bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economics of Dementia Prevention: Why the 2023 World Health Global Guidelines on Dementia May Not Reduce the Dementia Epidemiology in Developing Countries
Authors: Mostert Cyprian M 
Published: January 2025

AbstractBackgroundIn 2023, the World Health Organization (WHO) presented the Mental Health Gap Action Programmes to avert Dementia. In this publication, the WHO presented a high certainty that physical activity interventions prevent Dementia. The organization presented low levels of certainty that psychosocial interventions, non‐pharmaceutical interventions, depression, and anxiety treatments are effective for Dementia prevention in low‐income and middle‐income countries (LMICs). This policy paper utilizes Global evidence, Continental perspective, Regional insight, and County outlook and presents the potential global policies that can avert Dementia, which were omitted in the 2023 WHO report.MethodThis review uses World Bank, World Health Organization, and United Nations datasets. We also comprehensively searched the medical literature for published articles on social and commercial determinants of Dementia.ResultWe demonstrate that the current WHO report does not comprehensively present policies that may yield positive returns in averting Dementia for developing countries. Physical activity is high in LMICs and may do little to prevent Dementia. Countries need to reduce poverty, hunger, tobacco consumption, alcohol consumption, sugar consumption, and other substances as crucial risk factors that drive Dementia outcomes in LMICs. Other policies that may improve Dementia epidemiology are welfare programs presented in Figure 1. These policies have robust chance of averting sixty percent of the Dementia cases.ConclusionThere is a significant risk of failing to improve Dementia outcomes if the current 2023 WHO report is not amended. Policymakers must address both the social and commercial determinants factors of Dementia as countries seek to achieve healthy brain aging.
Potential roles for BACE inhibitors in AD therapeutic trials
Authors: Aisen Paul S. 
Published: January 2025

AbstractBackgroundNow, at the beginning of the era of disease‐modifying drugs for AD, many questions must be addressed in the effort to optimize benefits. Important issues remain regarding the timing and duration of amyloid‐removing immunotherapy and the potential advantages of combination therapies. Anti‐fibrillar amyloid antibodies effectively remove amyloid but may not be appropriate for maintenance of the low amyloid state; secretase inhibition is a reasonable alternative. Evidence suggests that the earlier amyloid is removed the larger the benefit; by extension, beginning anti‐amyloid therapy before plaque accumulation may be optimal but may require targeting the generation of amyloid monomers. The toxicity of diffusible amyloid species suggests that combining immunotherapy with secretase inhibition may provide additive benefit. As reviewed in this session, the availability of substantial pre‐clinical and clinical data on BACEi therapy suggests that this approach can provide fine‐tuned reduction in amyloid peptide generation while avoiding the reversible cognitive toxicity associated with this class of drug.MethodsFindings from trials with amyloid‐removing antibodies and various BACE inhibitors along with growing data on accurate plasma markers of AD neurobiology inform considerations of the next generation of trials needed to clarify the role of BACEi therapy for disease‐modification.ResultsExperience from ongoing clinical trials indicates that plasma biomarkers, particularly mass spectroscopy assays of abeta and ptau217 ratios, accurately predict amyloid levels by PET below the normal range. Further, changes in plasma ptau assays precede reaccumulation of fibrillar amyloid after cessation of amyloid‐lowering immunotherapy. These findings suggest that marrying accurate monitoring of plasma markers to BACEi therapy can provide a path to optimization of anti‐amyloid therapy. Future studies may demonstrate that screening individuals in late‐middle age with these plasma measures facilitates management of amyloid dysregulation at the pre‐plaque stage for primary prevention of AD.ConclusionCoupled with plasma biomarkers of AD pathology, BACE inhibitor therapy may provide a feasible approach to the optimization of anti‐amyloid therapy for established AD as well as primary prevention of the disease.
Plasma synapse proteins discriminate between AD, DLB, and FTD dementias and closely predict memory dysfunction
Authors: Taddei Raquel N , Kivisäkk Pia , de Geus Matthijs B , Klein Charles N , Zetterberg Henrik , Gomez‐Isla Teresa , Arnold Steven E 
Published: January 2025

AbstractBackgroundRobust biomarkers are urgently needed to detect, diagnose, and predict memory decline in the three most common neurodegenerative dementia syndromes, Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). The currently used diagnostic and therapeutic compounds target the disease‐defining neuropathologic signatures (amyloid, tau, alpha‐synuclein, TDP43) but show limited efficacy. Growing evidence suggests that synapses form the anatomical basis of cognition and that synapse dysfunction closely predicts dementia onset and progression in these dementing disorders. Yet, the plasma synapse signatures characterizing the three most common neurodegenerative dementia syndromes remain unexplored.MethodWe analyzed plasma samples from 100 individuals with autopsy‐confirmed neurodegenerative dementias (24 AD, 30 DLB, 30 FTD) and 16 controls without dementia or neuropathological abnormalities enrolled in the Massachusetts ADRC longitudinal cohort. Samples were obtained ≤3 years prior to death and analyzed using unbiased mass‐spectrometry (ProteographTM Seer Inc.). Plasma proteins were cross‐referenced with the SynGO database to select synaptic, and with the Human Protein Atlas to include brain‐expressed proteins. ANOVAs, Bonferroni corrections, and t‐tests were applied using R functions on log‐transformed data. Linear correlation analyses evaluated associations of synapse protein levels and cognitive scores (MoCA, CDR‐global, CDR‐SoB) in each dementia syndrome.ResultWe detected >80 synaptic proteins in the plasma of the 100 cases. A subset of 14 plasma synapse proteins significantly differed between dementia cases and controls. Some synapse proteins were increased across dementia syndromes (HABP4, RAP2A), while subsets of them were selectively altered in only one specific neurodegenerative condition (ARL8A, WASF3, AP1S1 in AD; ADDB, L1CAM in DLB; SRGP2, PP2BA, MADD, DEMA, NCAN in FTD). Significant correlations with memory scores were found for some synapse proteins (ARL8A, RAB3C in AD, ADDB in DLB, and DEMA in FTD).ConclusionSynapse‐associated proteins are altered in the plasma of AD, DLB, and FTD, compared with non‐demented control cases. Select synapse protein signatures may serve as biomarkers to detect global cognitive dysfunction in various dementing diseases, and to accurately discriminate between dementia syndromes. The future investigation and validation of plasma synaptic biomarkers may provide an unprecedented tool for the detection and differential diagnosis of neurodegenerative dementia syndromes in research and clinical settings.
Topography and Predictitve Value of Enlarged Perivascular Spaces in Patients with Cognitive Impairment beyond Aneurysmal Subarachnoid Hemorrhage
Authors: Gong Li , Liu Xueyuan 
Published: January 2025

AbstractBackgroundTo explore the correlation between the topography of EPVS and cognitive impairment after aSAH.MethodPatients clinically diagnosed as aSAH by DSA and CT; Head magnetic resonance imaging was performed between 1 week and 1 month after onset, combined with clinical and neuroimaging variables to assess the incidence of hydrocephalus and delayed cerebral ischemia after aneurystic subarachnoid hemorrhage. Follow‐up was performed at 3 months, and the patients' prognosis and cognitive function were evaluated by mRS and the Montreal Cognitive Assesement (MoCA), respectively. The clinical characteristics of aSAH patients with EPVS <10 and EPVSV10 in basal ganglia and centrum semioval were compared, and a binary Logistic regression model was used to study the severity of EPVS and its correlation with DCI, subacute hydrocephalus, poor prognosis and cognitive impairment.ResultBG‐EPVS predominance pattern (BG‐EPVS > CSO‐EPVS) was more common in the aSAH group (53.8%) than in other primary SAH patients without aneurysm(15.8%). A total of 159 patients completed 3‐month MoCA assessment, of which 63 (39.6%) were diagnosed with cognitive impairment (MoCA<22). EPVS >10 (no matter CSO or BG) was associated with unfavorable functional outcomes at 3 months. BG‐EPVS >10 linked to subacute hydrocephalus and DCI, but not with cognitive impairment after adjusting for established predictors. In contrast, CSO‐EPVS>10 predicted worse cognitive function after adjustment for established variables.ConclusionCSO‐EPVS is associated with cognitive impair beyond aSAH, but not with subacute hydrocephalus and DCI, suggesting distinct lymphatic drainage and mechanism after an attack of aSAH.
Therapeutic Poetry Program for Indigenous People Living with Dementia
Authors: Guzman Antonio Paniagua 
Published: January 2025

AbstractBackgroundDue to its accessibility and connection with cognitive and linguistic abilities, poetry has been used to study diverse characteristics of experiential and emotional outcomes of people living with dementia (PLWD). Previous studies have shown that the practice of poetry has the potential of improving health, cognitive, and communicational outcomes of PLWD. Also, it is supportive in understanding the experiences and needs of PLWD and has proved to be an effective mechanism to improve the relationships between PLWD and their caregivers. Even though much needed poetry interventions have been developed and implemented to serve diverse populations in the United States, no culturally safe programs specifically for Indigenous PLWD have been developed.MethodUsing a community‐based participatory research (CBPR) framework and Indigenous methodologies, this study is based on the development and implementation of a pilot therapeutic poetry program for Indigenous PLWD and their caregivers in an Indigenous Nation in Minnesota, through the adaptation of existing techniques used to deliver poetry‐based therapy for PLWD. Aligned with CBPR principles, this pilot program will be facilitated and evaluated by community members.ResultsN/AConclusionWith the participation of 12 Indigenous dyads, this project aims to (a) implement a sustainable program that can be replicated in other communities; (b) assess the effects of the program on dyads’ relationships, quality of life, intra‐community relationships, cultural performance, and Indigenous identity; and (c) identify mechanisms that improve quality of life, quality of care, relationships, and the regulation of behavioral issues for PLWD in the Indigenous context.
Unraveling Pathways in Alzheimer’s Disease: Insights into Rap1 Signaling Associations with Focal Adhesion and Shigellosis
Authors: Garg Meher , Lee Inhan 
Published: January 2025

AbstractBackgroundExisting therapeutic approaches in Alzheimer’s disease (AD) targeting beta‐amyloid and tau proteins have shown limited success. Shigellosis, an intestinal infection caused by Shigella, is capable of colonizing the human intestinal epithelium and has been associated with focal adhesions. Rap1 signaling is associated with cancer and cell adhesions. Upregulation of the RAP1 signaling pathway and its interactions with other signaling pathways could contribute to synaptic dysfunction, neuronal damage, and cognitive deficits and has emerged as a candidate pathway for study in Alzheimer’s disease. Associations between the Rap1 signaling pathway, focal adhesion and shigellosis could shed further light on pathogenesis of AD.MethodWe leveraged the Gene Expression Omnibus (GEO) GSE109887 dataset, available on the NIH’s GEO2R website, comprising microarray RNA expression data from medial temporal gyrus of 46 AD patients and 32 controls. Differential gene expression analysis was conducted using GEO2R. Gene interaction analysis and identification of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed using STRING‐DB. Gene function insights were obtained from Gene Cards. Statistical analysis and heatmap visualization were conducted using R/R Studio.ResultsAfter analyzing using STRING, the top 250 expressed genes in AD patients were associated with upregulated KEGG pathways. The Rap1 signaling pathway had a false discovery rate (FDR), p‐value of 0.0212, strength of 0.64, and count in network of 10/201. The shigellosis pathway had a FDR of 0.00088, strength of 0.71, and count in the network of 13/218. The focal adhesion pathway had a FDR of 0.0212, strength of 0.65, and count in network of 10/195. The upregulated genes present in Rap 1 signaling and shigellosis were ITGB1, TLN2, PLCB1, PLCE1, and PLCG1. The genes found in Rap 1 signaling and focal adhesion were ITGB1, TLN2, RAF1, PDGFRB, and PRKCG.ConclusionOur findings provide valuable insights into the molecular mechanisms underlying AD. The dysregulated pathways in AD show an association between Rap1 signaling and focal adhesion and shigellosis. Upregulation of the Rap1 signaling, focal adhesion and shigellosis pathways could be a biomarker/potential therapeutic target and should be evaluated in future study.
Adapting healthcare infrastructure for disease‐modification in early Alzheimer’s disease
Authors: Rothwell Simon , Polotti Enea , Eksteen Christine 
Published: January 2025

AbstractBackgroundWith the emergence of disease‐modifying therapies (DMTs) for early Alzheimer’s disease (AD), evolution of healthcare infrastructure is needed to identify patients eligible for treatment with an AD DMT, and to adequately treat and monitor patients throughout. Our research aimed to assess current practices and available infrastructure, to identify bottlenecks, and to propose solutions to increase patient access to AD DMTs in the EU4+UK.MethodsWe searched publicly available information (to August 2023) to derive a foundational understanding of the current level of healthcare infrastructure in each country. Subsequent primary research with 11 neurologists and 39 hospital administrators across the 5 countries informed an assessment of AD diagnostic, infusion, and monitoring capacity.ResultsMagnetic resonance imaging (MRI) is recommended for differential dementia diagnoses and will be required for monitoring patients throughout treatment with an AD DMT. However, in most countries, capacity is expected to bottleneck due to shortages in MRI machinery, trained staff, and limited allocation of scans to AD. Optimizing the use of MRI will be key to expanding patient access to AD DMTs. Confirming amyloid positivity via cerebrospinal fluid testing/ lumbar puncture or positron emission tomography (PET) is recommended for AD diagnoses and a requirement for AD DMT eligibility. Amyloid PET is not widely conducted due to a lack of dedicated centers and/or reimbursement in some countries, whereas lumbar puncture is not expected to be associated with major access challenges. AD DMTs require administration via infusion; however, current neurology units are adapted for infusions of DMTs for multiple sclerosis. Infusion capacity may also be limited by trained staff shortages and lack of dedicated outpatient infusion units for AD. There is potential to repurpose some infusion capacity to AD.ConclusionsEuropean healthcare system infrastructure can adapt to improve access to AD DMTs. Establishing and/or expanding country‐wide networks of accredited hospitals and external/private partnerships could allow patients greater access to services across multiple locations and individual hospitals to better leverage external resources. At an organizational level, more resources can be allocated towards AD and efficient resource planning can help to optimize healthcare for patients with early AD.
Implication of Chronotherapy in mouse models of Alzheimer’s Disease
Authors: Shi Yu , Salinas Ricardo , McRoberts William , Rozen Stephen , Swint Jordan , Bloom George S , Güler Ali 
Published: January 2025

AbstractBackgroundSleep disturbances are commonly observed in early‐stage Alzheimer’s Disease (AD) patients and correlate with their cognitive performance over time. Sleep in mammals is governed by the central circadian system, which responds to environmental cues like light and aligns with daily routines such as eating.MethodIn this study, we developed a regimen with a shortened light phase (LD = 8:16), time‐restricted feeding, and exercise (LiFE) to strengthen the circadian system and enhance sleep quality in 5xFAD and 5xFAD‐PS19 AD mice.ResultThis approach enhanced cognitive performance in Morris water maze and novel object recognition tests. The LiFE treatment did not reduce amyloid plaques or tau phosphorylation.ConclusionOur study shows that, independent of AD histopathological changes, LiFE chronotherapy enhances cognition in AD model mice, with the potential to improve cognition in human AD patients. We are currently exploring the neural mechanisms and biological processes impacted by the LiFE treatment.
Activation of the muscle‐to‐brain‐axis reduces amyloid plaque accumulation and rescues behavioral deficits by enhancing synaptic integrity and neurotrophic signaling in a mouse model of Alzheimer’s disease
Authors: Taha Hash Brown , Birnbaum Allison , Matthews Ian , Aceituno Karel , Leon Jocelyne , Thorwald Max A , Godoy‐Lugo Jose A , Cortes Constanza J 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is associated with complex pathophysiology including synaptic dysregulation, compromised neurotrophic signaling, deficits in autophagic flux and neuroinflammation). Skeletal muscle regulates many brain functions relevant to aging, by activating the muscle‐to‐brain axis through the secretion of skeletal muscle originating factors (myokines) with cellular‐modifying, neuro and geroprotective properties. Our group developed transgenic mice that overexpress the skeletal muscle human Transcription Factor EB (TFEB), a master regulator of lysosomal‐to‐nucleus signaling, resulting in enhanced proteostasis and neuroprotection in a Tau mouse model. However, the precise mechanisms remain unknown. Therefore, we further validated these effects in an AD amyloid β (Aβ) mouse model and investigated the underlying mechanism.MethodWe crossbred female 5xFAD mice, carrying 5 AD familial mutations, with transgenic mice that overexpress human TFEB to create 5xFAD;cTFEB;HSA‐Cre (3FA) mice. At 4 and 8 months of age, we analyzed Aβ plaque accumulation through immunohistochemistry and conducted western blot analysis for multiple synaptic markers, growth factors, autophagic/lysosomal regulators, and myokines across the muscle‐to‐brain axis. We also performed a battery of neurocognitive tests (open field, the Barnes maze, and fear conditioning) at 8 months of age, when this model has previously been reported to demonstrate robust cognitive impairment.ResultSkeletal muscle‐targeted TFEB expression reduced Aβ plaque accumulation in cortices of 4‐month‐old female mice. Furthermore, muscle‐TFEB expression altered synaptic‐associated gene transcriptional signatures in hippocampi, and rescued behavioral deficits in 8‐month‐old female 5xFAD mice. Western blots of cortex from 8‐month‐old female 3FA mice confirmed a rescue of several synaptic markers including SNAP25, synaptophysin I, synaptotagmin I and PSD95, neurotrophic factors such as BDNF and autophagic/lysosomal regulators such as Cathepsin D and B, prosaposin (PSAP) and saposin C. Levels of PSAP (a recently identified exercise‐responsive myokine) were also increased in skeletal muscle, plasma and cortices, suggesting that PSAP may act as a novel myokine involved in muscle‐to‐brain rescue mechanisms. scle, plasma and cortices of 8‐month‐old female mice, suggesting that PSAP may act as a novel myokine involved in muscle‐to‐brain rescue mechanisms.ConclusionSkeletal muscle directly regulates CNS function and health in the 5xFAD model regulating synaptic integrity, neurotrophic signaling and autophagic flux, potentially through release of CNS‐targeting myokines.
A harmonized, histology‐based protocol for selection of medial temporal lobe cortical subregion ranges on magnetic resonance imaging
Authors: Adams Jenna N. , Baumeister Hannah , Doan Thanh , Maass Anne , Mazloum‐Farzaghi Negar , Tran Tammy T , Wuestefeld Anika , Augustinack Jean , Ding Song‐Lin , Insausti Ricardo , Kedo Olga , Bakker Arnold , Berron David , Canada Kelsey L. , Carr Valerie A , Dalton Marshall Axel , Daugherty Ana M. , de Flores Robin , La Joie Renaud , Mueller Susanne G , Olsen Rosanna K , Stark Craig EL , Wang Lei , Wisse Laura E.M. , Yushkevich Paul A. 
Published: January 2025

AbstractBackgroundThe medial temporal lobe (MTL) has distinct cortical subregions that are differentially vulnerable to pathology and neurodegeneration in diseases such as Alzheimer’s disease. However, previous protocols for segmentation of MTL cortical subregions on magnetic resonance imaging (MRI) vary substantially across research groups, and have been informed by different cytoarchitectonic definitions, precluding consistent interpretations. The Hippocampal Subfields Group aims to create a harmonized, histology‐based protocol for segmentation of MTL cortical subregions that can reliably be applied to T2‐weighted MRI with high in‐plane resolution.MethodNissl‐stained sections from the temporal lobes of three human specimens (66‐90 years old; 2 female) were annotated by four expert neuroanatomists for the following MTL subregions: entorhinal cortex (ERC), Brodmann’s Area 35 (BA35; largely corresponding to “transentorhinal” cortex), Brodmann’s Area 36 (BA36), and parahippocampal cortex (PHC). On each histology section, the number of annotations and the spatial overlap of annotations were analyzed to determine the consensus of the anterior to posterior range of each structure. Gross anatomical landmarks, detectable on MRI and reliably corresponding with each range, were then selected to create an MRI ranging protocol. Feasibility of this MRI protocol was tested by two independent raters across four MRI scans (two healthy adults, two older adults), and agreement in range selection was assessed using Cohen’s kappa statistic.ResultThe proposed MTL ranging protocol is shown in Fig. 1, and corresponding histology data substantiating the protocol is shown in Fig. 2. MRI‐visible gross anatomical landmarks that reliably corresponded with the anterior or posterior range of each subregion on histology included the anterior‐most appearance of the collateral sulcus (Fig. 3A), hippocampal head (Fig. 3B), hippocampal body, and anterior calcarine fissure (Fig. 3C). This protocol demonstrated high feasibility when applied to MRI, with average kappa values of 0.75 ± 0.07, representing a “substantial” level of agreement of range selection.ConclusionFuture directions include obtaining consensus on this protocol from the larger research community through a Delphi procedure, and expansion of the protocol to include slice‐by‐slice segmentation guidelines for full delineation. This harmonized, histology‐based protocol will facilitate critical research on MTL subregion vulnerability and their contributions to memory deficits in Alzheimer’s disease.