bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep complaints associates with anxiety in individuals with Subjective Cognitive Decline from a South‐Brazilian cohort
Authors: Rivas Gabriela Raquel Paz , Souza Victória Tizeli , da Mota Simone Sieben , De Marchi Bruno De Oliveira , Carvalho Guilherme Da Silva , De Souza Haniel Bispo , Beltrami Lucas Bastos , Santos Rhaná Carolina , Carnevalli Sarah Vitoria Bristot , de Albuquerque Ana Letícia Amorim , de Paula Leonardo Martins , Giordani Manuella Edler Zandoná , Borelli Wyllians Vendramini , Carello‐Collar Giovanna , Chaves Marcia L. Fagundes , Zimmer Eduardo R. , Castilhos Raphael Machado 
Published: January 2025

AbstractBackgroundSubjective cognitive decline (SCD) is defined by the presence of cognitive complaints in cognitively unimpaired (CU) individuals. Despite being part of the continuum of a neurodegenerative disease, the cause of the cognitive complaint is quite heterogeneous. Sleep disturbances may be associated with cognitive complaints and even objective cognitive decline. Therefore, our aim is to analyse sleep complaints in patients with SCD evaluated in a south‐Brazilian SCD (BRASCODE) cohort.MethodWe included CU individuals aged > 65 years‐old with cognitive complaints from the BRASCODE cohort. Exclusion criteria were uncontrolled psychiatric/clinical illness, cerebrovascular disease, and the use of psychotropic drugs. We applied the Memory Complaint Scale (MCS) (in both participant and informant), Geriatric Anxiety Inventory (GAI) and Geriatric Depression Scale (GDS), Pittsburgh Sleep Quality Index (PSQI), Mini Mental State Examination (MMSE), Mild Behavioral Impairment (MBI) and Neuropsychiatric Inventory (NPI) questionnaires. For this analysis we used the data collected in the 12‐month follow‐up only.ResultForty‐seven participants completed the 12‐month evaluation between March, 2022 and November, 2023. Of these, 74.5% (n = 35) were women, median age of 71 (69‐74.5) years‐old and 16 (11‐18) years of formal education. Their median interquartile range (IQR) on SCD‐patient and SCD‐informant scale was 8 (6‐9.5) and 4 (2‐6), respectively. The remaining scale’s ‐median and IQR scores‐ were the following: PSQI, 7 (4‐9); GAI, 6 (3‐9); GDS 2 (1‐4), MMSE, 29 (28‐30); NIP,1(0‐4); MBI‐patient, 3 (0.75‐6); and MBI‐informant, 3 (1‐9). The analysis showed that the PSQI scale only had correlation with GAI (p‐value = 0.02841, rho = 0.3466809). There was no association with the MCS‐participant and MCS‐informant scales, nor with MMSE, age, education and behavior scales, MBI or NPI.ConclusionThis result obtained for the PSQI score suggests that poor sleep quality in SCD individuals from a south‐Brazilian cohort may be associated with anxiety symptoms. Larger sample may provide additional information about the relationship of cognitive, anxiety and sleep complaints.
A systems‐biology approach to identify candidate genes associated with composite brain pathology scores in the Adult Changes of Thought (ACT) and the Religious Orders Study and Memory and Aging Project (ROSMAP) autopsy cohorts
Authors: Dutta Aheli , Broome Jai , Sinha Sagnik , Gibbons Laura E. , Shade Lincoln MP , Katsumata Yuriko , Travaglini Kyle J , Gabitto Mariano I , Zhao Zijie , Lu Qiongshi , Schneider Julie A. , Latimer Caitlin S , Keene C Dirk , Crane Paul K. , Fardo David W. , Mukherjee Shubhabrata 
Published: January 2025

AbstractBackgroundPreviously, we developed a co‐calibrated and harmonized brain pathology score (BPS) across prospective cohort studies with research brain donation that incorporates multiple forms of postmortem neuropathology, using confirmatory factor analysis. We sought to identify genetic loci associated with BPS using a systems‐biology approach, combining data from participants in the Adult Changes in Thought (ACT), the Religious Orders Study, and Rush Memory and Aging Project (ROSMAP) autopsy cohorts.MethodWe used PLINK in each cohort separately for genome‐wide association studies (GWAS) of BPS using HRC imputed data from European ancestry participants, adjusting for age at death, sex, and population substructure. We performed meta‐analysis using the adaptively weighted Fisher’s approach in METAL. We performed gene‐wide analysis using the meta‐analyzed results which we then integrated into the human protein‐protein interaction (PPI) network using a dense module searching (DMS) method to identify network hub genes for BPS. We interrogated the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA‐AD) dataset on the middle temporal gyrus to determine which cell types both hub genes were expressed in and how they differed across donors with higher degrees of AD pathology (i.e. along AD pseudo‐progression).ResultThe sample size consisted of 1,848 brain donors (Table 1). The quantile‐quantile plot and genomic inflation (λ = 1.005) for GWAS meta‐analyses showed no bias (Figure 1a), with the Manhattan plot in Figure 1b. Apart from significant SNPs around the APOE region, we identified two candidate loci a) (Chr 9: rs1332179; MAF = 0.1; P_meta = 8.7 × 10‐8) and b) (Chr 17: rs11078196; MAF = 0.34; P_meta = 1.9 × 10‐7). Regional association plots for these two loci are shown in Figure 1c. The PPI network analysis identified VCP and IQCB1 as hub genes (Figure 2a). While both hub genes were expressed broadly across cell types, IQCB1 was specifically higher with higher degrees of AD pathology in Microglia and VCP was lower with higher degrees of AD pathology in several neuronal populations (Figure 2b).ConclusionWe identified two potentially useful candidate loci associated with BPS using a systems‐biology approach. Further functional enrichment analysis is needed to determine whether these novel loci may identify targets for interventions to ameliorate AD.
Primary progressive aphasia in sporadic and familial (type 8) amyotrophic lateral sclerosis ‐ A longitudinal study
Authors: de Araujo Caroline Martins , Machado Thais Helena , Collares Mariana Asmar Alencar , de Paula França Resende Elisa , de Souza Leonardo Cruz 
Published: January 2025

AbstractBackgroundLanguage is frequently affected in patients with sporadic amyotrophic lateral sclerosis (sALS), with reduced performance in naming, syntactic comprehension, grammatical expression, and orthographic processing. In a previous study, we demonstrated that the language profile of patients with familial type 8 ALS (ALS8), linked to p.P56S VAPB mutation, is similar to sALS. From a neuropsychological standpoint, there appears to be an overlap between primary progressive aphasia and ALS (PPA‐ALS) even in phases of the disease with little functional impairment. We aimed to investigate whether language decline has prognostic value in patients with ALS.MethodFirst, we performed a cross‐sectional evaluation. We included two groups of participants: 1) patients with sALS (n = 17); 2) patients with familial ALS8 (n = 22). The groups were matched for age, sex, and education level. All participants underwent a comprehensive language battery, including the Boston Diagnostic Aphasia Examination, the reduced Token Test, letter fluencies (FAS), categorical fluency (animals), word definition from the Cambridge Semantic Memory Research Battery, and a narrative discourse analysis. We also applied the Addenbrooke’s Cognitive Exam ‐ Revised Version (ACE‐R), the Hospital Anxiety and Depression Scale (HADS), and the ALS Functional Rating Scale‐Revised (ALSFRS‐R). The patients were reassessed 10‐65 months after the baseline visit with ALSFRS‐R, to follow up the progression rate of the disease.ResultWe observed that the memory item of the ACE‐R test was able to predict functional declining in the fine motor domain in patients with sALS (F (1,16) = 19.443, R2 = 0.549, p<0,001).. The use of phonological cues in patients with ALS8 was able to predict global functional declining in this group (F (1,20) = 21.361, R2 = 0.516, p<0.001).ConclusionOur data suggest that language decline may have prognostic value in cases of sALS and ALS8.
Toxic Interplay Between Small Dipeptide Protein Repeats and Tau in Tauopathies
Authors: Bhatt Nemil , Puangmalai Nicha , Jerez Cynthia , Shchankin Nikita , Kayed Rakez 
Published: January 2025

AbstractBackgroundTauopathies, including Alzheimer’s Disease and Frontotemporal Dementia, are characterized as intracellular lesions composed of aggregated tau proteins. Soluble tau oligomers are shown to be one of the most toxic species and are responsible for the spread of tau pathology. Recent studies have found that several proteins such as amyloid b, a‐synuclein, and TDP‐43 can aggregate tau. In this study, we investigated the ability of small metabolites like C9orf72 associated dipeptide protein repeats (DPRs) to interact with and aggregate tau to form toxic soluble tau oligomers.MethodWe have developed various models which express dipeptide protein repeats to understand the interaction between short peptides and tau. The dipeptide protein repeat induced tau aggregates were characterized using biophysical, as well as biochemical assays in vitro and in cellular models. Furthermore, we evaluated their toxicity, and seeding potency to understand the biological effects of this interaction.ResultOur results suggest the propensity for DPRs, especially glycine‐arginine and proline‐arginine repeats to form oligomeric structures which interact and seed tau in a prion like fashion. This leads to the production of tau oligomers causing alterations in the microtubule dynamics in cell lines as well as primary neuronal culture systems.ConclusionMany studies have investigated the toxicity of small protein repeats, however, the role of DPR oligomers in inducing tau aggregation is still unclear. Thus, the ability to understand the toxic interplay between small peptide repeats and tau oligomers has great potential to further the understanding of tau progression and aid in the development of targeted therapeutics.
Altering ApoE in mice expressing human amylin in the pancreas exacerbates brain amyloid pathology and behavior deficits
Authors: Leibold Noah S , Viswanathan Velmurugan Gopal , Radulescu Laura , Kotiya Deepak , Verma Nirmal , Despa Florin 
Published: January 2025

AbstractBackgroundThe APOE ε4 allele is the most prominent genetic predisposition for sporadic Alzheimer’s disease (AD). Amylin, a neuroendocrine hormone co‐secreted with insulin from the pancreas, is increased in blood in AD and readily forms neurotoxic homo‐ and hetero‐oligomers with β‐amyloid in AD. Previously, we showed that intravenously infused ApoE4 in rats expressing human amylin specifically in the pancreas led to increased brain amylin accumulation. Further, we showed increased blood levels of human amylin disrupts β‐amyloid efflux. Therefore, we investigated whether mice humanized for amylin and ApoE demonstrate ApoE isoform‐specific alterations in cerebrovascular amylin deposition and β‐amyloid homeostasis.MethodsSix‐month‐old male mice humanized for ApoE3 or ApoE4 and amylin (ApoE3HIP and ApoE4HIP) and mice humanized for amylin without ApoE expression (ApoE‐KO‐HIP) were tested for behavior deficits before brain microvessel isolation and amylin quantification by ELISA. β‐amyloid was quantified using the MesoScaleDiscovery platform. GFAP‐amylin colocalization in the brain was quantified using immunohistochemistry (IHC) while double‐immunofluorescence (double‐IF) and STORM imaging were used for amylin‐ApoE colocalization. Immunoprecipitation experiments were conducted to confirm brain amylin‐ApoE binding interactions.ResultsApoE4HIP mice demonstrated worsened behavioral deficits when compared to E3HIP mice. IHC of ApoE4HIP and ApoE3HIP brains revealed significantly increased deposits of GFAP and amylin in ApoE4HIP mice. Amylin in brain parenchyma, but not capillaries, was higher in ApoE4HIP vs. ApoE3HIP mice (p<0.0001 and p = 0.4455) while ApoE‐KO‐HIP mice demonstrate reduced amylin in both fractions as measured by ELISA. β‐amyloid 40, but not 38 or 42, levels were significantly higher in ApoE4HIP brain and microvessels (p<0.0001 and p = 0.0123) vs. ApoE3HIP. Analysis of double‐immunofluorescence, STORM, and immunoprecipitation experiments is ongoing.ConclusionsOur data suggest ApoE may function as a transporter of amyloid‐forming amylin in the brain with amylin binding ApoE4 stronger than ApoE3. The increased affinity of amylin for ApoE4 coincides with worsened brain amyloid pathology, disrupted β‐amyloid homeostasis, increased astrogliosis suggesting neurodegenerative insult, and functional impairments due to elevated amylin amyloid burden. These data may implicate the amylin‐ApoE interaction as a mechanism underlying ApoE4‐specific neuropathology. Additional studies to delineate the mechanisms by which amylin and ApoE interact at the BBB interface and alter amyloid deposition are needed.
Amylin vasculopathy impairs cerebral Aβ efflux through altering cerebral vasodilation
Authors: Davargaon Ravichandra S , Leibold Noah S , Verma Nirmal , Powell David K , Despa Florin 
Published: January 2025

AbstractBackgroundImpaired interstitial fluid drainage in the brain is indicated by the presence of perivascular β‐amyloid (Aβ) deposits and is attributed to alterations in contractility and relaxation of vascular smooth muscle cells (SMCs). The brain microvasculature in Alzheimer disease (AD) accumulates amyloid‐forming amylin secreted from the pancreas. Here, we tested the hypothesis that cerebrovascular amylin deposits perturbs cerebral Aβ efflux by impairing cerebral vasodilation.MethodsUsing transgenic rats expressing amyloid‐forming human amylin in the pancreas (HIP rats) (aged 16‐months) and wild‐type (WT) littermates that express non‐amyloidogenic rat amylin, we conducted comparative analyses of cerebral blood flow (CBF), pressure myography in isolated pial arteries and vascular SMC oxidative stress experiments.ResultsLongitudinal brain MRI measurements revealed consistent structural alterations that progressed more rapidly with aging in HIP vs. WT rats, leading to 14.9% reduction in CBF in HIP rats. Plasma nitrite and nitrate, stable nitric oxide (NO) end products, were increased in HIP vs. WT by 84.7% and 24.87%, respectively. Pressure myography experiments using pial arteries showed that both WT and HIP arteries developed arterial tone (e.g. pressure‐induced constriction); however, arteries from HIP rats show significant elevations (56.9‐142.3%) in arterial tone compared to WT rats at physiologically‐relevant intravascular pressures (e.g. 60‐100 mmHg). Consistent with these results, vascular SMCs from HIP rats showed elevated (12.6% increase) lipid peroxidation, which was replicated in SMCs incubated with exogenous human amylin (29.6%). Increased lipid peroxidation contributes to oxidative stress in the vascular wall and reduces NO bioavailability, altering vasodilatory function. Both arginase activity and expression (of Arginase 1 and 2) were increased in brain microvascular lysates from HIP rats compared to those from WT by 17.6%, 63.9%, and 57.8%, respectively, suggesting arginase‐NO dysregulation. A possible impact of increased blood amylin concentration on cerebrovascular arginase‐NO regulation was further tested in brain microvascular lysates from rats intravenously injected with amyloid‐forming human amylin (55.0% reduction in arginase activity).ConclusionOur results indicate perivascular Aβ deposits in the setting of AD are potentially linked to amylin vasculopathy and altered spontaneous contraction/relaxation of cerebrovascular SMCs. Future experiments will focus on delineating molecular markers of amylin‐induced alterations of SMC contractile phenotype.
Second‐Generation Epigenetic Clocks and Socioeconomic Status Predict Midlife Cognitive Status
Authors: Bell Sophie A. , Beam Christopher R. , Finkel Deborah , Barna A. Cevelle , King Ariel , Sikes Kendra , Ryan Lesa , Davis Deborah Winders , Turkheimer Eric 
Published: January 2025

AbstractBackgroundDNA methylation (DNAm) age measures, or ‘epigenetic clocks’, surpass chronological age in their ability to predict age‐related morbidities and mortality. The Louisville Twin Study (LTS) presents an opportunity to clarify the role of early life environmental exposures and development in biological and cognitive aging in midlife. We expect that second‐generation DNAm age measures trained to predict age related outcomes and death, independent of chronological age, will be sensitive to cognitive ability in midlife.MethodData collection of the midlife phase of the LTS is ongoing. This study utilizes data from 281 middle‐aged twins, including 56 monozygotic and 41 dizygotic complete twin pairs (mean age 51.9 years ± 7.03). Midlife cognitive ability (IQ) was measured using the Wechsler Adult Intelligence Scale Fourth Edition. DNAm age acceleration was calculated using five clock algorithms: Horvath 1, Horvath 2, Hannum, GrimAge, and PhenoAge. We conducted an exploratory factor analysis to identify common factors as latent variables among the five clocks. Composite scores for factors were calculated, and genetically informed, quasi‐causal regression models were fitted in which adult IQ was predicted from childhood socioeconomic status (SES), DNAm factor composite score, and the interaction between DNAm age and SES.ResultFactor analysis produced a two‐factor structure: first‐generation clocks (Horvath 1, Horvath 2, and Hannum) and second‐generation clocks (PhenoAge and GrimAge). As predicted, childhood IQ and childhood SES predict adult IQ. Acceleration in the second‐generation factor predicts lower midlife cognitive ability (b = −0.15, SE = 0.068, p <.05). Additionally, there is an interaction in the second‐generation model such that people raised in higher SES families show a less negative relationship between DNAm age acceleration and adult IQ (b = 0.092, SE = 0.036, p <.05). However, there is no significant effect of the first‐generation factor on adult IQ, and no SES interaction effect.ConclusionSecond‐generation DNAm age measures show promise in their predictive value for cognitive aging processes. Moreover, the longitudinal twin design of the LTS serves as a quasi‐experimental framework to investigate hypothesized causal effects of DNAm on cognitive aging. Finally, our findings related to childhood SES suggest that the epigenome is malleable and responsive to early‐life stressors.
Non‐invasive Flicker Neurostimulation Mitigates Stress Pathology in a Sex‐Dependent Manner
Authors: Franklin Tina Carla , Goodson Matthew , Zepeda Hector , Kye Nancy , Bitarafan Sara , Kraus Jacob , Braun Luke , Prichard Ashley , Wood Levi B , Singer Annabelle C 
Published: January 2025

AbstractBackgroundChronic stress promotes life‐long risk for neuropsychiatric decline by increasing neuroinflammation and disrupting synaptic health and plasticity. Our lab and others have recently demonstrated that non‐invasive gamma sensory stimulation (flicker) modulates immune signaling, restores microglial function, and improves cognitive performance in mouse models of Alzheimer’s disease (AD). However, no research to date has studied the effects of flicker in the context of stress. Accordingly, our goal for this study was to determine if flicker mitigates neuropsychiatric‐like behavioral deficits and rescues glial and synaptic pathology following chronic stress.MethodDaily audiovisual flicker intervention was introduced concomitantly with daily stress exposure (28 days) at multiple frequencies in male and female C57BL6 mice (n = 6/group per sex). The mice were then tested for anxiety‐like behaviors and anhedonia using a range of behavioral tests. We quantified transcriptomic changes in cortical Thy1+ pyramidal neurons, microglia, and astrocytes to identify cell‐type specific genes modulated by flicker intervention in chronically stressed mice. To determine how flicker mitigates stress‐induced cellular changes in the prefrontal cortex, a region vulnerable to stress and AD pathology, we next quantified spine density changes in Thy1‐GFP mice and measured glial morphology changes as a proxy for microglial and astrocyte reactivity using the semi‐automated Imaris imaging software to determine synaptic health and inflammatory profile, respectively.ResultWe found that stress‐induced molecular changes in the prefrontal cortex are modulated in a sex‐, and frequency‐specific manner that coincides with behavioral resilience in stressed mice. Our findings indicates that audiovisual flicker protects against stress‐induced behavioral deficits and mitigates stress‐induced neuroimmune responses in a sex‐ and frequency‐specific manner.ConclusionTogether, these findings show frequency optimized flicker intervention improves stress pathology and may prevent neuropsychiatric health decline in conditions with sex dimorphic symptoms and prevalence.
The relationship of subjective cognitive decline (SCD) and the Stages of Objective Memory Impairment (SOMI) system in preclinical AD
Authors: Petersen Kellen K. , Rabin Laura , Grober Ellen 
Published: January 2025

AbstractBackgroundSelf‐awareness of declining cognition in the absence of objective cognitive impairment is called subjective cognitive decline (SCD). Herein, we examine the association of SCD measured by the Cognitive Function Index (CFI; Amariglio, et al. 2015) with the Stages of Objective Memory Impairment (SOMI) system (Grober, et al. 2018) that classifies cognitively normal individuals into one of five stages based on the Free and Cued Selective Reminding Test (FCSRT; Grober & Buschke, 1987) and that maps onto the presence of AD pathology (Grober, et al. 2022 & Petersen, et al. 2023). In early SOMI stages (SOMI‐1, 2) there is increasing retrieval difficulty; in later stages (SOMI‐3/4) storage deficits emerge.MethodsWe used baseline data from 4109 neuropsychologically normal, older adults from the Anti‐Amyloid Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. All participants had amyloid PET measures and completed the FCSRT used for determing SOMI classification. Additionally, all participants and study partners completed the CFI. An adjusted CFI score was used that excluded three items that assess functional rather than cognitive ability. CFI positivity was defined by cutoffs, 7.8 and 6.5 for participant and partner versions respectfully, representing one standard deviation above the mean. Analysis of Variance (ANOVA) with post hoc analysis was used to assess differences of CFI scores between SOMI stages.ResultsWe found fewer A+ participants were SOMI‐0 compared to A‐ participants (34.1% vs. 42.7%, p<0.001, Figure 1). Additionally, more A+ participants were SOMI‐3/4 compared to A‐ participants (15.4% vs. 10.3%, p<0.001). Among A+ participants, memory impairment (SOMI‐2/3/4) was more prevalent among those with self‐perceived SCD (34.9%) than those without SCD (29.5%, p = 0.016). Similarly, among A+ participants, prevalence of memory impairment was higher among those with partner‐perceived SCD (40%) than those without (28%, p<0.001). Post hoc results found higher SOMI stages were associated with higher partner and study partner CFI scores except between SOMI‐2 and SOMI‐3/4 (p<0.05 for all, Figure 2).ConclusionsMemory impairment was found to be more prevalent among A+ participants with self‐ and partner‐rated SCD. SCD increases with increasing memory impairment.