bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep Brain Stimulation of the Medial Septum Improves Okadaic Acid‐Induced Impairment of Spatial Working Memory and Restores the Cholinergic Activity in the Hippocampus
Authors: CHIGHLADZE MARIAM , Rusadze Khatuna , Burjanadze Maia , Dashniani Manana , Kruashvili Lali 
Published: January 2025

AbstractBackgroundThere is growing evidence from laboratory and clinical trials that deep brain stimulation (DBS) at memory associated structures enhances cognitive functions. Best site for memory enhancing‐DBS is still unclear. The medial septum (MS), the important modulator of the hippocampal neural network, might be a key target to accomplish therapeutic efficacy in memory impaired patients.In the present study, we evaluated the effect of medial septum (MS) deep brain stimulation (DBS) on okadaic acid (OA) induced impairment of spatial working memory and neuropathological changes in the hippocampus in rats.MethodRats were divided in four groups: rats in the normal group had no surgical procedure (group – N); rats in the lesion group had ICV administration of OA (group – O); rats in the implantation group had ICV administration of OA and implantation of an electrode in the MS (group – O/I); rats in the stimulation group had ICV administration of OA and electrical stimulation of the MS (group – O/S). In the chronic DBS experiment, animals received stimulation (60 Hz, 60 𝜇s, 50 𝜇A) 2 hr daily for a period of 2 weeks. In behavioral experiments the possible beneficial effect of chronic DBS of MS on the OA‐induced spatial short‐term memory impairment was examined in spontaneous alternation task in the plus‐maze. At the end of the behavioral experiments, six rats from each group were used by random sampling in the histological studiesResultThe results showed that MS DBS improves OA‐induced impairment of spatial working memory and restores acetylcholinesterase (AChE) immune‐stained cells numbers in the hippocampal CA1 and CA3 fields. We hypothesize that the enhancement of working memory function may be associated with an increase in hippocampal neurogenesis and hippocampal cholinergic activity induced by MS DBS in a rat model of AD.Conclusionwe suggest that the enhancement of working memory function may be associated with an increase in hippocampal neurogenesis and recovery of the AChE immune‐stained cells numbers in the hippocampus induced by MS DBS in a rat model of AD. These results allow us to identify the medial septum as one of the stimulation sites for improving memory function.
Particularity of Cerebral Microcirculatory Changes in Dementia Patients with Alzheimer’s Disease Compared to Other Cerebrovascular Diseases
Authors: Maksimovich Ivan V 
Published: January 2025

AbstractBackgroundDementia aggravates most cerebrovascular lesions, which requires differentiating the developed microcirculatory changes when making a diagnosis.We consider the features of cerebral microcirculation disorders in Alzheimer’s disease (AD), distal cerebral atherosclerosis, Binswanger’s disease (BD), and vascular parkinsonism (VP).MethodThe study included 1024 patients who underwent: assessment of CDR, TDR, MMSE, cerebral MRI, MRA, CT, MSCTA, scintigraphy (SG), rheoencephalography (REG), cerebral multi‐gated angiography (MUGA).Patients were divided into:• Test group ‐ 93 people with AD aged 34‐80 (average age 67.5): men ‐ 32 (34.40%), women ‐ 61 (65.59%). According to dementia severity, patients were divided into (TDR‐0) ‐ 10, (TDR‐1) ‐ 29, (TDR‐2) ‐ 36, (TDR‐3) ‐ 18 people;• Control group ‐ 931 people aged 29‐81 (average age 78): men ‐ 687 (73.79%), women ‐ 244 (26.21%) with distal cerebral atherosclerosis ‐ 842 (90.44%), BD ‐ 27 (2.9%), VP – 62 (6.66%) people. According to dementia severity, patients were divided into unnoticed dementia ‐ 570, dementia at level (CDR‐1) – 333, (CDR‐2) ‐ 28 people.ResultIn all test group AD patients, changes in angioarchitecture and microcirculation manifest themselves in:• absence of atherosclerotic changes in intracerebral arteries,• increased tortuosity of intracranial arteries’ distal parts,• the capillary bed reduction in the temporal and frontoparietal regions,• development of multiple, large arteriovenous shunts with early venous discharge of arterial blood in the same sections,• abnormal, intracerebral venous trunks development,• development of intracerebral venous blood stagnation,These changes are called “Dyscirculatory Angiopathy of Alzhemer’s type” (DAAT).In control group patients, changes in angioarchitecture and microcirculation manifest themselves in:• multiple deposits of calcium salts and atherosclerotic changes in intracerebral arteries,• local decrease in cerebral capillary blood flow in the same sections,• development of local small intracerebral arteriovenous shunts,• absence of marked intracerebral stagnation of venous blood.ConclusionDyscirculatory angiopathy of Alzheimer’s type (DAAT), regardless of dementia severity, is a cerebrovascular and microcirculatory brain lesion specific to AD, not associated with the atherosclerotic process.In patients with distal intracerebral atherosclerosis, BD and VP, there are no specific changes similar to DAAT. Vascular and microcirculatory changes are atherosclerotic in nature.
Physical Characterisation of pre‐clinical progressive model of Alzheimer’s Disease
Authors: Iqbal Abdullah Asad , Almari Bushra 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease research lacks a suitable model to match the sporadic version of Alzheimer’s Disease (SAD). We a propose a model that will use 7PA2 cells which is a CHO modified to express the V717F mutation for APP (Indiana mutation). The 7PA2 cells will then be placed inside alginate microbeads to produce a factory that constantly produces amyloid species. Then the injected into the brains of rats. Generating pathological changes which can be compared against previous models and human data to test whether this model is more appropriate than current models.MethodAlginate beads where produced of various different concentrations of alginate (Alg) and the gelling agent (calcium chloride ‐ CaCl2). 0.4 ‐ 8%Alg and 0.1M CaCl2 ‐ 1M CaCl2.Stability measured as change in diameter using a Keynes microscope and comparing diameter for beads containing bv2 cells and no cells.Stability also compared in aCSF.Young Modulus was measured using a texture analyser and rheometer.Inflammatory effects of alginate on BV‐2 cells characterised through TNF‐alpha.ResultWe found no changes in stability with changes in Alg or CaCl2 or if beads were in aCSF or distilled water for 4 weeks. (n = 50).No significant effects of alginate on TNF‐alpha expression levels.Young Modulus of Alg beads of 1.5% Alg and 0.3%M closely matches brain environment.ConclusionAlginate beads are stable over time in a brain‐like environment. Furthermore alginate beads of 1.5% Alg and 0.3%M closely match the brain environment. Alginate also causes no significant inflammatory response. Therefore alginate is a suitable carrier for 7PA2 further work must now be done in characterising 7PA2 cells and their amyloid species and the eventual effects in the brain.
sTREM2 mediates the correlation between BIN1 gene polymorphism and tau pathology in Alzheimer’s disease
Authors: Guo Fan , Sheng Ze‐Hu , Ou Ya‐nan , Wang Zuo‐teng , Zhao Qing‐Fei , Shan Tan Meng , Tan Lan ,   tanlan
Published: January 2025

AbstractBackgroundBridging integrator 1 (BIN1), one of the most strongly associated gene with Alzheimer’s disease (AD). It has been reported to play a role in the pathological processes of AD; however, the exact mechanism has not yet been completely found.MethodAlzheimer’s Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and the Chinese Alzheimer’s Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model was used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia‐soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of sTREM2 on AD pathology.ResultIn the ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and the levels of CSF phosphorylated‐tau (P‐tau) (Pc = 0.017; 0.010, respectively) and total‐tau (T‐tau) (Pc = 0.011; 0.013, respectively). The BIN1 loci were also found to be correlated with the levels of CSF sTREM2 (Pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of the BIN1 loci with P‐tau (rs7561528: Prop = 20.9% of total effect; rs744373: Prop = 24.9% of total effect) and T‐tau (rs7561528: Prop = 36.6% of total effect; rs744373: Prop = 44.1% of total effect). The analysis in CABLE study replicated the mediation role of rs7561528.ConclusionThis study demonstrated correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarker, particularly in preclinical AD. Additionally, the link between BIN1 loci and AD pathology was partially mediated by CSF sTREM2
An endolysosome pathway specific polygenic risk score for Alzheimer Disease predicts cell‐type specific transcriptomic and morphological phenotypes
Authors: Prater Katherine E , Rose Shannon , Johnson Corbin S.C. , Strohbehn Sam , Cochoit Alexandra J , Mamde Sainath , Sun Wei , Keene C. Dirk , Shojaie Ali , Garden Gwenn A , Blue Elizabeth E , Young Jessica E. , Jayadev Suman 
Published: January 2025

AbstractBackgroundLate onset Alzheimer disease is a complex syndrome, genetically, clinically and pathogenetically heterogeneous. Genome Wide association studies have identified risk alleles for AD harboring genes in the endolysosomal network (ELN). We hypothesize that aggregate burden of these endolysosomal risk alleles impacts cell type specific ELN function, thus contributing to LOAD pathogenesis.MethodTo test this hypothesis, we first developed an endolysosomal polygenic risk score (ePRS) using a curated list of established GWAS AD risk loci. We identified a cohort in the top quartile (high) and bottom quartile (low) of ePRS scores within our LOAD biobank with rich clinical and pathological phenotype data, enabling brain tissue omics and cell based functional studies from the same donor. To explore cell type specific implications of ePRS burden, we studied frozen cortical brain tissue and primary cells derived from the same set of LOAD cases.ResultWe identified cell type‐specific gene expression and regulatory network shifts associated with ePRS burden. Immunohistochemistry revealed that high ePRS was associated with enlarged neuronal endosomes and microglial lysosomes. We explored whether ePRS itself predicted ELN changes in cells that are not exposed to pathologic protein deposition. Leptomeningeal cells isolated from the ePRS cohort also manifested changes to ELN morphology and bulk RNA sequencing revealed ePRS‐dependent gene expression changes, suggesting that ePRS directly influences ELN related transcriptomic phenotype.ConclusionTaken together, our data suggests that AD risk loci implicating genes within the endolysosomal system do in fact impact the cellular ELN, giving more confidence to the pathogenic relevance of “endolysosomal” risk loci. Dysfunction of endolysosomal pathways likely contributes to AD pathogenesis in LOAD and may highlight more specific points of intervention. Pathway‐specific polygenic risk scores can enhance our understanding of the complex mechanisms contributing to AD and pave the way for more specific targeted therapies in the clinic.
Five‐year Trajectory of Mild Behavioral Impairment in People with Subjective Cognitive Complaints
Authors: Creese Byron 
Published: January 2025

AbstractBackgroundMild Behavioral Impairment (MBI) describes a spectrum of late‐life onset, sustained neuropsychiatric symptoms grouped in five domains: mood/anxiety, apathy, impulse dyscontrol, social inappropriateness and psychosis. MBI is a well‐established correlated of incident dementia and is associated with PET amyloid and blood biomarker profiles consistent with early AD however little is known about the trajectory of MBI. This study set out to determine the course of MBI symptoms in a cohort of older adults with and without subjective cognitive complaints (SCC).MethodData from 3,428 adults aged over 50 were analysed. All had five years of annual follow up assessments. SCC was determined by self‐completed IQCODE scale at baseline(mean score <3.3: normal cognition (NC); >3.3: SCC). MBI was assessed using the MBI Checklist (MBI‐C) (higher scores indicating more severe symptoms). Change in MBI‐C score by SCC status was conducted using zero‐inflated negative binomial models. A random intercept was included to allow for correlations between repeated measurements on the same individual. Trajectories of mood/anxiety and apathy were also analysed. The other three domains were not due to low counts of non‐zero scores.ResultThe mean age at baseline was 64 and 78% of the sample were women. Fifteen percent (n = 514) had SCC. The SCC group had higher MBI scores than NC. For the SCC group, there was a statistically significant exponential increase in MBI‐C score over 5‐years. At baseline, total MBI‐C score was 3.5[3.1‐4], rising to 4.6[4.1‐5.2] in year 4 and 6[5.2‐7] in year 5 (Figure 1). For NC, the increase over 5 years was more modest, rising from 1 at baseline to 2.2 by year 5.ConclusionTo our knowledge this is largest study of trajectories of MBI symptoms. We show that symptoms are not stable but show an exponential increase over time in those with SCC, while in those with normal cognition the overall trend was flat. These are population averaged estimates and there will be a degree of variability in the data which may warrant more individual‐level prediction modelling in future. As well as being a marker of cognitive risk, SCC may also represent a risk state for worsening neuropsychiatric symptoms.
Unusually young onset of spastic paraparesis in a carrier of both the A431E PSEN1 and A713T APP variants
Authors: Ringman John M , Sheikh‐Bahaei Nasim , Villareal Enrique Israel Velazquez , Craig David , Islas Miguel Angel Macias 
Published: January 2025

AbstractBackgroundThe ways in which diverse genetic variants interact to affect the phenotype of AD is poorly understood. The relatively consistent phenotype associated with specific mutations causing autosomal dominant AD (ADAD) provides the opportunity to study how other genetic variants contribute to disease manifestations.MethodWe performed an in‐depth case study of a patient with the A431E PSEN1 mutation who had onset of progressive spastic paraplegia at age 20.ResultThe proband was a Mexican woman known to be at 50% risk for inheriting the A431E PSEN1 mutation that commonly presents with cognitive changes and/or spastic paraplegia at age 40. At age 20 she began developing stiffness in her legs and difficulty walking. When seen at age 26 she had diffuse spasticity worse in the legs, slurred speech, and was cognitively intact. A flortaucipir PET scan at the time was negative as was a florbetaben scan 21 months later despite marked differences from controls in DTI measures in the corticospinal tract. Genetic screening demonstrated the presence of the A431E PSEN1 mutation and an A713T APP variant which was confirmed by WGS. The A713T APP variant was not present in her mother who had more typical disease nor in 62 other persons of Mexican origin.ConclusionThe A713T variant in APP has been shown to affect APP processing and Abeta nucleation and is considered to be a risk factor for AD. We hypothesize that the presence of this variant led to the early onset of spastic paraparesis in our proband despite Abeta deposition in brain being undetectable on PET. This finding suggests spastic paraplegia may be related to aberrant APP processing in a manner distinct from plaque formation.This study was funded by R01AG062007 and R01AG069013
P2RX7 deficiency prevents cognitive deficit, brain atrophy and tauopathy progression in PS19 mice via suppression of extracellular vesicle secretion and mitochondrial toxicity
Authors: Santos Victor B , Abdullah Mohammad , Ellison Justice , Ruan Zhi , Ikezu Tsuneya , Ikezu Seiko 
Published: January 2025

AbstractBackgroundWe previously identified the novel mechanism of pathological tau transfer via extracellular vesicles (EVs) in Alzheimer’s disease (AD). Targeting EV secretion to mitigate tau transfer is therefore a promising therapeutic approach for AD. P2X purinoreceptor 7 (P2RX7), an ATP‐gated cationic channel, regulates microvesicle shedding or secretion of multivesicular body‐derived exosomes. We aim to investigate the effect of P2rx7 deficiency on disease progression in PS19 tauopathy mouse model in vivo and by proteomic profiling of brain EVs.MethodPS19:P2rx7–/– mice at 9 months of age were tested for the fear conditioning, and pathology assessment of the brain atrophy and tau using immunofluorescence against aggregated tau (Alz50) or phosphorylated tau (AT8) and ELISA. Mice were intracranially injected with viral vectors expressing mEmerald‐CD9 in microglia and P301L tau in neurons to visualize the secretion of microglial EV and extracellular tau in vivo. Brain EV samples were subjected to proteomic profiling by data independent acquisition mass‐spectrometry.ResultPS19:P2rx7–/– mice showed significant improvement in contextual and cued memory compared to age‐matched PS19 mice, which was accompanied by preserved cortical and hippocampal volume, and significant reduction of hippocampal tau pathology and pS396 tau in sarkosyl‐insoluble fraction of brain tissues. The number of GFP+ microglial EVs were significantly reduced in P2rx7–/– compared to WT mice. Gene ontology pathway analysis of EV proteome showed significant enrichment of mitochondrial pathways in PS19 group compared to WT group, which was significantly downregulated in PS19:P2rx7–/– group.ConclusionOur study demonstrated that P2rx7 deficiency ameliorates cognitive dysfunction and tau pathology development in PS19 mice by dampening microglial EV secretion and EV‐mediated mitochondria transfer, further indicating the therapeutic potential of targeting P2RX7, an EV regulatory molecule, to ameliorate AD progression.
Human brain microglia responses to amyloid beta and tau pathology in high pathology controls and across disease stages
Authors: Melnik Mikhail , Mitri Vivianne , Atluri Swetha , Knitowski Nina , Kodavatikanti Achyutha , Bilousova Tina , Rexach Jessica E , Gylys Karen H 
Published: January 2025

AbstractBackgroundMicroglia responses to Aβ and tau pathology and the dysregulation of the microglial role in synaptic function may determine the onset and course of Alzheimer’s disease (AD). While significant work has been performed in mouse models, we still lack a complete understanding of physiological and pathological microglial states and functions in human AD brain.MethodFor immunoblotting of brain homogenates against multiple microglial markers, and flow cytometry (FC) analysis of synaptosomal fractions (SNAP25/CD47/Aβ(10G4)/phospho‐tau(AT8)), 49 cryopreserved human parietal cortex samples were categorized into four groups: low pathology control (LPC), high Aβ control (HAC), high pathology control (HPC), and AD. Selected microglia markers were assessed in the snRNAseq dataset (Rexach et al., 2023, bioRxiv) and validated by immunohistochemistry (IHC) analysis.ResultIn the LPC group, only 22.5% of Aβ‐positive (+)/p‐tau‐negative (‐) synaptosomes expressed CD47 on their surface, with a significant progressive increase in the percentage (%) of CD47+ events in the Aβ+/p‐tau‐ group across disease stages, reaching 53.4% in the AD group. Surprisingly, Aβ+/tau+ synaptosomes expressed the highest CD47 levels, suggesting protection from elimination. Higher levels of P2ry12 and CD206 were found in the LPC group compared to all other groups in brain homogenates. Interestingly, the levels of P2ry12, CD206, and Axl1 were significantly higher, and the level of Clec7a was significantly lower in the HPC group compared to the AD group. Linear regression modeling revealed a significant negative association between P2ry12 and synaptic tau pathology, as well as CD47 expression in p‐tau‐positive synaptosomes. Interestingly, in primary tauopathy microglia (but not AD microglia), IKFZ1‐regulated genes, including P2ry12, were upregulated according to snRNAseq and around p‐tau‐bearing neurons by IHC.ConclusionOur data suggest that in normal aging, synaptic Aβ accumulation leads to a diminishing of synaptic CD47 (‘don’t eat me’) signal, accelerating the clearance of malfunctioning Aβ but not p‐tau positive synapses. Upregulation of P2ry12 and CD206, accompanied by downregulation of Clec7a, may represent an early and potentially protective response to pre‐tangle tau pathology. Later in disease progression, P2ry12 reduction may drive a more reactive, phagocytic phenotype in response to tau pathology, leading to an increase in synaptic CD47 levels and synaptic pathology accumulation.
Depression Significantly Predicts Clinical Functioning Among Hispanic older adults
Authors: Duarte Andres , Padron Dilianna , Garcia Patricia , Mendoza Lisandra , Fiala Jacob , Marsiske Michael , Duara Ranjan , Rodriguez Miriam J. 
Published: January 2025

AbstractBackgroundHispanics are disproportionately affected by Alzheimer’s disease and related dementias (ADRD) when compared to non‐Hispanic Whites (NHW). Previous studies have shown that neuropsychiatric symptoms can further exacerbate clinical functioning among ADRD patients, leading to increase in caregiver burden and poorer quality of life. However, most studies in this area have focused on predominately Caucasian samples, and relationships between emotional and clinical functioning among Hispanic older adults at risk of ADRD are poorly understood. The aim of the current study was to examine predictive associations between emotional and clinical functioning among Hispanic ADRD older adults at risk of developing ADRD.MethodsThe Geriatric Depression Scale (GDS) and the modified Clinical Dementia Rating scale (mCDR) were administered to Hispanic (n = 159) and NHW (n = 101) participants from the 1Florida Alzheimer’s Disease Research Center (ADRC). Participants were aged 60‐90 years (Hispanics: M = 70.87, SD = 7.28; NHW: M = 73.24, SD = 7.72) and were either cognitive normal (n = 52) or diagnosed with Mild Cognitive Impairment (MCI, n = 208). Multiple linear regression analyses controlling for age and diagnosis were applied to examine predictive relationships between the emotional and functional measures for the two ethnic groups separately.ResultsResults showed significant positive relationship between the mCDR and the GDS (β = 0.01, SE = 0.00, t = 2.33, p > .05) among the Hispanic sample and interaction effects between diagnosis and GDS scores were not significant (β = 0.00, SE = 0.01, t = ‐0.41, p = 0.68). No significant associations were noted among the NHW group (β = 0.01, SE = 0.00, t = 1.13, p = 0.26).ConclusionDepression significantly predicted poorer clinical functioning among the Hispanic group only even when controlling for the effects of diagnosis. These findings indicate that the effect of emotional symptoms has a clinical impact on functioning among Hispanic older adults and may be related to increased risk of further decline and ADRD diagnosis. These results have important implications for dementia care. Future studies should examine these associations as they relate to ADRD risk and longitudinal clinical functioning.