bluuebunny/crossref_metadata_2025_split huggingface dataset:
Psychosocial Stress‐Accelerates Alzheimer’s Disease Progression via the Xanthine Oxidase Pathway
Authors: Burrage Emily , Prabhu Saina , Oudomvilay Crystal , Simpkins James W , Kelley Eric E , Chantler Paul D 
Published: December 2022

AbstractBackgroundVascular contributions to cognitive impairment and dementia are a key pathology associated with Alzheimer’s disease (AD). We have shown that chronic stress induces cerebrovascular dysfunction due to a pro‐oxidative environment, a phenotype similar to that noted with AD. Epidemiological studies also suggest a link between chronic stress and dementia. We tested the hypothesis that chronic stress accelerates the AD pathology via the xanthine oxidase (XO) pathway.MethodsWild type (WT) and Triple transgenic (AD) mice were separated into 1) WT control, 2) WT+UCMS, 3) AD control, 4) AD control+Feb, 5) AD+UCMS, 6) AD+UCMS+Feb. At 4 months‐of‐age, dependent upon group, the unpredicted chronic mild stress (UCMS) model with or without Febuxostat (Feb) treated water (50mg/L) began for 8 weeks. Mice were either euthanized at 6 or 9 months‐of‐age. The middle cerebral artery (MCA) was removed for pressure myography. Brains were homogenized to extract soluble and insoluble fractions of tau proteins using Western blot normalized to GAPDH or B‐actin.ResultsAt 6 months‐of‐age, AD mice displayed a 72% impaired MCA dilation to acetylcholine compared to WT control mice (p<0.05). WT and AD mice that underwent UCMS displayed similar MCA dysfunction compared to AD control mice. UCMS accelerated total and phosphorylated tau protein expression by 83% (p<0.05) and 350% (p<0.001), respectively, compared to AD controls. Treatment with Feb prevented MCA dysfunction in AD control mice, WT UCMS mice, and AD UCMS mice. Feb prevented the increased expression of phosphorylated tau and lowered the total tau protein expression in the AD‐UCMS group. However, total tau protein expression remained higher compared to AD control levels. At 9 months‐of‐age, the majority of these trends persisted with the one exception being a significant impairment in the AD UCMS group compared to both AD control or WT UCMS mice. Tau levels have yet to be processed for 9‐months.ConclusionOverall, these data suggest that chronic stress accelerates cerebrovascular pathology with AD and via a pro‐oxidative state driven by activation of the XO pathway. We will further explore Aβ1‐42 and XO in 3xTg brain homogenates at 6 and 9 months‐of‐age, to better understand how stress accelerates AD pathology.
Detecting genetic loci for preservation of cognition in the Midwestern United States Amish
Authors: Main Leighanne R. , Song Yeunjoo E. , Laux Renee A. , Miskimen Kristy L. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Osterman Michael D. , Lynn Audrey , Dorfsman Daniel A. , Caywood Laura J. , Prough Michael B. , Adams Larry D. , Clouse Jason E. , Herington Sharlene D. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L. 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) is the most common form of dementia and has limited treatments. While AD risk has a large genetic component, under 50% of the genetic risk has been identified. By focusing on identifying genetic variants that delay or prevent the onset of AD, our goal is to identify new associated genes and variants. To detect such loci, we studied cognitive preservation in the Midwestern Amish, a genetically and culturally isolated population of European descent.MethodsWe studied 946 Amish individuals (ages 76‐95) from Ohio and Indiana. Participants were classified as cognitively impaired (33.8%) or cognitively unimpaired (66.2%) by consensus review of cognitive examinations. These individuals were all connected in a 15‐generation 8,222‐person pedigree. This pedigree was divided into 104 sub‐pedigrees via PedCut for linkage analysis. MERLIN was used for autosomal linkage analysis, while MINX was used for X‐chromosome linkage analysis. The association analysis, corrected for genetic relationship, used GENESIS for autosomes and XWAS for the X chromosome.ResultsOver 250,000 SNPs were used for association and two‐point linkage analyses, and a subset of 5,294 uncorrelated SNPs was used for multipoint linkage analyses. on 15 different chromosomes, with the highest two‐point heterogeneity LOD score (HLOD = 5.85) on chromosome 2 (∼79Mb) and highest multipoint HLOD (3.55) on chromosome 12 (∼25Mb), neither overlapping with known AD genes. Two linkage results overlapped with known AD genes (Chr 6: CD2AP; Chr 11: PICALM) and do not overlap with association results. Significant (p ≤ 6.4x10‐7) and suggestive (p ≤ 1x10‐4) thresholds for association were determined using SimpleM. While no significant associations were found, suggestive associations were found for 103 SNPs (11 loci) across 10 chromosomes. Three of these (chr 11: MS4A2; chr 14: SLC24A4; chr 16: IQCK) fall near known AD genes. These significant and suggestive regions are being followed up currently with fine mapping.ConclusionPreliminary analyses suggest that using cognitive preservation as our phenotype of interest identifies both known AD loci and novel regions that warrant further evaluation and may lead to a further understanding of both AD and cognitive preservation.
Targeting neuroinflammation reduces synaptic, neuronal and cognitive loss in 5xFAD Alzheimer mice.
Authors: Lecca Daniela , Yung Yoo Jin , Scerba Michael T , Tweedie David , Hsueh Shih Chang , Hoffer Barry , Kim Dong Seok , McDevitt Ross A , Greig Nigel H 
Published: December 2022

AbstractBackgroundNeuroinflammation is a consistent characteristic of Alzheimer’s disease (AD); however, whether its development drives disease progression or is an epiphenomenon remains unknown (Gyengesy et al., 2020). In this study, we evaluated how treatment with the Immunomodulatory imide drugs (IMiDs) Pomalidomide (Pom) and more potent novel analog 3,6’‐dithioPomalidomide (3,6’‐DP) affects neuronal and synaptic loss as well as cognitive impairment in a 5xFAD transgenic mouse model of AD, by targeting neuroinflammation. These mice are known to develop neuroinflammation consequent to excessive amyloid‐b (Ab) peptide generation.MethodAs a first step, Pom and 3,6’‐DP neuroprotective and anti‐inflammatory potential were characterized on primary cell cultures challenged with Ab. 5xFAD mice were evaluated over a 4‐month period, during which cognitive deficits develop. Behavioral tests were performed to establish whether selective resolution of neuroinflammation could mitigate cognitive impairment. Pom and 3,6’‐DP effects were assessed on markers of neuronal death, microglial activation, astrogliosis, and expression of PSD‐95 post‐synaptic protein. Changes in levels of inflammatory cytokines and Ab in hippocampus and cortex 5xFAD mice were also measured. Lastly, the teratogenic potential of both compounds was appraised by a cereblon/BRD3 binding FRET assay.ResultPom and 3,6’‐DP reduced neuronal and neurite network loss, as well as microglial cell activation in primary cortical cultures challenged with Ab. In hippocampus and cerebral cortex of 5xFAD mice, 3,6’‐DP, in particular, mitigated elevated expression of Iba1, TNF‐a and GFAP proteins, markers of microglial and astrocyte activation. This was accompanied by reductions in synaptic and neuronal cell loss as well as mitigation of behavioral impairment but, notably, no alteration in either Ab plaque or peptide generation. Both 3,6’‐DP and Pom bound cereblon; however, 3,6’‐DP did not lower Ikaros, Aiolos or SALL4, which are key downstream neo‐substrates involved in the anticancer and teratogenic actions of the IMiD drug class. Hence, 3,6’‐DP could represent a potentially safer drug to lower TNF‐a levels.ConclusionMitigating neuroinflammation in the absence of actions on Ab generation to alleviate neurodegeneration and behavioral impairment indicates that neuroinflammation is a primary causative event in the Ab‐mediated pathological cascade leading to neuronal loss/cognitive impairment. Targeting neuroinflammatory mediators with IMiDs represent a promising AD therapeutic strategy.
PROPOSING THE NEUROGENESIS HYPOTHESIS FOR ALZHEIMER’S DISEASEWITH A CASE STUDY‐ PHASE 2 CLINICAL TRIALS OF NA‐831
Authors: Tran Lloyd , Kurkinen Markku 
Published: December 2022

AbstractBackgroundIn the hippocampus, new neurons are generated throughout life via a process called adult hippocampal neurogenesis (AHN). In mild cognitive impairment (MCI) and mild to moderate AD (early AD), AHN is reduced suggesting that AHN impairment compromises hippocampal functions. Augmenting AHN could help prevent or slow cognitive decline in MCI and early AD. The neurogenesis hypothesis is supported by the results of a Phase 2 randomized, double‐blind, placebo controlled clinical trial of NA‐831.MethodNA‐831 is a small drug molecule, which activates synaptic AMPA receptors, and increases the expression of brain derived neurotrophic factor (BDNF), which is crucial in synaptic plasticity, learning and memory formation in the hippocampus. NA‐831 restores neurogenesis by increasing the number of DCX+PCNA+ neuroblast cells. The study was conducted in 56 patients with MCI, mild and moderate Alzheimer’s disease, who received 10mg to 30 mg of NA‐831 or placebo orally per day for 24 weeks.ResultNA‐831 provided a significant delay in cognitive decline in MCI as measured by ADAS‐Cog‐13, an average score difference of 3.4 compared to placebo (p = 0.01; ITT) after 24 weeks of treatment. Similarly, NA‐831 delayed cognitive decline in early AD, an average score difference of 4.1 com‐pared to placebo (p = 0.001; ITT). CIBIC‐Plus showed 78% of the study participants receiving NA‐831 improved (p = 0.01; ITT). NA‐831 was well‐tolerated at 30 mg/day for 24 weeks, and no serious adverse events were observed.ConclusionThe Neurogenesis Hypothesis, and details of the Phase 2 clinical trials will be presented and discussed.
In vivo cholinergic system integrity and cognition using [18F]‐FEOBV PET in healthy postmenopausal women: a pilot study
Authors: Conley Alexander C , Castellano Tonnar , Boyd Brian , Begnoche John Patrick , Rosenberg Adam J , Shokouhi Sepideh , Dumas Julie , Newhouse Paul A 
Published: December 2022

AbstractBackgroundWomen are at a higher risk of developing Alzheimer’s disease (AD), and a possible reason for this may be the effects of estrogen depletion and cholinergic system activity following menopause. The investigational radiotracer [18F]‐fluoroethoxybenzovesamicol (FEOBV) can assess in vivo cholinergic integrity, as the tracer binds to the vesicular cholinergic transporter at the synapse. FEOBV has previously shown cholinergic system decline in AD patients. The present study is an investigation of cholinergic system integrity in a sample of cognitively normal postmenopausal women, aged 50‐70 years that were part of a larger study examining cholinergic compensation following menopause. We predicted that higher FEOBV standardized uptake value ratios (SUVR) would be associated with larger basal forebrain cholinergic volumes, lower levels of amyloid SUVR, and better cognitive performance as measured by the RBANS.MethodsTen postmenopausal women (mean age: 57.3 ± 5.1 years) completed an FEOBV PET scan (6.5 mCi dose), MRI and cognitive assessments. The FEOBV PET images were co‐registered to the participant’s structural MRI data. FEOBV SUVR was normalized in reference to the supraventricular white matter to avoid partial volume effects from ventricular tissue. Preliminary analyses focused on associations between FEOBV SUVR and the key outcome variables.ResultsPreliminary analyses showed a positive relationship between FEOBV SUVR and the gray‐matter volume of the cholinergic basal forebrain of both hemispheres (L: r=0.51, R: r=0.65). Two participants were amyloid positive, and their FEOBV SUVR values were lower compared to the amyloid negative participants. A positive relationship was also seen between FEOBV SUVR and the RBANS total score, with higher SUVR associated with better cognitive performance (r=0.43).ConclusionsIn a small sample of cognitively normal postmenopausal women, greater FEOBV uptake was positively associated with both basal forebrain volume and cognitive performance. The results of this pilot sample show the importance of cholinergic system integrity in cognitive performance following menopause, supporting the idea that cholinergic integrity may be linearly related to performance and amyloid aggregation. Deterioration of cholinergic integrity post‐menopause may increase the risk of future cognitive decline and development of AD.
VGL101 Rescues CSF1R Dysfunction in Human Microglia And Macrophages: Evaluation of In Vitro Trem2 Agonism in Models Of A CSF1R‐Dependent Leukodystrophy
Authors: Larson Kelley C. , Gergits Frederick , Tchessalova Daria , Renoux Abigail , Figley Matthew , Fisher Richard , Papapetropoulos Spyros , Mirescu Christian 
Published: December 2022

AbstractBackgroundAdult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal dominant primary microgliopathy caused by kinase loss‐of‐function mutations in the CSF1 receptor (CSF1R). The cardinal features of ALSP include demyelination, axonopathy, and symptoms ranging from frontal temporal dementia‐like behavior, movement disorders, epilepsy, and psychiatric manifestations. Many of these hallmarks further resemble Nasu‐Hakola disease, another rare leukoencephalopathy associated with homozygous mutations in triggering receptor expressed on myeloid cells 2 (TREM2) or its tyrosine kinase binding adaptor (TYROBP) which result in complete loss‐of‐function of TREM2 or its signaling partner DAP12. Following binding to its cognate ligands, IL‐34 or CSF‐1, CSF1R dimerization initiates a signaling cascade both through its kinase domain and through DAP12, which together activate SYK to promote myeloid cell survival, proliferation, and morphological changes. While analogous to CSF1R in cellular expression and interaction with DAP12, TREM2 lacks intrinsic signaling capacity and therefore requires DAP12 to translate extracellular damage‐associated cues and orchestrate a constellation of intracellular and functional responses which phenocopy CSF1R activation. Accordingly, we hypothesize TREM2 activation may rescue CSF1R loss‐of‐function and ameliorate ALSP‐associated pathology.MethodsTo test whether TREM2 gain‐of‐function could compensate for CSF1R loss‐of‐function, we developed multiple approaches to model ALSP in human myeloid cells by CSF‐1/IL‐34 depletion or CSF1R kinase inhibition using PLX‐5622 and explored functional intervention via a human TREM2 agonistic antibody, VGL101, currently in Phase‐1 clinical development. Rescue for CSF1R was quantified using a combination of live‐cell morphology captured via automated longitudinal microscopy, viability monitored by ATP Cell‐Titer Glo, and apoptosis quantified by Caspase‐3/7 fluorogenic‐imaging.ResultsIn vitro phospho‐SYK profiling of VGL101 in iPSC‐derived microglia is consistent with its agonist profile (EC50: 0.77 ± 0.08 nM), while the absence of pSYK induction in TREM2‐knockout microglia demonstrates exquisite on‐target selectively. In both CSF‐1/IL‐34 depletion and CSF1R kinase inhibition paradigms of ALSP, VGL101 demonstrated full rescue of microglial and monocyte‐derived macrophage viability, inhibited apoptosis, and promoted morphological changes resembling intact CSF1R activation.ConclusionCollectively, our studies support the hypothesis that TREM2 agonism can compensate for CSF1R dysfunction and highlight the therapeutic potential for treating ALSP with TREM2 agonism via VGL101 passive immunotherapy.
How white matter hyperintensities impacts Alzheimer's disease and frontotemporal dementia across underrepresented Latin American samples
Authors: Campo Cecilia Gonzalez , Fraile‐Vazquez Matias , Ibáñez Agustin 
Published: December 2022

AbstractBackgroundWhite matter hyperintensities (WMH) are frequently observed on MRI scans of older people. Usually interpreted as a sign of cerebrovascular disease (CVD), they are also associated with increased risk of cognitive impairment and dementia. While WMH and CVD are highly prevalent in Alzheimer's disease (AD), this has been less studied in behavioral variant frontotemporal dementia (bvFTD), letting alone their study in underrepresented populations with increased CVD. Here, we investigated WMH in AD and bvFTD patients in Latin America (Argentina, Chile and Colombia), a region with high prevalence of CVD. We analyzed total volume and regional distribution of WMH and its association with cognitive impairment and brain lacunes, a marker of CVD.MethodA total of 66 patients (43 AD, 23 bvFTD) and 66 controls (CN) from the ReDLat consortium underwent high‐resolution brain MRI and neuropsychological examination. WMH were extracted from Flair images using automated segmentation algorithms to perform analyses of total volume and spatial distribution. Brain lacunes were visually quantified from T1 and Flair images. Group differences in total and regional WMH volume and associations with different cognitive domains, age, and brain lacunes were examined.ResultTotal and regional WMH volumes were significant larger in AD patients compared to CN and to bvFTD. No differences were found between CN and bvFTD. Only in AD, regional WMH load correlated with worse performance in a particular executive functioning task. No differences were found in the proportion of lacunes among groups nor in the total load of WMH of subjects with or without lacunes. In CN and AD, but not FTD, there was a positive correlation between total WMH volume and age, with a differential topographic distribution with a selective involvement of the bilateral cingulum‐hippocampus bundle in AD.ConclusionEnhanced WMH was observed in AD but not in FTD. WMH loading in specific brain regions contribute to domain‐specific cognitive deficits in AD. WMH could be partially independent of vascular pathology (it was unrelated to brain lacunes) suggesting a specific neurodegenerative origin in AD. The typical earlier onset of brain abnormalities in FTD could mask the age‐related increase in WMH.
Exercise‐Associated Modulation of Neuroinflammation in Alzheimer's Disease
Authors: Birnbaum Allison , Nobles Amber C , Banks Macy Teya , McGraw Megan , Cortes Constanza J 
Published: December 2022

AbstractBackgroundExercise promotes powerful systemic and central nervous system anti‐inflammatory effects, even during aging. Exercise also limits neuroinflammation in models of Alzheimer's disease (AD), thereby inhibiting disease progression and promoting other well‐documented neuroprotective effects such as supporting neuronal plasticity, stimulating adult neurogenesis, and enhancing cognitive function. However, exercise is not always accessible to aging populations that are most at risk for developing AD.MethodWe have recently derived transgenic mice that moderately overexpress Transcription Factor EB (TFEB), a lysosome biogenesis promoter, in skeletal muscle (cTFEB;HSA‐Cre mice) which resulted in enhanced muscle proteostasis, similar to what is observed with long‐term exercise regimes. These mice were then bred with 5xFAD AD‐model mice and evaluated for CNS hallmarks of AD, hippocampal neuroinflammation, and CNS amyloid beta plaque accumulation, at two time points (age=4 months, 8 months).ResultcTFEB;HSA‐Cre;5xFAD mice were observed to have similar inflammatory expression patterns as plaque‐free controls compared to 5xFAD mice. Preliminary analysis also indicates lower amyloid beta plaque load in cTFEB;HSA‐Cre;5xFAD mice. We are currently performing Nanostring analysis with the AD nCounter panel and neuroinflammation nCounter panel to identify transcriptional changes in neuroinflammatory signaling and ameliorating mechanisms associated with skeletal muscle TFEB overexpression.ConclusionWe have identified an exercise‐regulated pathway through which AD‐associated neuroinflammation can potentially be ameliorated and plaque burden modulated. These results support the discovery of an exciting therapeutic intervention against AD progression that eliminates the need for strenuous exercise. We are currently identifying essential exercise‐associated cytokines that can reduce AD‐associated neuroinflammation and prevent disease progression, as well as establish a therapeutic exercise mimetic to combat amyloid beta‐associated neurodegeneration.
Association of acetylcholinesterase inhibitor and memantine treatment with cognitive function in patients with clinical dementia syndrome with and without post‐mortem Alzheimer pathology
Authors: Rosen Jurij , Jessen Frank 
Published: December 2022

AbstractBackgroundAcetylcholinesterase inhibitors (AchE‐I) and memantine are licensed and recommended for the treatment of dementia of Alzheimer type (DAT). Between 10 and 20 % of patients with DAT, however, do not have Alzheimer’s disease (AD) pathology. It remains unclear, if these patients also benefit from treatment. This project aims to examine the association of AchE‐I and memantine use with cognitive function in patients with DAT with and without evidence of AD pathology at autopsy.MethodThis study is based on The National Alzheimer‘s Coordinating Center‐Uniform Data Set (NACC‐UDS). Inclusion of participants for this analysis was based on the following criteria: 1) Diagnosis of DAT, 2) information on the extent of AD‐neuropathological change at autopsy (ABC score high/intermediate/low/not), 3) follow‐up time ≥ 6 months, 4) ≥ 2 Mini‐Mental State Examinations (MMSE) during follow‐up.Result1483 participants with 3.8 ± 1.7 visits met inclusion criteria. Of these, 1009 participants showed an ABC score of “high”, 265 of “intermediate” and 209 of “low/not”. Use of AD‐medication was more common in participants with pronounced AD pathology (ABC score “high”: 89 %, “intermediate”: 66 %, “low/not”: 53 %). Follow‐up time was 41 ± 23 months in participants with medication compared to 36 ± 24 months in participants without medication. In the group of participants with an ABC score of “high” and “intermediate”, those with treatment showed a baseline MMSE score of 23 ± 5 and a decline of 8 ± 6 points, while those without treatment scored 26 ± 4 at baseline with a decline of 4 ± 6 points. In the cohort of participants with an ABC score of “low” and “not”, both groups with and without medication showed a baseline MMSE score of 26 ± 4 points with a decline in those with medication of 6 ± 6 points and of 3 ± 4 points in those without medication.ConclusionThe present descriptive analysis does not provide evidence for a clear association of treatment with AD medication and the presence of AD pathology in patients with DAT. Modelling analyses including covariates will be presented.