bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel stop‐gain SORL1 mutation from Amerindian background in a Peruvian family with Alzheimer’s Disease of the PeADI Study
Authors: Cornejo‐Olivas Mario , Griswold Anthony J. , Saldarriaga‐Mayo Ana , Mena Pedro R. , Rodriguez Richard S. , Adams Larry D. , Whitehead Patrice L. , Isasi Rosario , Illanes‐Manrique Maryenela , Sarapura‐Castro Elison , Rajabli Farid , McInerney Katalina F , Milla‐Neyra Karina , Manrique‐Enciso Carla , Beecham Gary W , Castro‐Suarez Sheila , George‐Hyslop Peter St , Araujo‐Aliaga Ismael , Cuccaro Michael L. , Vance Jeffery M. , Pericak‐Vance Margaret A 
Published: January 2025

AbstractBackgroundCommon and rare variants in SORL1 have been associated with increased risk of Alzheimer’s disease (AD). Since 2019, we have run an international collaborative research initiative to ascertain a Peruvian cohort for Alzheimer’s disease and other related dementias for genetic studies (PeADI).MethodA Peruvian family (4 AD cases and two mild cognitive impairment (MCI) cases) was recruited through the PeADI study. All six family‐member completed a full cognitive assessment, had plasma‐based biomarkers pTau181 and Aβ42/40 measured via SIMOA chemistry on the Quanterix HD‐X, and underwent whole genome sequencing. Variants within AD risk genes as determined by the ADSP Gene Verification Committee were prioritized and variant interpretation was performed according to ACMG recommendations.ResultWe identified a SORL1 c.5019G>A (p.Trp1673Ter) variant of Amerindian background in the four AD diagnosed siblings within this family. The two MCI cases did not carry the novel variant. The identified SORL1 variant corresponded to a heterozygous stop‐gain variant in exon 36 replacing tryptophan by a stop codon at position 1673 of the SORL1 protein. In‐silico analysis predicts this variant promotes nonsense‐mediated mRNA decay. This variant has not been previously reported in databases including gnomAD, LOVD and ClinVar. The 4 AD cases had on average 2.3X higher plasma pTau181 concentrations compared to the 2 MCI (2.03 ± 0.28pg/µl vs 0.88 ± 0.7pg/µl). There was no noticeable difference in the Aβ42/40 ratio. This variant is classified as likely pathogenic according to ACMG.ConclusionWe report the first Peruvian AD family carrying a likely pathogenic stop‐gain SORL1 variant within an Amerindian background region. Further cosegregation and functional assays are required to establish the risk size of this variant for AD.
Nitro‐oxidation of BKCa mediates neuro‐ and micro‐vascular dysfunction in female 5x‐FAD mice
Authors: da Silva Josiane Fernandes , Polk Felipe Davis , Thai Stephenie H. , Frank Ella C. , Martin Paige E. , Pires Paulo 
Published: January 2025

AbstractBackgroundCerebral microvascular dysfunction and nitro‐oxidative stress are present in patients with Alzheimer’s disease (AD) and may contribute to disease progression and severity. A pro‐nitro‐oxidative environment can lead to post‐translational modifications of ion channels central to microvascular regulation in the brain, including the large conductance Ca2+‐activated K+ channels (BKCa). Nitro‐oxidative modulation of BKCa can resulting in decreased activity and vascular hyper‐contractility, thus compromising neurovascular regulation. We hypothesized that nitro‐oxidation of vascular BKCa function blunts micro‐ and neuro‐vascular responses in 5x‐FAD mice.MethodsSix‐months‐old female 5x‐FAD and wild‐type (WT) littermates were used. Brain lysates were used to quantify BKCa nitro‐oxidation. Cerebral arteries lysates were used to assess BK subunit expression by qPCR. A different set of cerebral arteries were used for patch clamp electrophysiology assessment of BKCa currents, ex vivo pressure myography and quantification of calcium (Ca2+) sparks in smooth muscle cells (SMC) by spinning‐disk confocal microscopy. Basal cerebral perfusion and neurovascular coupling were assessed by laser speckle contrast imaging. Differences between means were tested using t‐tests and considered statistically significant when P<0.05.ResultsWe observed that BKCa S‐nitrosylation, a proxy for nitro‐oxidative modification, was increased in the brain of AD patients and in 5x‐FAD females. In functional experiments, we observed that BKCa currents were lower in cerebral artery SMC of 5x‐FAD than in WT. As a consequence, microvascular reactivity to BKCa blockade (iberiotoxin, 30 nM) was blunted in 5x‐FAD, suggesting lower basal BKCa activity. This reduction in microvascular BKCa activity was independent of SMC Ca2+ sparks or BKCa mRNA expression. We then performed rescue experiments by incubating membrane patches and pressurized arteries with the reducing agent dithiothreitol (DTT, 10 µM), and observed that DTT restored BKCa currents and sensitivity to iberiotoxin in cerebral artery SMC from 5x‐FAD. In vivo experiments showed that basal perfusion to the frontal cortex and neurovascular coupling were lower in 5x‐FAD when compared to WT littermates.ConclusionThese data suggest that excessive nitro‐oxidation of BKCa mediates neuro‐ and micro‐vascular impairments in female 5x‐FAD mice, and that this process is reversible and can be rescued by reducing agents.Funding: National Institutes on Aging and Alzheimer’s Association
Using Motor Learning to Predict Cognitive and Functional Decline in Mild Cognitive Impairment and Alzheimer’s Disease
Authors: Koppelmans Vincent , Duff Kevin , Schaefer Sydney Y 
Published: January 2025

AbstractBackgroundPredicting decline over the course of Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD), especially on relatively short time frames, is vital for appropriate treatment planning and to tailor patient and support systems’ expectations. The current study tested if a functional upper limb motor learning task could predict one‐year change in cognition and daily function.MethodCognitively unimpaired (n = 61), MCI (n = 35), and AD (32) older subjects (age: 74.6 ±5.7 years) completed a simulated feeding task (SFT) at baseline for which they used a plastic spoon to scoop two raw kidney beans at a time with their non‐dominant hand from a central cup and transport them to one of three distal cups. They completed this sequence five times for a total of 15 out‐and‐back movements. Time was recorded as outcome measure, and 6 trials of the test were completed. This test was completed 6 times with trial time as the outcome measure for each trial. At baseline and one‐year follow‐up visits, the Mini Mental Status Examination (MMSE) was administered to assess cognition and a knowledgeable collateral completed the Quick Dementia Rating System (QDRS) to assess daily functioning. Linear regression analysis, adjusted for age, sex, and years of education, was used to test the association between SFT performance over the six trials (mean/sd) and regression‐based one‐year change scores on the QDRS and MMSE.ResultSFT performance speed and variability significantly predicted change in performance on the QDRS (total score, cognitive domain score, and behavioral domain score; p = .013‐.024). SFT variability (a measure of learning), but not average performance, over six trials predicted change on the MMSE (p = .031). These effects were small to medium in size (eta^2 = 0.04‐0.05).ConclusionSpeed and variability on a brief, easy‐to‐administer (∼5‐7 minutes), cost‐efficient functional upper limb motor learning task predicted cognitive and functional change over one year across the AD spectrum. These promising results suggest that the SFT could be used in clinical practice to help predict disease progression, as well as a screening tool in clinical trials in MCI and AD.
Cytoplasmic expression of TDP‐43 in aged mice display hippocampal sclerosis‐like degeneration and neuronal loss with reduced lifespan
Authors: Anderson Ashley J. , Dopler Matthew B , Arezoumandan Sanaz , Osei‐KanKam Damian , Davis Stephani A. , Ajroud Kaouther , Lilek Jaclyn N , Bambakadis Eva , Shapiro Rachel , Gitcho Michael A. , Flanagan Margaret E , Cairns Nigel J 
Published: January 2025

AbstractBackgroundTDP‐43 is a multifunctional heterogeneous nuclear ribonucleoprotein and is the major pathological protein in motor neuron disease. Previously, TDP‐43 pathology has been described in up to 50% of those with Alzheimer’s disease. Recent evaluation of this cohort revealed a distinct pathological staging of TDP‐43 proteinopathy in an aged population, called Limbic predominant age‐related TDP‐43 encephalopathy(LATE). Hippocampal sclerosis of aging (HS‐A) is an age‐related neuropathology characterized by severe neuronal loss and gliosis, also seen as a co‐pathology in AD and LATE. HS‐A is evident in ∼80% of cases in the hippocampal region of cases that are positive for phosphorylated TDP‐43.MethodWe examined aged mice that selectively express human TDP‐43 and TDP‐43 with a defective nuclear localization signal (ΔNLS) in the hippocampus in an APP/PSEN1 background, six genotypes of interest were evaluated; WT, APP/PS1, Camk2a/TDP‐43, Camk2a/TDP‐43ΔNLS, Camk2a/TDP‐43/APP/PS1, and Camk2a/TDP‐43ΔNLS/APP/PS1 in 24 month old mice. A sample size of n = 3 was used for each genotype. Protein lysates as well as fixed tissues were prepared and analyzed.ResultThese 24‐ month‐ old mice display severe neuronal loss in the hippocampus, a decrease in beta‐amyloid plaque deposition, an increase in neuroinflammation, and reduced survival.ConclusionThis aged hippocampal sclerosis‐like model may provide a greater understanding of the pathogenesis of neurodegeneration seen in TDP‐43 proteinopathies.
Potentially heritable biomarkers of neurodegeneration in a marmoset model of Alzheimer’s disease
Authors: Kumar Sonal , Spruce Catrina , Haber Annat , Schultz Laura , Huhe Hasi , Murai Takeshi , Choi Sang‐Ho , Hachem Stephanie , Mou Yongshan , Ha Seung‐Kwon , Park Jung Eun , Bailey Lauren , Mongeau Lauren , DeSana Andrew , Stein Brianne , Schaeffer Lauren K Hayrynen , Homanics Gregg E , Silva Afonso C , Rizzo Stacey J Sukoff , Carter Gregory W 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common global cause of dementia, with no real cure available. Despite extensive genetic findings from large‐scale genetic associations and similar studies, our understanding of AD is largely hindered by its long, asymptomatic progression with limited access to human brain tissue. Animal models like the marmoset allow for longitudinal analysis of disease by enabling the assaying of disease‐specific phenotypes that mimic human pathophysiology. Here, we have analyzed genetic associations with disease biomarkers in a cohort of wild type and PSEN1 C410Y mutant marmosets.MethodWhole genome sequencing was carried out for a cohort of largely wild‐type and a few PSEN1 mutant carriers. A wide variety of disease associated biomarkers were analyzed to assess for the progression of neurodegeneration. The correlation structure underlying collected biomarkers and related phenotypes was calculated, separating for sex. Composite phenotypes were computed based on correlation strength, and genetic associations studied via QTLs for composite and individual phenotypes.ResultFemales showed greater correlations between disease specific biomarkers like total tau (tTau), neurofilament light protein (NfL), the astrocytic marker GFAP, and β‐amyloid peptides with 40 and 42 amino acids, as well as the Aβ42:Aβ40 ratio. Correlations between markers were found to be weaker but still significant in males. Variants predicted to be pathogenic were found for many genetic loci implicated by human genome‐wide association studies. Standing genetic variation in the marmosets was found akin to what is seen in humans, but overall population structures varied significantly between the two species.ConclusionCorrelations between AD‐relevant biomarkers in marmosets exceeded those observed in humans, which were not explained by age. This suggests a strong potential genetic contribution. Leveraging possible heritable associations with disease markers discovered in the marmosets to explain the progression of neurodegeneration could directly provide insights into human AD biology from a genetic point of view.
Elucidating the phenotypic landscape of neurodegeneration using multiplexed single‐cell sequencing of defined neuronal co‐cultures in vitro
Authors: Vaikunthan Mathini , McFaline‐Figueroa José 
Published: January 2025

AbstractBackgroundMany putative factors may contribute to the neurodegeneration seen in Alzheimer’s Disease (AD), including the build‐up of toxic amyloid‐beta plaques and the aberrant reactivity of non‐neuronal cell types such as astrocytes and microglia. However, the precise contribution of these factors to normal and disease states of neurons remains poorly defined.MethodWe employed in vitro rat neural co‐culture models to determine how changes in cell interactions alter the transcriptional response of neural cell types to agents associated with neurodegeneration. We performed single‐cell RNA‐seq using the 10x Genomics Chromium on neuron‐enriched (Neu) fractions alone or with the addition of an astrocyte‐enriched (Ast) fraction or both astrocyte‐ and microglia‐enriched (Ast + Mic) fractions. We then exposed different cell‐type composition conditions to AD‐related (i.e., Aβ42 aggregates), oxidative/nitrosative (hydrogen peroxide, sodium nitroprusside), and inflammatory/anti‐inflammatory (tumor necrosis factor ɑ, transforming growth factor β, interleukin‐4, lipopolysaccharides, short chain fatty acids) compounds, yielding 20 conditions (including controls). We use multiplexed sci‐RNA‐seq to process all conditions within one experiment. Ongoing work includes gene knockouts of AD relevant genes with CRISPR‐Cas9 Ribonucleoprotein particles before exposure to compounds.ResultThe initial coculture experiment yielded transcriptomes for ∼12k cells. We show that variations in cell‐type composition led to changes in the expression of genes associated with neurodegeneration, including 11 late‐onset AD (LOAD) genes, suggesting that neurodegenerative gene expression changes can occur as a function of altered neural cell interaction alone. Changes in early‐onset AD (EOAD) genes in specific cell‐types were also observed, including increasing Psen1 expression in neurons upon cell‐type composition changes. Our multiplexed 20‐condition experiment yielded ∼40k transcriptomes. MultiNicheNet–a pipeline for analyzing cell‐cell interactions over multiple conditions–inferred downregulation of LOAD‐associated receptor‐ligand pairs such as Apoe‐Sorl1 in the context of the “high microglia” coculture model over a number of exposures, recapitulating a transcriptional phenotype seen in AD patients.ConclusionBy enacting simple perturbations to cell‐type composition and exposures in a neuronal model, we have modeled a subset of the phenotypes displayed in AD patients. This study can help elucidate the order of events of changes observed in AD, including those likely to directly induce neuronal cell death.
Relationship between brain stiffness, microstructural integrity, beta‐amyloid accumulation, and cognitive decline in beta‐amyloid positive individuals
Authors: Triolo Em , Langan Mackenzie , Khegai Oleksandr , Diaz Aislinn , Binder Sarah , Hedden Trey , Balchandani Priti , Kurt Mehmet 
Published: January 2025

AbstractBackgroundLeveraging non‐invasive ultra‐high field, 7 Tesla (7T) MRI, with increased signal‐to‐noise ratio and improved soft tissue contrast afforded by 7T allows us to accurately map tissue microstructure. We aim to use 7T MR Elastography (MRE), 7T Diffusion Tensor Imaging (DTI), 3T amyloid‐PET, and Preclinical Alzheimer Cognitive Composite (PACC) score to determine the relationships between these metrics in a cohort of older individuals with either normal cognition (CN), mild cognitive impairment (MCI), or Alzheimer’s Disease (AD).Methods7T MRE, 7T DTI, 3T PET (Fig. 1A), and PACC test were performed on CN 14 subjects (Avg. age 70.3±5.2 years), and 6 subjects (Avg. age 70.0±9.4 years) with MCI/AD (Clinical Dementia Rating >4.0 in the Clinical Dementia Rating Scale Sum of Boxes). We performed multiple Shapley Regressions in subjects with amyloidosis (average SUVR above the region threshold, described in Bullich, et al.) in five PET‐relevant cortical regions with the imaging metrics acquired and PACC score.ResultsWe found significant differences (p<0.05) between the CN and AD/MCI groups in complex shear stiffness (|G*|) of the hippocampus and frontal lobe, and SUVR of all brain regions investigated. A significant negative correlation was found between average SUVR and |G*| in multiple brain regions (Fig. 1B). We also found significant correlations between SUVR and mean diffusivity (MD), and |G*| and MD in the temporal cortex (Fig. 1C). There was a significant negative correlation between SUVR and PACC, and positive correlation between |G*| and PACC, in all regions.Excluding PACC, |G*| was the best predictor of SUVR in subjects with amyloidosis, apart from in the temporal and parietal cortexes, where MD was a better predictor (Fig. 2 A, B). Again, excluding PACC, SUVR was the best predictor of |G*|, apart from the temporal cortex.ConclusionsThe Shapley regression analyses demonstrated that SUVR and |G*| were the most interrelated imaging covariates for multiple brain regions, which is promising for finding correlates of PET through MRE. Additionally, correlations between SUVR or |G*| and MD, but not SUVR and |G*| in the temporal cortex may be indicative of cascades which contribute to Aβ deposition, microstructural damage, and tissue softening and degradation.
Incidence of early neurodegenerative disease pathology in a forensic cohort
Authors: Hunter Mikayla L , Williamsen Hannah R , Cooper Benjamin J , Pierson Samantha R , Marcinkiewcz Catherine A , Hefti Marco M , Fiock Kimberly L 
Published: January 2025

AbstractBackgroundIt is increasingly apparent that tau pathology in Alzheimer’s disease (AD) begins in the brainstems of middle‐aged patients, decades before the onset of symptoms. Most studies are, however, based on brain‐bank cohorts and focus on patients dying of natural causes. The true incidence of tau pathology in the brainstem thus remains unclear. In this study, we report a systematic characterization of Alzheimer’s disease and related dementia (ADRD) pathology in the brainstems of a statewide cohort of patients coming to forensic autopsy.MethodPostmortem human brain samples were obtained from asymptomatic forensic deaths in the state of Iowa (n = 12; 6 male and 6 female). Formalin‐fixed, paraffin embedded tissue samples were stained by immunohistochemistry (IHC) on the dorsal raphe (DR), locus coeruleus (LC), and hippocampus (HPC) to assess the presence of tau (AT8), α‐synuclein, and beta amyloid pathology. All stains were independently evaluated by two experienced neuropathologists, with discrepancies resolved by consensus.ResultWe identified a total of 12 cases in our initial cohort (median age 51, range 25‐74). Six of the 12 cases contained tau pathology in the HPC, five of 12 contained tau in the DR, and five of 12 contained tau in the LC. Additionally, one case contained beta amyloid in neocortex and alpha synuclein in the DR. All cases positive for pathology were greater than 50 years of age.ConclusionOur data suggests that incidental ADRD pathology is extremely rare in younger adults, with alpha‐synuclein and beta‐amyloid only seen in a single 74‐year‐old patient. These findings suggest such pathology is less common than previously thought and emphasizes the unique advantage of studying it in forensic cohorts dying of non‐natural causes, which better represents the population as a whole.
AD pathology‐independent effects of astrocyte‐ or microglia‐specific replacement of APOE4 with APOE2
Authors: Nolt Georgia L , MacLean Steven M , Golden Lesley R , Stephens Isaiah O , Hernandez Gabriela , Siano Dahlia , Woodward Ellen , Moses Joshua , Morganti Josh M. , Johnson Lance A 
Published: January 2025

AbstractBackgroundCompared with the E3 allele of Apolipoprotein E (APOE), E4 increases late‐onset Alzheimer’s Disease (AD) risk up to 15‐fold, while the E2 allele substantially decreases risk. In the CNS, ApoE is predominantly synthesized by astrocytes and microglia, making these two cell types promising targets for ApoE‐directed therapeutic approaches. Our lab has generated an inducible “switch” mouse model (APOE4s2) in which we can conditionally replace E4 with the protective E2 in a cell‐specific manner. To elucidate potential mechanisms by which astrocytes and microglia expressing E2 or E4may modulate AD risk, we characterized the immuno‐metabolic response of astrocyte‐ and microglia‐specific “switch” mice to a variety of CNS‐related challenges.MethodAged APOE4s2 mice were administered tamoxifen to induce an in vivo transition from expression of E4 to E2 selectively in astrocytes (Aldh1l1‐CreERT2) or microglia (Tmem119‐CreERT2). A separate cohort of APOE4s2 mice received LPS to induce an inflammatory response 24 hours prior to tissue collection. Immunohistochemical analysis of gliosis (GFAP, IBA1), cytokine measurements, and targeted metabolomics and lipidomics were performed on brain tissue from these groups. Additionally, a cohort of 6‐week‐old microglia‐APOE4s2 mice were administered lysophosphatidylcholine (LPC) via intracranial injections to promote demyelination. Mice were sacrificed 10 days post‐LPC injection, and myelin content and glial reactivity were quantified via staining of myelin basic protein (MBP), degraded MBP (dMBP), and Luxol Fast Blue (LFB).ResultAs measured by plasma and brain cytokine levels, the inflammatory response was not modified by glial E2 expression in either age or LPS. However, aged E4 mice in which only astrocytes selectively expressed E2 showed decreased microglia reactivity (Iba1 immunoreactivity) compared to mice expressing E4 in all cell types. In contrast, aged mice in which only the microglia express E2 showed increased microglia reactivity relative to E4 expressing controls. Interestingly, a similar increase in Iba1 signal was noted in mice expressing only astrocytic E2 following an acute exposure to LPS. Finally, E2 expressing microglia appear to have higher levels of myelin following LPC injections compared to E4 expressing microglia.ConclusionGlial cell‐specific expression of E2 alters microglia reactivity in response to various pathological challenges, including aging, inflammatory stimuli, and demyelination.