bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational potential of JAX humanized APOE mice: Metabolism and body composition in very old mice
Authors: Bhattrai Avnish , McLean John W. , Raikes Adam C. , Wiegand Jean‐Paul L. , Skopp Stacy M , Brinton Roberta Diaz 
Published: December 2022

AbstractBackgroundApolipoprotein (APOE) is the strongest genetic risk factor for the development of late‐onset Alzheimer’s disease (LOAD). Clinically, LOAD exhibits strong sex effects with females being twice at the risk of developing AD than males. Models exhibiting strong AD etiology are used in preclinical settings, however lack of translatability necessitates model development with a reverse translational approach. This study explores metabolic hallmarks of LOAD assessing the clinical translatability of the JAX humanized APOE (hAPOE) mouse model.MethodhAPOE mice (M/F, n = 65, mean age = 23.35 +/‐ 0.90 months) with e3/3, e3/4 or e4/4 genotype underwent a metabolic and body composition screening assay including fasting blood glucose (FBG) and ketone (FKB) measurement, EchoMRI, and 18F‐FDG‐PET brain imaging, prior to being sacrificed. Blood plasma was analyzed for triglyceride levels. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum. All data were analyzed with genotype x sex analysis of variance. P ≤ 0.05 was considered statistically significant and post‐hoc pairwise analyses were conducted for interaction effects with p ≤ 0.1 (FKB, adipose index) for future study planning.ResultFemales had significantly lower lean mass (p < 0.0001) and FBG (p=0.05), with a trend toward lower glucose uptake on FDG‐PET compared to males (p=0.072). Post‐hoc interaction analyses of FKB (interaction p=0.105) demonstrated lower ketone body levels in male e4/4s compared to female e4/4s (uncorrected p=0.0685) and male e3/4s (p=0.034). Post‐hoc interaction analyses of adipose index (interaction p=0.093) demonstrated greater adiposity in female e4/4s compared to male e4/4s (uncorrected p=0.005) and female e3/3s (uncorrected p=0.035). No effects of APOE genotype were observed.ConclusionIn a mouse cohort at a comparable human age of ∼ 70 years, lower lean mass, fasting blood glucose, and glucose uptake in the brain for female mice indicates ongoing bioenergetic deficits and is corroborated by observations within clinical populations. Greater adiposity in female e4/4s suggests that brain bioenergetic demand is not being met through fat reserves. However, the overall lack of genotypic effects suggests this bioenergetic crisis is not driven by hAPOE in this animal model, limiting clinical translatability.NIA R01AG057931; University of Arizona TBIR (NIH S10 OD025016).
BDNF expression partially mediates greater verbal learning and memory ability in a cohort enriched with risk for Alzheimer’s disease
Authors: Edmunds Kyle J , Rogers Christine C , Pandos Alyssa A , Mamlouk Gabriella M , Motovylyak Alice , Johnson Sterling C. , Okonkwo Ozioma C. 
Published: December 2022

AbstractBackgroundIn cognitively normal adults, women score higher than men in verbal learning ability (VLM)—a cognitive domain sensitive to decline in Alzheimer’s disease (AD). Sex‐specific mechanisms of action in brain‐derived neurotrophic factor (BDNF), a growth factor important for modulating memory and long‐term brain health, may explain this observed sex difference. Therefore, this study examines whether circulating BDNF expression mediates sex differences in VLM scores in a cohort enriched with risk for AD.MethodCognitively unimpaired participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n=201, age 63.81±6.04y, 66.2% women, 65.7% family history of AD, 38% APOE‐ε4 carriers) underwent the Rey Auditory Verbal Learning Test (RAVLT). Scores from the delayed recall test and trials 3‐5 and were aggregated as a VLM performance index. Serum BDNF levels were measured using a Human BDNF Quatikine Immunoassay (R&D Systems). Mediation analysis and bootstrapping were performed using the Hayes and Preacher macro for SPSS, first using the full participant sample. Stratified models were then assembled to test the conditional dependence of BDNF mediation on APOE‐ε4 allele carriage.ResultFrom the full sample, women had significantly higher VLM scores [β=‐0.68; p<0.01] and serum BDNF levels [β=‐0.61; p<0.01] than men; BDNF expression was likewise positively correlated with VLM [β=0.17; p=0.014]. Bootstrapping indicated that BDNF was indeed a significant partial mediator of the association between sex and VLM [β=‐0.07; 95% CI: ‐0.164, ‐0.005]. Models stratified by APOE‐ε4 carriage showed no significant association between sex and BDNF in APOE‐ε4+ individuals [β=‐0.13; p=0.63], but women in this group again had significantly higher VLM scores than men [β=‐0.57; p=0.02]. By comparison, in the APOE‐ε4‐ group, women had significantly higher BDNF levels [β=‐0.65; p<0.01] and VLM scores [β=‐1.01; p<0.01], and bootstrapping again showed BDNF to be a significant mediator [β=‐0.16; 95% CI: ‐0.324, ‐0.037].ConclusionOur findings indicate that higher circulating BDNF levels in women might be an important factor in building resilience against verbal memory decline, but this relationship may be attenuated by the deleterious effects of APOE‐ε4 allele carriage.
Construct validity of cognitive intraindividual variability: A replication study
Authors: Scott Bonnie M. , Royall Donald R. , O'Bryant Sid E. , Hilsabeck Robin C. 
Published: December 2022

AbstractBackgroundWe previously found intraindividual variability (IIV) in performance between cognitive domains to predict subsequent declines in cognitive and functional status over a 5‐year period in the Texas Alzheimer’s Research and Care Consortium (TARCC) Hispanic Longitudinal Cohort. However, we later examined the construct validity and predictive utility of this metric in a follow‐up study and found that IIV‐between domains was driven primarily by IIV‐within the executive function domain in the non‐Hispanic cohort and by IIV‐within the language domain in the Hispanic cohort. The present study aimed to replicate these findings in two independent samples: (1) FRONTIER, and (2) HABLE.MethodsBaseline data for cognitively normal participants in the TARCC (N = 651), HABLE (N = 1199), and FRONTIER (N = 197) studies were included for analysis in the present study. All participants ranged from 50–95 years of age with 0–22 years of education. Although cognitive measures varied across studies, mean composite and standard deviation z‐scores were calculated from similar tasks for an Attention/Processing Speed, Language, Delayed Verbal Memory, and Executive Functioning domain. Measures of functional independence also varied across studies.ResultsAcross studies, non‐Hispanic individuals were generally older with higher levels of education, fewer depressive symptoms, and higher cognitive and functional status. Only variability in the executive domain was found to consistently differ between Hispanic and non‐Hispanic individuals across studies and no consistent between‐group differences were observed in the relationship between cognitive IIV scores with each other and with clinical characteristics and measures of general cognitive and functional status.ConclusionsFindings suggest that the construct validity and predictive utility of cognitive IIV scores varies across studies differing in methodology and clinical characteristics.
Neuroinflammatory profiles of the human female brain in midlife resembles the human male late‐life Alzheimer's brain
Authors: Delatorre Nicole , Van Rossum Hannah , Mishra Aarti , Padilla‐Rodriguez Marco , Rodgers Kathleen E. , Brinton Roberta Diaz 
Published: December 2022

AbstractNicole Delatorre & Hannah Van Rossum are co‐first authorsBackgroundNeuroinflammation is a well‐documented feature of Alzheimer’s Disease (AD). Two important questions in defining the role of the neuroimmune system in AD remain unaddressed: 1) the initiation phase of inflammation and 2) sex differences in the inflammatory cascade. Previous preclinical findings from our group demonstrated elevated inflammatory and immune transcripts including CD3, CD4, and MHCII. With this work, we extend and translate our preclinical discoveries to test the hypotheses that the inflammatory phenotype of LOAD is initiated in midlife of the human aging process and sex differences are prevalent.MethodBoth fixed and frozen human tissue samples were obtained from NIH NeuroBioBank (University of Maryland, University of Miami, and Mt. Sinai) that included the corpus callosum, hippocampus, and hypothalamus of 40 brain donors that were sex and age matched. For the purposes of this study, samples were sub‐classified into 3 groups: healthy aging 40‐49 years‐old, healthy aging 50‐59 years‐old, and AD age 60‐80 years‐old. Transcriptomic analyses were conducted to determine neuroinflammatory gene expression and to identify common signaling profiles. Neuroinflammatory markers were visualized using 3,3’‐diaminobenzidine immunohistochemistry and included microglia (IBA‐1), activated microglia (HLA), and T‐cells (CD3, CD4, CD8).ResultGene expression change was determined by comparing each group to the young male. The profiles were compared using fisher exact tests and revealed region‐specific and sex‐specific transcript regulation. Midlife females exhibited significant differences in genes involved in hypothalamic adaptive immune response (p=0.0054), hippocampal astrocyte function p=0.007, and hypothalamic inflammatory signaling p=0.028). AD males exhibited altered gene expression in corpus callosum neurotransmission (p=0.0355), hippocampal innate immune response, and hypothalamic adaptive and innate immune response (p=0.0496, p=0.0208). Both midlife female and AD male showed hippocampal upregulation of innate immune transcripts and hypothalamic upregulation of adaptive and innate immune response genes.ConclusionThese results provide evidence of early activation of the immune response in brain as a potential sex‐dependent risk factor for AD. Outcomes of these analyses support future studies that identify neuroimmune biomarkers of the AD prodrome and present an early opportunity for intervention in order to reduce risk and/or delay AD.NIH: R01AG057931, R01AG057931‐02S1, T32AG061897, R01AG057931‐01A1
Translational potential of JAX humanized APOE mice: Hippocampal volume decline in very old mice
Authors: Raikes Adam C. , Bhattrai Avnish , McLean John W. , Wiegand Jean‐Paul L. , Brinton Roberta Diaz 
Published: December 2022

AbstractBackgroundWhole brain and hippocampal atrophy are the most prominent structural features of late‐onset Alzheimer’s disease (LOAD) and are accepted endpoints in many clinical trials. The APOE ε4 allele is the strongest genetic risk factor for LOAD, with the ε4/ε4 genotype associated with the greatest atrophy rates. To date, there is limited hippocampal volume reporting in preclinical APOE models. To assess the translational potential of a humanized APOE (hAPOE) mouse model, we report age, sex, and genotype effects on total brain and hippocampal volume.MethodHigh resolution ex‐vivo MRIs were obtained from two separate cohorts of male and female hAPOE mice (Cohort 1: n=53, 18.47±0.99 months; Cohort 2: n=33, 24.24±0.58 months). A validated mouse brain atlas was used for volumetric analysis. Cohorts were analyzed separately with genotype by sex analyses of variance for total brain volume (sum of all regions in atlas) as well as left and right hippocampal volume as percent of total brain volume.ResultIn Cohort 1, hAPOEε4/ε4 mice had significantly larger brains than hAPOEε3/ε3s or hAPOEε3/ε4s, with female hAPOEε4/ε4s having the largest brains (p<0.001). Regardless of genotype, females had smaller left (p=0.006) and right (p<0.001) hippocampi relative to males. In Cohort 2, there were no genotype or sex differences in total brain volume. However, left (p=0.044) and right (p=0.034) hippocampal volumes were smaller for hAPOEε4/ε4 mice compared to hAPOEε3/ε4 mice without sex effects.ConclusionOur findings capitalize on a large dataset (n=88) of high‐resolution MRIs. At 18‐20 months old (∼60 human years), hAPOEε4/ε4 mice had greater total brain volume than comparably aged hAPOEε3/ε3 or hAPOEε3/ε4 mice without hippocampal atrophy. However, hippocampal atrophy was evident when mice were aged to 24‐25 months (∼70 human years). These findings of larger brain volume and greater hippocampal atrophy in hAPOEε4/ε4 carriers are consistent with large‐scale AD imaging datasets. The timing of evident hippocampal atrophy in these mice also coincides with the global average age of clinical diagnosis. Based on these findings, the translational potential of this model requires utilizing very old mice, limiting the window for therapeutic testing.AcknowledgementsNIA R01AG057931, RF1AG059093; University of Arizona TBIR (NIH S10 OD025016)
Regional Differences of the Impact of Healthy Aging on Myeloarchitecture at 7T
Authors: Mueller Susanne G 
Published: December 2022

AbstractBackgroundCortical gray matter (cGM) loss in healthy aging has been well documented by volumetric MRI. Less well known though is if this age‐related cGM loss is layer‐specific or diffuse. Benefiting from the higher resolution at 7T and the close relationship between cortical cyto‐ and myeloarchitecture (1) this project used a newly developed technique for the differentiation between heavily (layers IV‐VI) and sparsely (layers I‐III) myelinated cortical layers to investigate this question.MethodThe 7T MP2Rage images (TR/TE/TI1/TI2=5000/2.45/900/2750 ms, 0.7x0.7x0.7mm) of 45 healthy controls (age: 19‐75, f/m=23/22) from the ATAG data repository (http://doi.org/10.5061/dryad.fb41s) were used for this project and the following contrasts generated: 1. T1 weighted image (UNI). 2. T1 relaxation image (T1map). 3. Inv1/Inv2 ratio map (In1/In2 ratio). After skull‐stripping and intensity calibration a fourth contrast (UNI/T1map ratio) was calculated. The UNI was segmented in SPM and a binary cortical rim mask calculated. With these four contrasts as input K‐means clustering was used to identify 6 clusters within this mask: CSF cluster, CSF/cGM transition cluster, WM cluster, WM/cGM transition cluster, heavily myelinated cGM cluster (hcGM) and sparsely myelinated cGM cluster (scGM) (Figure 1). The hGM and scGM maps were warped into a common space with SPM’s DARTEL. SPM was used to compare hcGM and scGM differences of young adults (n=27, 19‐27 years) with that of older adults (n=18, 42‐75 years).ResultFigure 2 shows that hcGM loss was restricted to the mid‐posterior cingulate and parahippocampal gyrus. Age‐related scGM loss was more diffuse and affected mesial prefrontal, opercular cortex and superior temporal gyrus.ConclusionAge related cGM loss affects sparsely and heavily myelinated layers differently. The heavily myelinated posterior cingulate belongs to the late myelinating structures. The hcGM loss there is consistent with the “last in, first out” hypothesis. The scGM loss in the mesial prefrontal, opercular, superior temporal region affects sparsely myelinated layers I‐III that are known to have a high synaptic density (1) indicating that it is probably mostly driven by dendritic loss. Although preliminary, the data presented here indicate that this new technique might provide a better insight into the nature of GM loss in healthy and abnormal aging.1. Neuroimage 2019;197:716‐741
Alpha‐synuclein co‐pathology in Alzheimer’s disease identified by RT‐QUIC identification
Authors: Pilotto Andrea 
Published: December 2022

AbstractBackgroundalpha‐synuclein co‐pathology may influence Alzheimer’s disease (AD) phenotype but its presence has never been tested in large series of patients. Real‐time quaking‐induced conversion (RT‐QuIC) recently provided evidence of alpha‐synuclein seeding activity in CSF and olfactory mucosa of patients with alpha‐synucleinopathiesMethoda preliminary set of 82 AD patients (mean age 70,3 + 7.3 years) underwent CSF analyses for Tau, P‐tau and A‐beta amyloid and an extensive cognitive, behavioral and motor assessment. RT‐QuiC for alpha‐synuclein was performed on CSF samples.Resultalpha synuclein RT‐QuIC resulted positive in thirty‐nine out of 82 AD patients (47.6%). AD patients with positive alpha‐synuclein were comparable for age and disease severity those negative to RT‐QuIC assay including Tau/P‐Tau and A‐beta CSF markers in cross‐sectional analyses but exhibited higher prevalence of parkinsonism (p=0.02).Conclusionthese preliminary findings indicate that alpha‐synuclein co‐pathology might be detected in more than one third of Alzheimer’s disease patients. These findings might potentially explain the clinical variability of AD including age at onset, progression and response to treatment observed in clinical series. Larger longitudinal studies are warranted to confirm and extend these findings.
Analyzing Medical Claims Data to Identify Health Care Provider Specialties Diagnosing Frontotemporal Dementia
Authors: Chenette Devon , McCaughey Stella , Wolfus Charles , Fisher Daniel 
Published: December 2022

AbstractBackgroundFrontotemporal dementia (FTD) is a rare, early‐onset form of dementia presenting with changes in personality, speech, executive function, and movement. Early diagnosis of FTD is challenging due to lack of definitive clinical tests and biomarkers. FTD patients are misdiagnosed with Alzheimer’s disease, vascular dementia, Parkinson’s disease, or psychiatric disorders. Analysis of medical claims data can help better understand the journey to FTD diagnosis.MethodAn analytical model was developed using deidentified medical claims data from 2008−2021 to determine those patients recently diagnosed with FTD through diagnosis codes. To achieve greater confidence in the FTD diagnosis, patients may not have had coding for non‐FTD forms of dementia subsequent to their most recent FTD diagnosis. All patients were attributed to the health care provider (HCP) on the medical claim in which the patient was diagnosed with FTD.Result26,155 HCPs were identified based on their unique National Provider Identifier (NPI); provider specialty was sourced from the National Plan and Provider Enumeration System (NPPES) registry. Attributed to each HCP was the distinct number of FTD patients diagnosed in the most recent 12 months with International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) codes for Frontotemporal dementia, Other frontotemporal dementia, Pick’s disease, or Corticobasal degeneration. Data were sorted by provider specialty. Combined, Family Medicine and Internal Medicine providers comprised 48% of diagnosing HCPs; followed by Neurologists (10%), Emergency Medicine (3%), Psychiatry (3%), and Geriatric Medicine (3%). To further analyze this data, HCPs were divided into quartiles based on the relative volume of FTD patients diagnosed in the most recent 12‐month time period. The top quartile averaged 12 FTD patients diagnosed annually with Neurologists comprising the greatest percentage (40%) of HCP specialties. The bottom quartile averaged 1 FTD patient diagnosed annually with Primary Care Providers comprising the greatest percentage (49%) of HCP specialties.ConclusionHCPs across several specialties diagnosed FTD patients; including Family Medicine and Internal Medicine, Neurologists, Emergency Medicine, Psychiatry, and Geriatric Medicine. Neurologists comprised the greatest percentage (40%) of top quartile diagnosing HCP specialties.
Construct Validity Indicators from the ARMADA STUDY for the Tablet Computer‐Based NIH Toolbox Cognition Battery
Authors: Giordani Bruno , Goldstein Felicia C , Rigby Taylor , Gregoire Allyson , Reader Jonathan M , Fisher Jordan , Gurecki Sydney , Bhaumik Arijit K , Ho Emily , Ustsinovich Vitali , Gershon Richard C. , Weintraub Sandra 
Published: December 2022

AbstractBackgroundThe Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study was designed to validate and further develop the full tablet‐based NIH Toolbox Assessment of Neurological and Behavioral Function within an older, racially diverse sample. This ARMADA cohort study of the Toolbox Cognition Battery (NIHTB‐CB) reports construct validity, assessed through its two components: convergent (high correlations to related constructs) and discriminant (low correlations with dissimilar constructs) validity.MethodsParticipants (age range 65–99 years, 142 aged 85+) were consensus conference‐diagnosed with normal cognition (N = 367), amnestic mild cognitive impairment (N = 136), and Alzheimer’s disease (N = 68). NIHTB‐CB assesses domains of Fluid Executive, including Set Shifting (Dimensional Card Sort/DCCS), Inhibitory Control and Attention, (Flanker) and Working Memory (List Sort Working Memory/LSWM); Fluid Processing Speed (Pattern Comparison/PCPS), Fluid Episodic Memory (Picture Sequence Memory/PSM) and Crystalized Language (Oral Reading/ORR, Vocabulary/TPVT). Participants were also given the National Alzheimer’s Disease Coordinating Center Unified Data Set (UDS3) cognitive measures: Memory Composite (Benson Figure and Craft Stories Delayed Recall); Executive Composite (Trail Making, Semantic Fluency), Auditory Attention (Digit Span Forward), Figure Copy (Benson), and Language (Multi‐lingual Naming Test). Unadjusted, (uncorrected) standard scores were created based on the full Toolbox and UDS populations.ResultBased on the large sample size, most all correlations between NIHTB‐CD and UDS3 were significant, though patterns were clear. NIHTB‐CB/Fluid Executive tests had highest correlations with the related UDS3 Executive factor composite (r = 0.53‐0.60), approaching threshold for a “good” designation (>0.6), and “low” designation correlations (r<0.3) for Auditory Attention. PSM correlated highest with UDS Episodic Memory (r = 0.55), and lowest with Auditory Attention (r = 0.23). PCPS was highest with the Executive Composite (r = 0.53) and lowest with Language (r = 0.26). Crystalized NIHTB‐CB correlated highest with UDS Language (r = 0.41‐0.50) versus ORR with Memory (r = 0.22) and TPVT with Copy (r = 0.26).ConclusionResults demonstrated that the highest correlations between NIHTB‐CD and UDS3 measures were between related constructs and lowest correlations were between dissimilar constructs. Thus, convergent/discriminant expectations were supported across NIHTB‐CB measures, reinforcing NIHTB‐CB construct validity. Consistent results across diagnoses and other analytic approaches are also presented, supporting these findings.