bluuebunny/crossref_metadata_2025_split huggingface dataset:
Floor‐effect in the performance of the Spanish‐language MoCA by cognitively unimpaired Peruvian individuals with low educational background
Authors: Custodio Nilton , Calandri Ismael Luis , Montesinos Rosa , Custodio Belen , Malaga Marco , Chambergo‐Michilot Diego , Bustamante‐Paytan Diego , Aguero Katherine , Verastegui Graciet , de la Colina Adrián Noriega 
Published: January 2025

AbstractBackgroundThe Montreal Cognitive Assessment (MoCA) stands as a prominent cognitive impairment screening tool, finding widespread use globally and existing in official versions across 14 languages, including Spanish. Despite this, the challenges emerge due to the extensive variations within the Spanish language, which is not only the fourth most spoken language worldwide but also possesses significant geographic diversity, particularly evident in regions like Peru. Here, the intersection of regional nuances, low educational backgrounds, and culturally distinct tasks complicates the application of a standard MoCA version. We aimed to assess MoCA performance in individuals with both high and low education levels from an urban region of Peru to investigate the applicability of MoCA in low‐educated population.MethodsA total of 40 cognitively healthy individuals with low education (less than 6 years, mean = 3.8 ±1.8) and 40 individuals with higher education (more than 6 years, mean = 14.1 ±3.5) participated in the study. We assessed them with the Spanish version 7.0 of MoCA and estimated total score and domain indices. We fitted linear regression models to evaluate age‐ and sex‐adjusted differences between groups. We examined the presence of a floor effect in the low education group, defining it as the test’s minimum possible score surpassing the mean minus three standard deviations. This observation indicates a lack of sensitivity in capturing normal inter‐individual variation at lower values. To delve deeper, we employed a three‐parameter Item Response Theory model (IRT) to estimate the difficulty of each test item.ResultsWe observed significant differences in the total MoCA score (b = 9.3, 95% CI: 7.7,11, p<0.001) as well as in the memory index (MoCA‐MIS, b = 5.9, 95% CI: 4.4, 7.5, p<0.001), executive function (MoCA‐EIS, b = 5.0, 95% CI:4.0,6.0 p<0.001), attention (MoCA‐AIS, b = 5.5, 95% CI: 4.4, 6.6, p<0.001), and the remaining subscores (Figure 1). Floor effect was detected in memory, executive, language, and visuospatial indices. (Table 1) The more complex items identified were repetition and abstraction tasks (Figure 2)ConclusionOur results shows that MoCA indices can be significantly influenced by education, floor effect is present even in healthy individuals, and certain items need to be reconsidered due to their difficulty in this context.
Potential of dual orexin receptor antagonists to prevent Alzheimer’s disease
Authors: Lucey Brendan P , Musiek Erik S. 
Published: January 2025

AbstractSleep disturbances, such as insomnia, are associated with Alzheimer’s disease pathology and future risk of cognitive impairment. This raises the exciting possibility of repurposing existing drugs to prevent or delay Alzheimer’s disease since there are multiple drug approved by the Food and Drug Administration for the treatment of insomnia. Dual orexin receptor antagonists (DORAs) are one such class of medications. The orexin system regulates sleep‐wake activity and individuals with orexin deficiency have narcolepsy, a sleep disorder resulting in excessive daytime sleepiness, sleep paralysis, sleep‐related hallucinations, and cataplexy. Based on its role in narcolepsy pathophysiology, DORAs were developed as a treatment of insomnia. Growing evidence suggests that DORAs may be effective at preventing Alzheimer’s disease pathology. In amyloid precursor protein (APP) transgenic mice that develop amyloid deposition, treatment with a DORA decreased the soluble amyloid‐beta concentrations and prevented amyloid deposition. Recent evidence in humans shows that a DORA, suvorexant, acutely decreases amyloid‐beta and phosphorylated tau levels in human cerebrospinal fluid within hours. In this presentation, we will review recent advances testing the effects of DORAs on biomarkers for Alzheimer’s disease pathology, examine additional potential mechanisms that DORAs may reduce Alzheimer’s disease pathology, and discuss current knowledge gaps regarding the effects of other sleep drugs on Alzheimer’s disease biomarkers. Finally, we will discuss on‐going studies planned to test the effects of DORAs in preclinical animal models and humans to lay the groundwork for future phase III clinical trials to prevent or delay the onset of symptomatic Alzheimer’s disease.
Rescue of FTLD‐associated TDP‐43 pathology and neurodegeneration by peripheral AAV‐mediated expression of brain‐penetrant progranulin
Authors: Haass Christian 
Published: January 2025

AbstractBackgroundProgranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD‐associated pathologies may be their inefficient brain exposure and biodistribution.MethodWe therefore developed an adeno‐associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain‐penetrant (b) PGRN variant (AAV(L):bPGRN) in two mouse models of FTLD‐GRN, namely Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS‐administered AAVs while maintaining sustained levels of PGRN in the brain following a single dose.ResultAAV(L):bPGRN treatment reduced several FTLD‐GRN associated disease pathologies including severe motor function deficits, aberrant TDP‐43 solubility and phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis and neurodegeneration in the brain. Translatability of our findings was confirmed in a novel human in vitro model using co‐cultured human induced pluripotent stem cell (hiPSC)‐derived microglia lacking PGRN and TMEM106B and wild‐type hiPSC‐derived neurons. As in mice, aberrant TDP‐43, lysosomal dysfunction and neuronal loss were ameliorated after treatment with exogenous TfR‐binding protein transport vehicle fused to PGRN (PTV:PGRN).ConclusionTogether, our studies suggest that peripherally administered brain‐penetrant PGRN replacement strategies can ameliorate FTLD‐GRN relevant phenotypes including TDP‐43 pathology, neurodegeneration and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD‐GRN and potentially other CNS disorders.
Mechanistic links between TMEM106B and TDP‐43 dysfunction in AD‐related dementias
Authors: Prudencio Mercedes 
Published: January 2025

AbstractBackgroundInclusions of TAR DNA binding protein of 43kDa (TDP‐43) constitute the main characteristic pathology in the majority (∼97%) of amyotrophic lateral sclerosis (ALS) cases and approximately 50% of patients with frontotemporal lobar degeneration (FTLD). TDP‐43 is a nuclear RNA binding protein; however, in disease, it becomes hyperphosphorylated and/or insoluble, hindering its nuclear function in maintaining RNA homeostasis. Importantly, the incidence of TDP‐43 proteinopathy extends to aging brains (LATE) and may be concomitant with Alzheimer’s disease (AD) neuropathological changes (LATE/AD) in up to 70% of AD patients. Interestingly, LATE/AD cases are characterized by worse memory and greater hippocampal atrophy than AD alone. Therefore, TDP‐43 dysfunction could have diverse, disease‐specific effects on pathogenesis, making it imperative to elucidate the mechanism of TDP‐43 deposition in the brain and its role in AD‐related dementias (ADRDs).MethodWe used standardized molecular biology techniques and single‐nuclei RNA sequencing to evaluate TDP‐43 dysfunction across brain regions in both LATE/AD and FTLD‐TDP, identify common and distinct molecular mechanisms involved in each ADRD, as well as assess the relevance of TMEM106B rs3173615, a genetic variation linked to risk of FTLD haplotype, in TDP‐43 pathology.ResultWe detected misspliced, TDP‐43‐regulated cryptic RNAs in the amygdala and hippocampus of LATE/AD and FTLD‐TDP. FTLD‐TDP, but not LATE/AD, frontal cortex also showed significant accumulation of these aberrant transcripts. The topographic distribution of cryptic RNAs mimicked that of insoluble, phosphorylated TDP‐43, regardless of TDP‐43 subtype classification. Despite common misregulated transcripts in these ADRDs, we also identified unique transcriptome changes, even within each TDP‐43 subtype. Finally, we observed that TMEM106B core deposition, which is linked to the presence of the risk TMEM106B rs3173615 haplotype, was associated with enhanced TDP‐43 dysfunction and pathology, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD‐TDP.ConclusionOur results emphasize the use of cryptic RNAs to identify cases with TDP‐43 pathology, and raises the possibility that unique transcriptome signatures may further distinguish FTLD‐TDP from LATE/AD and within different TDP‐43 subtypes. We showed a relationship between increased TMEM106B core deposition and greater susceptibility to TDP‐43 dysfunction, potentially through dysregulation of endolysosomal function.
Asymmetrical hippocampal atrophy: an arrow in the quiver of imaging markers for LATE‐NC
Authors: Woodworth Davis C. , Greenia Dana E. , Bukhari Syed A. , Montine Thomas J. , Ezzati Ali , Kawas Claudia H. , Corrada María M. M. , Sajjadi S. Ahmad 
Published: January 2025

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) denotes TDP‐43 deposition in older age and is consequential for cognitive function. Currently there is no way to identify LATE‐NC during life. Some forms of TDP‐43 deposition in younger age, related to frontotemporal dementia (FTD), are associated with pronounced asymmetrical atrophy of the temporal lobe. Given the similar underlying proteinopathy of TDP‐43 in both LATE‐NC and FTD, we hypothesized LATE‐NC would be associated with asymmetrical hippocampal atrophy.MethodsWe included participants from The 90+ Study with both MRI and autopsy data. All participants were assessed for LATE‐NC, Alzheimer’s disease neuropathologic change (ADNC), and hippocampal sclerosis of aging (HS‐A). 3D‐T1w MRIs were segmented using FreeSurfer. We examined hippocampal asymmetry, and minimum and average hippocampal volumes (across left and right), in relation to LATE‐NC stages. We defined asymmetry as asym = log(100*abs(left. hipp. vol.‐right. hipp.vol)/(ave. hipp. vol)). We fit multiple linear regression models for each outcome, accounting for HS‐A presence and ADNC severity. Lastly, we examined prediction performance using area under the curve (AUC) for LATE‐NC stage 2 or higher, considering dementia status alone or including asymmetry, minimum, or average hippocampal volume. All models were adjusted for age at death, sex, education, and intracranial volume.ResultsTable‐1 displays participant characteristics (N = 104), with N = 37 (36%) having LATE‐NC. Increasing LATE‐NC stage was associated with increasing hippocampal asymmetry and decreasing minimum and average hippocampal volumes (Figure‐1). LATE‐NC stages 2 and 3 showed significant associations with hippocampal asymmetry (Figure‐2). HS‐A trended towards an association with, but ADNC was not associated with, hippocampal asymmetry (Figure‐2). Both asymmetry and minimum hippocampal volume appeared to be more strongly related to LATE‐NC compared to average hippocampal volume (Figure‐2). AUC analysis indicated that, for predicting LATE‐NC stage 2 or greater, the model which included asymmetry (AUC = 0.79) outperformed both the model with dementia status alone (AUC = 0.64, P = 0.005) and the models with average (AUC = 0.65, P = 0.007) and minimum (AUC = 0.69, P = 0.014) hippocampal volumes.ConclusionLATE‐NC is associated with asymmetrical hippocampal atrophy in a stage‐dependent fashion, independent of HS‐A and ADNC. Using measures of hippocampal asymmetry may lead to better identification of LATE‐NC during life.
Developing and Tailoring a Nutrition Intervention for Dementia Risk Reduction
Authors: Sheffler Julia L 
Published: January 2025

AbstractBackgroundNutrition and other lifestyle interventions hold promise for reducing dementia risk; however, significant barriers remain in translating these programs and recommendations to individuals at the greatest risk. We discuss application of the NIH Obesity‐Related Behavioral Intervention Trials (ORBIT) to the development and tailoring of a nutrition program for high‐risk older adults.MethodA mixed methods approach was used to evaluate factors that contribute to adherence and engagement with the nutrition program. Quantitative and qualitative data were drawn from two early phase clinical trials. Additionally, focus group data is reported to supplement the trial data.ResultProgram‐specific factors (e.g., group cohesion, delivery methods, quality of materials, and support for change) and personal factors (e.g., supportive family, health conditions, food‐related habits/experience) were identified as potential contributors to adherence and engagement. Further, focus groups provided specific feedback and recommendations about updates that can enhance adherence and engagement with the nutrition program.ConclusionIntervention development and adaptation is an iterative process that can be enhanced through mixed methods approaches that provide qualitative context for quantitative trial results.
Targeting Aging‐Related Neuroinflammation and Autophagy as Interventions for Late Onset Alzheimer’s Disease
Authors: Santos Diogo Francisco Silva , Haynes Katy A , Williams Sean‐Paul Gerard , Willis Jenny M , Nepali Umesh , Reddy Aman , Heaton Nicholas , Hart Jason T , Letica Leila , Dubberley Lauren R , Choi Sang‐Ho , Schaeffer David J , Silva Afonso C , da Silva Lais , Territo Paul R , Quinney Sara K , Liu Yuan , Chen Bill , Finkel Toren , Santos Diogo J Sukoff 
Published: January 2025

AbstractBackgroundThe bi‐directional autophagy and inflammation network becomes progressively dysregulated with age, with systemic inflammation as a biomarker of this dysregulation including in Alzheimer’s Disease (AD). We hypothesize that interventions which target the shared feature of systemic inflammation in the biology of aging and AD, via regulation of the autophagy‐inflammation network, will prevent the conversion to disease pathogenesis in AD as well as improve healthspan and longevity in aging populations. While previous studies report benefits of mTOR inhibition including rapamycin in transgenic mouse models of familial AD, the present studies aim to evaluate this pathway in a model of sporadic, late onset AD (LOAD) and test the contribution of AMP‐activated protein kinase (AMPK) as a critical regulator of the mTOR pathway.MethodA novel brain penetrable AMPK activator compound (BC1618) and the prototypical mTOR inhibitor rapamycin were administered chronically to male and female mice with genetic and environmental risk for LOAD. LOAD mice (APOE4/TREM2R47H/hAPP; JAX #030670) were conditioned on High Fat Diet (HFD) from 2 months of age which induced sustained inflammation. Drug exposure levels were measured by HPLC‐MS/MS for PK analysis. Subjects were evaluated through a comprehensive battery of tests longitudinally at 6‐month intervals throughout lifespan including motor, sensorimotor, cognitive behavior, frailty, blood‐based biomarkers, and PET/MR.ResultTreatment with rapamycin and BC1618 resulted in the expected appreciable exposure levels in brain and plasma. Interim analysis of LOAD+HFD mice at 22 months of age (10+ months treatment) revealed reduced survival and healthspan relative to non‐LOAD controls with no benefit of RAPA or BC1618 treatment. Ongoing studies evaluating translationally relevant PET/MR, biomarkers, pathology, and behavior throughout lifespan to evaluate effects on healthspan and lifespan are in progress.ConclusionLOAD+HFD mice model genetic x aging x environmental risk of sporadic late‐onset AD and provide a more translationally relevant model to study potential benefits of interventions that target the mTOR pathway. These studies are poised to inform influence of AMPK on autophagy and inflammation to attenuate disease progression in LOAD; which may be better predictive of effects on sporadic AD than previous studies in young transgenic early‐onset models of brain amyloid overexpression.
Subtle Inefficiencies in Everyday Tasks are Significantly More Frequent in People with Mild Cognitive Impairment and Associated with Episodic Memory Performance: Implications for Clinical Practice and Research
Authors: Mckniff Moira , Kaplan Marina , Holmqvist Sophia L. , Tassoni Molly B. , Simone Stephanie M. , Giovannetti Tania 
Published: January 2025

AbstractBackgroundMild functional difficulties begin in mild cognitive impairment (MCI) and precede functional disability, but people with MCI generally perform at ceiling on performance‐based tests of everyday function. This study examined whether inefficient reaching, touching, and extra movements (i.e., micro‐errors) on a performance‐based test (Naturalistic Action Test [NAT]) are more frequent in people with MCI vs healthy cognition and whether micro‐errors are associated with cognitive abilities, reflecting cognitive failures.MethodCommunity dwelling older adults over the age of 65 (N = 89; MAge = 73.54; SD = 6.9) completed tests of global cognitive status, episodic memory, executive functioning, language, and attention and were classified as having healthy cognition (n = 74) versus MCI (n = 15) using Jak/Bondi criteria. Participants also completed the NAT, which includes a breakfast and a lunch task, at two time‐points separated by 4‐6 weeks. NATs were scored for subtle, inefficient actions (i.e., micro‐errors) by coders who were blind to cognitive status and timepoint.ResultAn ANCOVA (controlling for age) showed participants with MCI made significantly more micro‐errors than participants with healthy cognition at both timepoints [Timepoint 1: F (1, 87) = 7.368, p = .008, η2 = .079; Timepoint 2: F (1, 87) = 15.167, p < .001, η2 = .151]. Micro‐errors at time 1 were correlated with global cognitive status [r = ‐.229, p = .031], episodic memory [r = ‐.223, p = .036], and micro‐errors at time 2, but were not correlated with measures of executive function, language, or attention. A Spearman’s rank order correlation to establish test‐retest reliability did not reach our .7 cut‐off, though the correlation was significant (r (87) = .465, p < .001), and both time‐points did not significantly differ from each other (p = .086)ConclusionAlthough people with MCI are functionally independent, they make more inefficient actions (micro‐errors) than healthy controls on highly familiar everyday tasks, and this difference was stable over time. Micro‐errors, which correlations suggest reflects cognitive failures, may be useful markers for early detection of MCI, identification of risk for conversion to dementia or functional disability, and may be used as functional outcomes in clinical trials.
A Computerized Cognitive Assessment Battery Optimized for At‐Home Testing
Authors: Hall Kathleen , Baldo Juliana , Pebler Peter , Herron Timothy J , Geraci Kristin , Blank Michael , Schendel Krista , Lwi Sandy J. , Chok Jas M. , Kahly Omar , Miranda Miranda , Jaramillo Isabella , Curran Brian , Santavicca Isabella , Thomas Lexie , Spinelli Maria G , Williams Garrett , Johnson David K , Woods David L. 
Published: January 2025

AbstractBackgroundThe administration of cognitive tests in patients’ homes facilitates access by underserved communities and increases testing capacity and efficiency. However, the validity of at‐home computerized cognitive tests is often questioned because of limitations in examiner monitoring, distractions, environmental noise, and potential cheating. Here, we compare performance of the computerized and proctored California Cognitive Assessment Battery (CCAB) when administered at‐home or in the laboratory using otherwise identical procedures.MethodThe California Cognitive Assessment Battery (CCAB) includes 17 verbal and 15 non‐verbal tests that have been optimized and normed for at‐home assessment on tablet computers (Figure 1). To reduce the influence of distractions and noise, CCAB verbal stimuli are adjusted for hearing loss and delivered at high intensities through noise‐attenuating circumaural headphones. Verbal responses are digitally recorded using a noise‐cancelling head‐mounted microphone. Most importantly, CCAB test administration is proctored through a control interface that warns of potential error conditions (e.g., performance failures, excessive noise, etc.), displays test performance in real time, facilitates patient observations, and incorporates video chat and test‐control capabilities to readminister tests should problems arise.During the COVID pandemic 310 participants (mean age 70.1 years) successfully completed three 90‐minute enrollment test sessions in their homes. Omnibus z‐scores were obtained by averaging z‐scores from 70 individual test measures. At 6 months, 277 participants were retested, 46% of them in the laboratory. At 18 months, 200 participants were retested, 57% in the laboratory.ResultTable 1 shows Omnibus z‐score correlations at enrollment, 6‐, and 18‐ months as a function of retest location: test‐retest reliability was similar for at‐home/in‐lab and at‐home/at‐home pairs. Table 2 shows mean z‐scores for at‐home and in‐lab assessments at 6‐ and 18‐months, estimated with a model that included Omnibus z‐scores at enrollment. No significant differences were observed as a function of test site at 6‐months (t(273) = ‐0.56, NS) or 18‐months (t(172) = 0.44, NS).ConclusionThe CCAB produces results with similar means, variances, and distributions whether assessments are administered at‐home or in a laboratory.