bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beyond Traditional Measures: Exploring Cognitive Intraindividual Variability in Traumatic Encephalopathy Syndrome
Authors: Altaras Caroline , Ly Monica T. , Barr William B. , Banks Sarah , Wethe Jennifer V. , Tripodis Yorghos , Adler Charles , Balcer Laura , Bernick Charles B. , Cantu Robert C. , Dodick David W. , Mez Jesse , Palmisano Joseph N. , Martin Brett , Cummings Jeffrey L. , Reiman Eric M. , Shenton Martha E. , Stern Robert A. , Katz Douglas I , Weller Jason , Geda Yonas E. , Alosco Michael L. 
Published: January 2025

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impacts in contact/collision sports. A core clinical feature of TES is cognitive impairment, particularly in memory and executive functions. Cognitive intraindividual variability (IIV) is the extent of variability in neuropsychological test performance (i.e., dispersion of test scores) and is believed to be an indicator of disruption in executive control, linked to altered fronto‐subcortical circuits. Here, we examined cognitive IIV as a method to detect subtle executive dysfunction in TES that may not be captured by traditional neuropsychological measures.MethodThe sample included former American football players (120 professional, 60 college); participants were males, aged 45‐74. Participants completed a baseline neuropsychological test battery (n = 8 excluded for suboptimal performance validity). A multidisciplinary diagnostic consensus conference classified participants using the 2021 NINDS Consensus Diagnostic Criteria for TES (see Table‐1): (1) No‐TES (n = 62); (2) TES‐CTE Suggestive (n = 35); (3) TES‐CTE Possible (n = 21); (4) TES‐CTE Probable (n = 54). TES‐CTE Possible and Probable were combined. The coefficient of variation (CoV) was used to measure cognitive IIV (CoV = iSD/iOTBM, iOTBM = average T‐score across neuropsychological tests; iSD = standard deviation of iOTBM). A higher CoV indicates greater score dispersion. To avoid circularity, memory and executive tests used for classifying TES groups were intentionally excluded from the CoV calculation. Analysis of covariance compared the TES groups on CoV, controlling for age, education, and race.ResultResults showed a significant difference in CoV between TES groups, F(2, 165) = 8.20 p<.001, partial η2 = .09. The TES‐CTE Possible/Probable group had the highest CoV (M = .226, SE = .007), compared with the TES‐no (M = .192, SE = .008, p<.001) and TES‐CTE Suggestive groups (M = .178, SE = .011, p<.001). CoV did not significantly differ between the TES‐no and TES‐CTE suggestive groups (Mdiff = 0.014, SE = .013, p = .293).ConclusionThe TES‐CTE possible/probable group had the highest cognitive IIV with ∼23% dispersion (vs. ∼18‐19% in TES‐no and TES‐CTE suggestive groups), suggesting greater cognitive variability in those with the greatest likelihood for having underlying CTE (based on TES criteria). This finding emphasizes the potential utility of exploring cognitive IIV as a method for detecting nuanced executive dysfunction in TES.
The association between focal prefrontal cortical atrophy and accelerated long‐term forgetting in presymptomatic autosomal dominant Alzheimer’s disease
Authors: Young Chloe , Fraser Maggie R , Lu Kirsty , O'Connor Antoinette , Crutch Sebastian J , Fox Nick C , Weston Philip SJ 
Published: January 2025

AbstractBackgroundAccelerated long‐term forgetting (ALF) is a form of episodic memory impairment where information is retained normally over 30‐60 minutes but lost at an accelerated rate over subsequent days to weeks, and is a very early – perhaps the earliest – cognitive change in both autosomal dominant and sporadic Alzheimer’s disease (AD). However, the neuroanatomical changes underlying ALF in AD have remained elusive. We explored associations between ALF and focal cortical thickness in presymptomatic autosomal dominant AD (ADAD).MethodEighteen asymptomatic ADAD mutation carriers (mean estimated years to symptom onset = 7.3) (SD = 4.4) and twelve non‐carrier controls underwent ALF testing for three tasks (list, story, figure). After learning, recall was tested at 1) 30 minutes and 2) seven days. ALF score was calculated as 7‐day recall/30‐minute recall. T1‐weighted MRI was acquired at baseline and annually over five years. Cortical thickness was estimated using FreeSurfer. Thirteen regions of interest were selected based on either a known vulnerability to AD‐related neurodegeneration or a known role in memory. Serum NfL– a neurodegeneration marker– was measured on the single molecule array platform. Spearman coefficients explored associations between ALF and 1) focal baseline cortical thickness, 2) future rates of thinning, and 3) serum NFL.ResultAcross all three tasks, ALF scores were significantly lower in mutation carriers than non‐carriers, despite no difference at 30‐minutes. In mutation carriers, verbal ALF (list and story) was associated with lower baseline cortical thickness in the prefrontal cortex (PFC) across four contiguous regions bilaterally (p<0.001 for each). This association was not present in non‐carriers. No associations were found between ALF and the thickness/volume of medial temporal lobe (MTL) structures. ALF was predictive of future cortical thinning across AD vulnerable regions. Higher serum NFL was associated with poorer long‐term list recall. Forgetting at 30 minutes was not associated with cortical thickness or NfL, i.e. associations were specific to ALF.ConclusionALF is an early presymptomatic marker of AD‐related cognitive decline, underscored by changes in the PFC but not the MTL. These findings advance our understanding of the neuroanatomical substrate of early AD memory decline. ALF could be used as a biologically relevant measure in future presymptomatic trials.
Uncovering the Role of an African‐specific ABCA7 Frameshift Deletion on Lipid Metabolism and Alzheimer’s Disease
Authors: Nam Younji , DeRosa Brooke A. , Golightly Charles G. , Simon Shaina A. , Arvizu Jamie , Ramirez Aura M , Whitehead Patrice L. , Adams Larry D. , Starks Takiyah D. , Cukier Holly N. , Cuccaro Michael L. , Haines Jonathan L. , Byrd Goldie S. , Beecham Gary , Dykxhoorn Derek M. , Young Juan I , Vance Jeffery M. , Pericak‐Vance Margaret A. 
Published: January 2025

AbstractBackgroundWe previously identified a 44‐base pair deletion in (ATP‐binding cassette sub‐family A member 7) (ABCA7) that is significantly associated with Alzheimer’s disease (AD) in African Americans (AA), producing a frameshift mutation resulting in a truncated protein (p.Arg578Alafs). ABCA7 is a lipid transporter across cellular membranes. While we have shown the mutant mRNA is present in neurons, whether it is translated into a stable protein is not known due to the lack of antibodies capable of recognizing the N‐terminus of endogenous ABCA7. The abrupt ABCA7 translation due to the deletion may alter the lipid metabolism, which can be investigated using isogenic iPSC and differentiated models.MethodsWe analyzed single‐cell RNAseq (scRNAseq) data from spheroid cultures of 12 individuals. We generated a recombinant version of the ABCA7 gene with and without the deletion and bearing an N‐terminal flag tag which were transfected into HEK cells. We utilized CRISPR‐based genome editing using induced pluripotent stem cell (iPSC) lines from three independent AA‐cognitively unimpaired individuals (WT) to introduce the AA‐specific ABCA7 homozygous or heterozygous deletions. These were differentiated using standard protocols in the HIHG iPSC core into monocultures of induced neuron‐like cells. C‐terminal antibodies were used to assess the presence of native ABCA7 in HEK cells.ResultsExamination of HEK cells revealed no detectable native ABCA7. The truncated ABCA7‐tagged protein appeared stable and localized in the plasma membrane as seen for the wild‐type protein (Figure 1). ScRNAseq confirmed that expression of ABCA7 is highest in neurons, identifying them as the iPSC differentiated cell of choice. We successfully generated both homozygous and heterozygous deletion isogenic lines in the three WT iPSC lines. Differentiated neurons from these isogenic lines have a normal phenotype, allowing for functional assays and lipidomic studies.ConclusionThe truncated protein p.Arg578Alafs appears to be expressed and stable in HEK cells, and surprisingly located in the plasma membrane despite the absence of most transmembrane domains. Our three isogenic iPSC pairs will be a great resource for studying the pathogenic effects of the ABCA7 truncation in differentiated cells.
Recruitment Efforts for the study “Development and Validation of TeleNeuropsychology Normative Data for Older Adults”
Authors: Perez‐Lao Ambar R , Ying Gelan , Marra David E , Santos Lauren , Arias Franchesca , Smith Glenn E. 
Published: January 2025

AbstractBackgroundRemote administration of well‐established neuropsychological instruments (TeleNeuropsychological or TeleNP) can reduce assessment wait times and expand access to cognitive assessments for medically compromised and socially disadvantaged patients. A major limitation in the widespread uptake of TeleNP relates to the need for more normative data compared to in‐person assessments. This presentation describes a novel ascertainment strategy used in Florida’s Older Adults TeleNeuropsychology (FLOAT) project to identify and recruit “cognitively healthy” older adults to norm well‐established neuropsychological instruments administered remotely. This abstract summarizes recruitment efforts during Phase I and II of this study.MethodWe utilize a previously developed machine learning algorithm to identify participants aged 50+ with a low‐to‐high probability of developing Alzheimer’s disease and related dementias (ADRD). We select those with low probabilities for invitation to participate. Prospective participants with severe psychiatric disorders (i.e., schizophrenia, bipolar disorder) or no internet access are excluded. About 7000 prospective participants between 51 to 104 years of age from the OneFlorida Data Repository were identified. Phases I and II used email to reach participants ages 60‐79 with the lowest ADRD risk.ResultOf the 5112 persons eligible for Phases I and II, 606 participants did not include emails in their contact information. Of those contacted, 4,347 did not respond to the first outreach contact, 55 declined to participate, and three did not meet the study criteria. Overall, 107 agreed to participate, and 30 are currently enrolled. As recruitment waves continue, these numbers will include participants aged 50‐59 and 80+.ConclusionFLOAT incorporates machine‐learning‐based informatics to efficiently identify a robust sample of cognitively healthy older adults to norm a TeleNP protocol. Our initial affirmative response rate (2.4%) is promising. Additional strategies to improve response and enrollment rates are underway. New methods to leverage the algorithm while enriching the cohort for underrepresented groups are being explored and discussed, and preliminary normative data will be presented. Recruiting older adults for norm development is resource‐intensive and requires efficient yet flexible methods.
Rapid Identification of Patients with Rapidly Progressive Dementia
Authors: Piura Yoav D , Tipton Philip W , Dunham S Richard , Satyadev Nihal , Graff‐Radford Neill R , Day Gregory S 
Published: January 2025

AbstractBackgroundPatients with the precipitous onset of cognitive symptoms (i.e., suspected rapid progressive dementia [RPD]) may continue to decline (true RPD) or may stabilize or improve (non‐RPD). Recognizing patients with RPD early in the disease course is important to support clinical care and enrollment in research.MethodPatients referred for the evaluation of suspected RPD were prospectively enrolled and followed for up to 2 years at Mayo Clinic in Florida (Jacksonville, FL; Jan‐2020 – Oct‐2023) and Washington University in St. Louis (Saint Louis, MO; Jun‐2016 – Dec‐2019). Clinical data were independently reviewed by two dementia specialists who established clinical diagnoses, referencing published criteria. Patients were diagnosed with RPD if they progressed to dementia (global Clinical Dementia Rating® [CDR] ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. Univariate statistics compared demographics, clinical details, and test results between patients with RPD and non‐RPD. Variables with p<0.1 were entered into a multivariate logistic regression model to identify factors associated with RPD.ResultOf 248 patients referred for suspected RPD, 187 (75.4%) met stated criteria for RPD. Patients with RPD were older (62.6±14.4 years vs 55.0±18.3 years; p<0.001), and more likely to be diagnosed with Alzheimer disease or related dementias (28.3% vs 9.8%; p = 0.003) or Creutzfeldt‐Jakob (19.1% vs 4.6%; p = 0.008). Non‐RPD cases were more often attributed to autoimmune/inflammatory disease (42.6% vs 29.4%, p = 0.061) or other causes (e.g., psychiatric, neoplasms, toxic/metabolic; 34.4% vs 16.6%, p = 0.006). After controlling for age, hallucinations (OR, 2.81; 95%CI: 1.21‐6.52), elevated CSF protein (OR, 2.43; 95%CI: 1.17‐5.03), and CSF white blood cell count <5 cells/mm3 (OR, 2.77; 95%CI: 1.32‐5.85) were independently associated with RPD. Cortical visual loss (15/183, 8.2%) and substantial brain atrophy on MRI (27/184, 14.7%) were specific to patients with RPD, representing additional distinguishing features.ConclusionHallucinations, cortical visual loss, substantial atrophy on MRI, elevated CSF protein, and normal CSF white blood cell count were independently associated with RPD. Early detection of these features in patients with suspected RPD may inform clinical care and enrollment in research studies of RPD.
New psychometric analysis and normative data for the Argentinean Psycholinguistic Naming test in color: PAPDIC
Authors: Vivas Leticia , Manoiloff Laura , Paolantonio Patricia , Lamenza Miguel Horacio , Aragones Carla Andrea , Moreno Maria Celeste López 
Published: January 2025

AbstractBackgroundNaming test are a very common tool in neuropsychological batteries. Some years ago, the Argentinean Psycholinguistic Naming test was developed, first with black and white drawings (Manoiloff et al., 2018) and then in colors (PAPDIC) (Vivas et al., 2020). Items were selected and organized on the basis of Argentinean psycholinguistic norms. At that time evidence of validity was reported (concurrent validity and contrasted groups analyses). Here we present new psychometric analysis and normative data for the Argentine population.MethodThe sample comprised 292 participants: 195 healthy, 70 MCI, 14 stroke patients without aphasia and 13 stroke patients with aphasia. They went through a complete neuropsychological battery to ensure that no other cognitive function alteration (apart from language) could interfere with the task. Items were rated as dichotomous responses, and the final score only included those correct responses given before the phonological cue.Resulto assess the test’s internal consistency a KR20 analysis was performed (as items were dichotomous) which showed a value of .879. Besides, a one factor ANOVA was performed to compare the full test score between groups and significant differences were observed (F(3,288) = 51.867; p < .001). Particularly, healthy participants differentiate from the MCI (p < .001) and stroke with aphasia (p < .001) groups, but no with stroke patients without aphasia (p = .133). Another comparison was performed between this version of the test and a previous black and white version by a chi‐squared analysis with each item, and it showed a similar performance for 24 items, a better performance in the color version for 5 items and a worse performance in one item. Additionally, a regression analysis was performed in order to obtain normative data for the Argentine population. As age was the only demographic variable that showed significant effect on the test score (R2 adjusted = .140; F(1,192) = 32.545; p < .001), it was considered for this calculus.ConclusionThese results show that the PAPDIC is a reliable naming test for the Argentine population that can be used both for patients with neurodegenerative diseases and post stroke aphasia.
The role of common structural variants in Alzheimer’s disease
Authors: Lee Songmi , Xia Rui , English Adam C , Peloso Gina M. , Bis Josh , Lin Honghuang , Choi Seung Hoan , Heard‐Costa Nancy , DeStefano Anita L. , Sedlazeck Fritz J , Fornage Myriam 
Published: January 2025

AbstractBackgroundStructural variants (SVs), genomic alterations exceeding 50 base‐pairs, are known for their significant impact on disease pathology. However, the role of SVs in Alzheimer’s Disease (AD) remains unclear. Using a novel high‐accuracy SV calling pipeline, we analyzed a diverse sample from the Alzheimer’s Disease Sequencing Project (ADSP). Our study investigated the role of SVs in known AD loci, providing insights into the genetic architecture of AD.MethodsWe included samples from ADSP 17K whole genome sequence data. SV discovery was performed using Biograph SV caller that leverages an assembly‐based method and graph‐based representation. After quality filtering at the sample‐ and variant‐ levels, there were 68,831 segmented deletions, 25,281 insertions, and 198 inversions with minor allele frequency > 1% in 11,890 individuals (5,585 cases and 6,305 controls). We focused on common SVs in linkage disequilibrium (LD) (R2 > 0.2) with 124 SNPs tagging known AD loci derived from previous genome‐wide association studies of AD. LD was calculated using PLINK 1.9. Association analyses of AD status were performed for each identified SV adjusting for sex, technical covariates, associated principal components, and familial relatedness using GENESIS.ResultsWe identified 15 deletions and 3 insertions in LD with 12 SNPs tagging known AD loci (Table). Of these, 9 SVs and 8 tagging SNPs showed nominal associations with AD (P<0.10) in the ADSP sample. The strongest AD associations were with two deletions located in an intron of KANSL1, in moderate LD (R2 = 0.65) with a SNP tagging the MAPT haplotype, which is known to associate with multiple neurodegenerative diseases including AD. Several SVs were in high LD with SNPs tagging AD loci. Notably, a 319‐bp deletion (R2 = 0.97) in the TPCN1 locus overlapped fully with a known 309‐bp deletion known to be associated with Lewy Body dementia. A 322‐bp Alu deletion in exon 8 of TMEM106B, previously identified through long‐read sequencing, also demonstrated strong LD with two AD‐related SNPs (R2 = 0.91 and 0.89, respectively).ConclusionUsing a novel SV calling pipeline, we identified multiple AD‐related SVs, which provides additional insights into the genetic architecture of AD. Integration of omics data is warranted to explore the functional impact of these SVs.
The heterogeneity of regional cortical atrophy in early Alzheimer’s disease
Authors: Page Frederick A , Suseelan Shayam , Kulkarni Gayatri , Nowell Joseph , Edison Paul 
Published: January 2025

AbstractBackgroundCortical atrophy in Alzheimer’s disease (AD) is typically thought to commence in the medial temporal lobe. However, growing evidence suggests that this may not be true for all patients. Here, we explored atrophy patterns in patients with mild cognitive impairment (MCI) and AD and whether atrophy patterns are associated with specific clinical and neuropathological outcomes.Methods1124 AD and MCI patients were selected from the Alzheimer’s Disease Neuroimaging Initiative. Baseline 3T magnetic resonance imaging scans were processed for all patients who were then subtyped based on regions of predominant atrophy. Baseline cognitive performance and rates of cognitive decline over one year were compared between atrophy subtypes. Regional tau pathology was also evaluated with [18F] AV1451 positron emission tomography.ResultsThe following atrophy subtypes were identified: medial‐temporal dominant, frontal‐dominant, parietal‐dominant, diffuse, and occipital‐dominant. Baseline cognitive performance and tau were indicated to differ between subtypes.ConclusionInitial cortical atrophy in AD and MCI may be highly heterogeneous. Additionally, since atrophy subtypes showed unique cognitive performances and tau distributions, they may respond differently to treatment. This study provides grounds for an increased research focus on cortical atrophy in regions outside the medial temporal lobe, especially the parietal lobe.
Degradation of gaze‐speech synchronization due to mild cognitive impairment in picture description tasks
Authors: Kleiman Michael J. , Galvin James E 
Published: January 2025

AbstractBackgroundWhen performing a picture description task, healthy individuals tend to look only briefly at a target before beginning its description, after which they move promptly onto the next target. This sequence may be disrupted in those with cognitive impairment. Just as cognitively impaired individuals produce greater numbers of disfluencies and pauses, those with mild cognitive impairment (MCI) may delay speech production by extending their gaze behavior towards a target before beginning its description.MethodTo explore this, we examined the gaze and speech behavior of 39 participants (27 HC, 12 MCI) while engaging in the Cookie Theft picture description task. Transcriptions with word‐level timings were generated using OpenAI’s Whisper in combination with the whisper‐timestamped Python package utilizing Dynamic Time‐Warping for more accurate timestamps with reduced hallucinations. Gaze was collected using a Tobii Pro Spectrum 300Hz eye tracker and processed using custom‐developed fixation filters, with gaze target timing identified as the first full fixation directed towards that area of interest. Speech timing was determined as the beginning of the sentence containing the target description.ResultMCI participants initiated speech production after a longer delay following target fixation than HC participants, and produced shorter and less descriptive responses. Gaze behavior was also more sluggish in MCI participants; visits onto targets were less frequent and longer, and saccadic movements between targets were less frequent.ConclusionThe intersection of gaze and speech behavior is a potentially powerful avenue for identifying early‐stage cognitive impairment, but is currently under‐utilized. Future research in gaze‐speech synchronization may identify patterns that could target biomarker‐confirmed preclinical Alzheimer’s disease.