, and difficulties maintaining daily activities. As the elderly population grows, interest in effective Alzheimer’s disease treatment is increasing.Current Concepts: The recent approval of drugs by the United States Food and Drug Administration with mechanisms based on the amyloid cascade hypothesis, in addition to existing therapies based on the cholinergic hypothesis, raises the possibility of introducing these novel agents in South Korea.Discussion and Conclusion: Currently, South Korea offers cholinesterase inhibitors and an N-methyl-D-aspartate receptor antagonist based on the cholinergic hypothesis for Alzheimer’s disease dementia. Each drug has different indications under national health insurance coverage depending on dementia severity. The development of new intravenous drugs targeting the amyloid cascade offers potential benefits not only for early-stage Alzheimer’s disease but also for mild cognitive impairment due to Alzheimer’s disease, suggesting a wider scope for future pharmacological intervention.

Empathy and support exchanges in couples coping with early-stage Alzheimer’s disease

Objectives Research has extensively examined spousal caregiving in Alzheimer’s disease (AD), but it remains unclear how people with AD help spousal caregivers. We aimed to describe emotional and practical support that people with AD and their spouses provide to each other and test the role their empathy plays in these support experiences. Methods Seventy-two people with early-stage AD and their spousal caregivers independently reported empathy (personal distress, empathic concern, perspective taking) and the frequency and appraisal of support provision. Caregivers reported both partners’ sociodemographic characteristics. Results People with early-stage AD and their spousal caregivers provided support to each other often. Caregivers provided more support but people with AD appraised support provision as more pleasant and less stressful. Lower personal distress in both partners and greater caregiver empathic concern were associated with more frequent caregiver support to people with AD. Greater empathic concern and perspective taking were associated with more pleasant appraisals of helping. Personal distress was positively associated with stress of helping. Conclusion Findings describe support reciprocity in early-stage AD and debunk the myth of people with AD being only recipients of care. We identify risk and resilience in couples per empathy and inform the design of dyadic interventions to promote mutually beneficial relationships in AD.

Multi-proteomic analyses of 5xFAD mice reveal new molecular signatures of early-stage Alzheimer's disease.

An early diagnosis of Alzheimer's disease is crucial as treatment efficacy is limited to the early stages. However, the current diagnostic methods are limited to mid or later stages of disease development owing to the limitations of clinical examinations and amyloid plaque imaging. Therefore, this study aimed to identify molecular signatures including blood plasma extracellular vesicle biomarker proteins associated with Alzheimer's disease to aid early-stage diagnosis. The hippocampus, cortex, and blood plasma extracellular vesicles of 3- and 6-month-old 5xFAD mice were analyzed using quantitative proteomics. Subsequent bioinformatics and biochemical analyses were performed to compare the molecular signatures between wild type and 5xFAD mice across different brain regions and age groups to elucidate disease pathology. There was a unique signature of significantly altered proteins in the hippocampal and cortical proteomes of 3- and 6-month-old mice. The plasma extracellular vesicle proteomes exhibited distinct informatic features compared with the other proteomes. Furthermore, the regulation of several canonical pathways (including phosphatidylinositol 3-kinase/protein kinase B signaling) differed between the hippocampus and cortex. Twelve potential biomarkers for the detection of early-stage Alzheimer's disease were identified and validated using plasma extracellular vesicles from stage-divided patients. Finally, integrin α-IIb, creatine kinase M-type, filamin C, glutamine γ-glutamyltransferase 2, and lysosomal α-mannosidase were selected as distinguishing biomarkers for healthy individuals and early-stage Alzheimer's disease patients using machine learning modeling with approximately 79% accuracy. Our study identified novel early-stage molecular signatures associated with the progression of Alzheimer's disease, thereby providing novel insights into its pathogenesis.

Traumatic Brain Injury in Mice Generates Early-Stage Alzheimer’s Disease Related Protein Pathology that Correlates with Neurobehavioral Deficits

Traumatic brain injury (TBI) increases the long-term risk of neurodegenerative diseases, including Alzheimer’s disease (AD). Here, we demonstrate that protein variant pathology generated in brain tissue of an experimental TBI mouse model is similar to protein variant pathology observed during early stages of AD, and that subacute accumulation of AD associated variants of amyloid beta (Aβ) and tau in the TBI mouse model correlated with behavioral deficits. Male C57BL/6 mice were subjected to midline fluid percussion injury or to sham injury, after which sensorimotor function (rotarod, neurological severity score), cognitive deficit (novel object recognition), and affective deficits (elevated plus maze, forced swim task) were assessed post-injury (DPI). Protein pathology at 7, 14, and 28 DPI was measured in multiple brain regions using an immunostain panel of reagents selectively targeting different neurodegenerative disease-related variants of Aβ, tau, TDP-43, and alpha-synuclein. Overall, TBI resulted in sensorimotor deficits and accumulation of AD-related protein variant pathology near the impact site, both of which returned to sham levels by 14 DPI. Individual mice, however, showed persistent behavioral deficits and/or accumulation of toxic protein variants at 28 DPI. Behavioral outcomes of each mouse were correlated with levels of seven different protein variants in ten brain regions at specific DPI. Out of 21 significant correlations between protein variant levels and behavioral deficits, 18 were with variants of Aβ or tau. Correlations at 28 DPI were all between a single Aβ or tau variant, both of which are strongly associated with human AD cases. These data provide a direct mechanistic link between protein pathology resulting from TBI and the hallmarks of AD.

Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer’s disease

BackgroundPatients with Alzheimer’s disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial.MethodsFour-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated.ResultsAPP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice.ConclusionOur results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.

Medical aid in dying to avoid late-stage dementia.

Many patients with dementia want the option of using medical aid in dying (MAID) to end their lives before losing decision-making capacity and other abilities that impact their desired quality of life. But, for over two decades, it has been widely understood that these patients cannot (solely because of their dementia diagnosis) satisfy three statutory eligibility requirements in all U.S. MAID laws: (1) decisional capacity, (2) the ability to self-administer the life-ending medications, and (3) a terminal condition with 6 months or less to live. Now, because of recent statutory amendments together with the use of voluntarily stopping eating and drinking (VSED) to quickly advance to a terminal condition, this dementia exclusion from MAID might no longer apply. If combining VSED and MAID is now a possibility for patients with dementia, then clinicians need more guidance on whether and when to support patients seeking to take this path. In this article, we begin to provide this guidance. First, we describe the recent case of an Oregon patient with early-stage Alzheimer's dementia who successfully used VSED to qualify for and use MAID. Second, we discuss prior barriers to using VSED as a bridge to MAID for people with dementia. Third, we describe recent legal changes that might make this path now possible.

MMGK: Multimodality Multiview Graph Representations and Knowledge Embedding for Mild Cognitive Impairment Diagnosis

The diagnosis of mild cognitive impairment (MCI), which is an early stage of Alzheimer’s disease (AD), has great clinical significance. Medical imaging and gene sequencing technologies have provided sufficient multimodality data for MCI diagnostic studies. However, how to effectively extract the rich representations from multimodality data remains a challenging task. To address this challenging task, we propose a new multimodality multiview graph representations and knowledge embedding (MMGK) framework to diagnose MCI. First, to obtain rich information from multimodality data, we extract multiview feature representations from magnetic resonance imaging (MRI) and genetic data. Afterward, considering the correlations between subjects, all subjects are constructed into a graph based on the different single-view feature representations, respectively. To further enrich the correlations between subjects, demographic data are utilized through knowledge embedding. Finally, to perform MCI diagnosis on multiview graphs, graph convolutional networks (GCNs) are utilized. In addition, to further improve the performance of MCI diagnosis, a two-step ensemble learning method is proposed. The proposed framework is evaluated on 188 subjects from the AD Neuroimaging Initiative (ADNI). Experimental results show that our proposed framework achieves good performance with accuracy reaching 0.888, and outperforms some state-of-the-art (SOTA) methods. In addition, the proposed framework is applied to Parkinson’s disease (PD) diagnosis and achieves 0.856 accuracy. Overall, our proposed method has potential for clinical application in MCI diagnosis and other diseases via integrating MRI, genetic data, and demographic data. Our code is available at: https://github.com/miacsu/MMGK.

MiR-34a/TAN1/CREB Axis Engages in Alleviating Oligodendrocyte Trophic Factor-Induced Myelin Repair Function and Astrocyte-Dependent Neuroinflammation in the Early Stages of Alzheimer's Disease: The Anti-Neurodegenerative Effect of Treadmill Exercise.

Reduced myelin stability observed in the early stages of Alzheimer's disease leads to spatial learning and memory impairment. Exercise has been shown to protect nerves, reduce the risk of Alzheimer's disease, and strengthen synaptic connectivity. However, the underlying mechanisms of how exercise can promote myelin repairand coordinate inflammation and proliferation are still uncertain. In this study, we conducted histological and biochemical assays of cortical lysates after behavioral testing to detect pathological changes, myelin sheath thickness, and mRNA and protein levels. It is notable that D-galactose model mice exhibited elevated miRNA-34a levels, overactive astrocytes, decreased myelin staining scores, increased apoptosis, and decreased synaptic plasticity in the brain. Significantly, after eight weeks of exercise, we observed improvements in LFB scores, NeuN( +) neuron counts, and myelin basic protein (MBP) expression. Additionally, exercise promoted the expression of oligodendrocyte markers Olig2 and PDFGR-α associated with brain proliferation, and improved spatial cognitive function. Furthermore, it decreased the inflammation caused by astrocyte secretions (TNF-α, Cox-2, CXCL2). Interestingly, we also observed downregulation of miR-34a and activation of the TAN1/PI3K/CREB signaling pathway. Our data shed light on a previously unsuspected mechanism by which exercise reduces miR-34a levels and protects neuronal function and survival by preventing excessive demyelination and inflammatory infiltration in the CNS.

Treatment with glatiramer acetate in APPswe/PS1dE9 mice at an early stage of Alzheimer's disease prior to amyloid-beta deposition delays the disease's pathological development and ameliorates cognitive decline.

Alzheimer's disease (AD) is characterized by neuroinflammation, which is frequently accompanied by immune system dysfunction. Although the mechanism of neurodegenerative lesions is unclear, various clinical trials have highlighted that early intervention in AD is crucial to the success of treatment. In order to explore the potential of immunotherapy in the early period of AD, the present study evaluated whether application of glatiramer acetate (GA), an immunomodulatory agent approved for remitting-relapsing multiple sclerosis (RRMS), in the early stages of AD prior to amyloid beta (Aβ) deposition altered the Aβ pathology and cognitive impairments in APPswe/PSEN1dE9 (APP/PS1) transgenic mice. We treated two cohorts of pre-depositing and amyloid-depositing (2- and 6-month-old) APP/PS1 mice with weekly-GA subcutaneous injection over a 12-week period. We then tested spatial learning and memory using the Morris water maze (MWM) and the Y maze. Immunohistochemistry staining was utilized to analyze Aβ burden in the brain as well as activated microglia. Furthermore, the inflammatory cytokine milieu within brains was estimated by quantitative real-time polymerase chain reaction, and the peripheral CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the spleen were measured by flow cytometry. We found that early GA administration reduced Aβ burden and ameliorated cognitive decline. Meanwhile, the immune microenvironment had changed in the brain, with an increase in the production of anti-inflammatory cytokines and a decrease in microglial activation. Interestingly, early GA administration also modulated the peripheral immune system through the amplification of Tregs in the spleen. Overall, our findings revealed that GA treatment might enhance the central and peripheral immune systems' protective capabilities in the early stages of AD, eventually improving cognitive deficits. Our research supports the advantages of immunomodulatory treatments for AD at an early stage.

Dual role of α7 nicotinic acetylcholine receptors in the retrosplenial cortex for aversive memory acquisition and retrieval.

In the retrosplenial cortex (RSC), the role of cholinergic modulation via α7 nicotinic receptors and their involvement in memory is unknown. In recent years, the RSC has been shown to deteriorate in the early stages of Alzheimer's disease (AD). Likewise, the cholinergic system has been postulated as one of those responsible for cognitive impairment in patients with AD. Great interest has arisen in the study of α7 nicotinic receptors as more specific targets for the treatment of this disease. For this reason, we aim to study the role of α7 receptors of the RSC in memory processing. We infused a selective α7 receptor antagonist into the anterior part of the RSC (aRSC) to assess its role in different phases of aversive memory processing using an inhibitory avoidance task. We found that α7 nicotinic receptors are involved in memory acquisition and expression, but not in its consolidation. These results identify aRSC α7 nicotinic receptors as key players in aversive memory processing and highlight their significant potential as therapeutic targets for Alzheimer's disease.

Super-Resolution Ultrasound Reveals Cerebrovascular Impairment in a Mouse Model of Alzheimer's Disease.

Increasing evidence has suggested a link between cerebrovascular disease and the cognitive impairment associated with Alzheimer's disease. However, detailed descriptions of microvascular changes across brain regions and how they relate to other more traditional pathology have been lacking. Additionally, the efforts to elucidate the interplay between cerebral microvascular function and Alzheimer's disease progression are complicated by the necessity of probing deep-brain structures since early-stage Alzheimer's disease typically involves hippocampal pathology. The purpose of this study was to examine changes in microvascular dynamics in a mouse model of Alzheimer's disease using cohorts that were age-matched to wild-type controls. Data from both sexes were included in this study. Super-resolution ultrasound localization microscopy revealed microvascular functional and structural features throughout the whole brain depth to visualize and quantify. We found that functional decreases in hippocampal and entorhinal flow velocity preceded structural derangements in regional vascular density. Co-registered histological sectioning confirmed the regionalized perfusion deficits seen on ultrasound imaging, which were co-localized with amyloid beta plaque deposition. In addition to providing global vascular quantifications of deep brain structures with a high local resolution, this technology also permitted velocity-profile analysis of individual vessels and, in some cases, allowed for decoupling of arterial and venous flow contributions. These data suggest that microvascular pathology is an early and pervasive feature of Alzheimer's disease and may represent a novel therapeutic target for this disease.