bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating Potential Racial Differences in Dementia‐Related Plasma Biomarkers
Authors: Pettway Erika C , Labonte Jacob , II Robert W Turner , Bragg Tahlia , Turner Arlener , Banks Sarah J , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J. , Karikari Thomas K , Tripodis Yorghos , Martin Brett M , Palmisano Joseph N , Stern Robert A , Killiany Ronald J , Aparicio Hugo J , Goldstein Lee E , Qiu Wendy , Budson Andrew E , Mez Jesse B. , Alosco Michael L 
Published: December 2023

AbstractBackgroundBlack self‐identified individuals are disproportionately affected by dementia, a phenomenon best attributable to differences in social determinants of health (SDOH). Plasma protein levels can serve as antemortem indicators of dementia pathology; recent findings indicate potential race‐specific differences in these biomarkers of tau and non‐tau pathologies between Black self‐identified or White individuals.MethodsThis sample included 568 participants (77, 13.56% Black self‐identified, Table 1) from the Boston University Alzheimer’s Disease and Research Center (BUADRC). Participants completed a battery of neuropsychological tests and cognitive diagnoses were made during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using ELISA methods for YKL‐40 levels and using Simoa platform for phosphorylated tau (p‐tau 181, p‐tau231), total‐tau, glial fibrillary acidic (GFAP), and neurofilament light chain (NfL) levels. ANCOVAs tested for a cross‐sectional association between racial identity and each plasma biomarker and stratified by cognitive impairment status with covariates for age, education (in years), sex assigned at birth, and APOE ε4 carrier status. Cox proportional‐hazards models were used for longitudinal analyses of the interaction effect between racial identity and plasma biomarkers in the risk for conversion from normal cognition (NC) to mild cognitive impairment (MCI) and reversion from MCI to NC.ResultsBaseline YKL‐40 was lower among Black self‐identified participants (adjusted mean diff = 0.37 SD, p<.001); this association was particularly salient within the MCI group (adjusted mean diff = 0.62 SD, p<.001). The longitudinal analysis revealed interaction effects between race and GFAP for risk for conversion from NC to MCI and reversion from MCI to NC. Among White participants, higher GFAP predicted increased risk for conversion from NC to MCI and lower levels predicted reversion. However, no significant effects were found among Black self‐identified participants; these findings might be limited by sample size (n = 18) resulting from the high occurrence of baseline MCI diagnoses and subsequent lack of conversion or reversion among Black self‐identified participants.ConclusionIn the context of an unrepresentative sample, we found trivial differences in plasma biomarkers between Black self‐identified and White participants. Recruitment of Black self‐identified participants representative of the population and further exploration of SDOH is essential in understanding the disproportionate risk for dementia carried by Black self‐identified individuals.
Differential diagnosis of Lewy body dementias using multivariate EEG classifiers
Authors: Yoder Keith J , Brookshire Geoffrey , Gerrol Spencer , Quirk Colin , Lucero Ché 
Published: December 2023

AbstractBackgroundLewy body dementia (LBD) results from pathology in ɑ‐synuclein and is the second most common cause of dementia. LBD has two manifestations: Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). There is currently no non‐invasive, fast, reliable way to distinguish between early‐stage PDD, DLB, and Alzheimer’s disease (AD). Although previous traditional EEG visual rating methods have not been useful in delineating dementia subtypes, resting‐state electroencephalography (rsEEG) is a promising method for differential diagnosis of dementia, because it is inexpensive, non‐invasive, and widely available for clinical use. Here, we demonstrate how a multivariate classifier using rsEEG as input can differentiate PDD, DLB, and Alzheimer’s disease.MethodWe analyzed rsEEG data from older adults (N = 133, age 59‐89) with AD (n = 33), DLB (n = 27) or PDD (n = 45). We computed the aperiodic and periodic parameterization of brain activity, along with metrics of variation in fractal dimension within specific frequency bands. We then used these features, along with age and sex, to develop XGBoost machine‐learning models to predict patient diagnoses. Models were evaluated using cross‐validation with balanced accuracy, weighted sensitivity, and weighted specificity.ResultThe first task was a two‐way classification: Control vs Dementia (accuracy = 86%, sensitivity = 93%, specificity = 79%, p < .001). The second task was a three‐way classification: AD vs DLB vs PDD (accuracy = 66%, sensitivity = 70%, specificity = 82%, p < .001). We also evaluated two‐way models distinguishing between AD vs DLB (accuracy = 86%, sensitivity = 87%, specificity = 86%, p < .001), AD vs PDD (accuracy = 84%, sensitivity = 85%, specificity = 83%, p < .001), AD vs LBD (combined DLB and PDD; accuracy = 82%, sensitivity = 85%, specificity = 78%, p < .01), and DLB vs PDD (accuracy = 68%, sensitivity = 71%, specificity = 65%, p < .05).ConclusionMachine‐learning and rsEEG are capable of distinguishing between AD and LBD. Moreover, machine‐learning combined with spectral and fractal features can distinguish between DLB and PDD, despite both forms of dementia arising from ɑ‐synuclein pathology.
Diagnostic Challenges in Progressive Supranuclear Palsy: Early Identification and Mimics
Authors: Taiwo Tolulola O 
Published: December 2023

AbstractBackgroundProgressive supranuclear palsy (PSP) is an often‐undiagnosed neurodegenerative disorder. There are often delays in diagnosing PSP.MethodRetrospective chart review of all newly diagnosed PSP patients referred to an outpatient clinic. We conducted a review of all initial/new PSP cases in our geriatric clinic. The most common preliminary diagnosis the patients had been given included was idiopathic Parkinson’s disease. Other common diagnoses were vascular Parkinson’s, frontal lobe dementia, psychotic depression and late life psychosis.Clinical records with the subjective accounts, cognitive assessments and brain imaging reports of 23 PSP patients were reviewed.ResultsThe most common cognitive deficits were visuospatial changes (100%), semantic fluency deficits (80.4%), dysexecutive function. Sleep disruption with insomnia with intermittent awakening was also commonly reported.A propensity for falls and multiple falls were also reported. The interval from the onset of symptoms and initial presentation to a clinical provider to diagnosis ranged from 1 ‐ 7 years.ConclusionA high index of suspicion and recognition that PSP might not be as uncommon as previously thought is needed. A timely diagnosis and recognition of the various cognitive and behavioral changes is important.
Association Between Age and Cognitive Severity in Participants from the Longitudinal Early‐Onset Alzheimer’s Disease Study
Authors: Hammers Dustin B. , Eloyan Ani , Thangarajah Maryanne , Taurone Alexander , Kirby Kala , Polsinelli Angelina J , Carrillo Maria C. , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G. 
Published: December 2023

AbstractBackgroundAge‐related cognitive declines are well‐documented in cognitively normal adults (van der Willik et al., 2021), as are greater cognitive impairments with advancing age in traditional‐ (or “late‐”) onset Alzheimer’s disease (LOAD; Davis et al., 2018). Early‐onset Alzheimer’s disease (EOAD; diagnosis ≤65 years old) possesses a unique disease course and underlying pathology relative to LOAD (Mendez, 2012), consequently it is unknown if the association between age and cognitive severity is similar. The objective of the current study is to examine the relationship between cognition and age‐at‐baseline in participants enrolled in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS; Apostolova et al., 2019).MethodCross‐sectional cognitive data from 371 participants (aged 40‐64) enrolled in the LEADS protocol were analyzed, using composites for the domains of Episodic Memory, Speed/Attention, Visuospatial skills, Language, and Executive skills. Relationships between age‐at‐baseline and cognition were examined using linear regression based on diagnostic group classification (cognitively normal [CN], amyloid‐positive EOAD, and amyloid‐negative Early‐Onset non‐Alzheimer’s disease [EOnonAD]), controlling for the effects of age and education years.ResultDemographic characteristics for each group are shown in Table 1. Across cognitive domains, the CN group displayed either non‐significant or negative relationships (Executive skills; r = ‐0.30, p = .006) between age‐at‐baseline and cognitive performance (Figure 1 and Table 2). Conversely, the EOAD group showed consistent positive relationships for domains of Speed/Attention (r = 0.23, p<.001), Visuospatial Skills (r = 0.19, p = .01), and Episodic Memory (r = 0.16, p = .02). A similar non‐significant trend was observed for the EOnonAD group for Speed/Attention (r = 0.17, p = .19). When considering those with amnestic‐variant early‐onset dementia across diagnostic groups, positive relationships between age‐at‐baseline and cognition were observed for Speed/Attention (r = 0.19, p = .006) and Visuospatial skills (non‐significant trend; r = 0.14, p = .05), but not for Episodic Memory (r = ‐0.06, p = .35).ConclusionWorse cognitive severity was associated with younger age‐at‐baseline for EOAD participants in LEADS. Similar trends were observed for EOnonAD participants, though to a lesser magnitude. These results were counter to those observed for CN participants, and to what is known about cognitive trajectories in normal aging or LOAD. These findings further support previous suggestions that EOAD appears to be a distinct entity relative to LOAD.
Sex‐ and APOE‐Specific Transcriptomic Signatures in Alzheimer’s Disease: An AZ‐ADRC‐Research Education Scholars Team Science Project
Authors: Vitali Francesca , Raikes Adam C. , Hernandez Gerson D , Yin Fei 
Published: December 2023

AbstractBackgroundAge, female sex and APOEε4 allele are among the top risk factors for developing late‐onset Alzheimer’s disease (LOAD). To enable Precision medicine for AD drug development, it is crucial targeting specific biological pathways driving AD pathology. While individual effects of sex or APOE have been studied, genes and biological pathways commonly or uniquely altered by these two factors are less understood.MethodROSMAP RNA‐Seq data were obtained from AMP‐AD including 369 frontal cortex samples from APOEε3/ε3 and APOEε3/ε4 individuals. Of these, 209 had an AD diagnosis and 160 were controls. Differentially expressed genes (DEGs, pvalue<.05) between LOAD and cognitively normal individuals were identified using a generalized linear regression model. Gene Set Enrichment Analysis (GSEA) was performed using Gene Ontology Biological Processes (GOBP). Redundant GOBP enriched terms were removed computing semantic similarity measures (adjusted pvalue<.05). Comparison analyses were conducted to identify common and unique DEGs and enriched GOBPs across sex‐genotype conditions.ResultAPOEε3/ε3 female brains exhibited the greatest DEG number (n = 11,851) while APOEε3/ε3 males exhibited the least (n = 714). Nine DEGs were shared across all comparisons, which were involved in metabolic processes, synaptic function, myelination, and GPCR signaling. GSEA revealed comparable numbers of LOAD‐enriched pathways in all female groups and male APOEε3/ε4s (n = 144‐155 GOBP terms), whereas APOEε3/ε3 males exhibited the fewest enriched terms (n = 13). Identified GOBP terms included pathways related to metabolism, cellular responses and regulation, and immune response regulation. However, there were no common GOBP terms across all sex‐genotype conditions.ConclusionOur analyses provide evidence of sex‐ and APOE‐ specific transcriptomic signatures and biological processes altered in LOAD brains. The findings suggest significantly greater transcriptomic dysregulation in female APOEε3/ε3 brains despite the similar extent of affected biological pathways as other sex‐APOE conditions. In contrast, a significantly smaller number of affected biological processes were identified in male APOEε3/ε3s despite having comparable transcriptomic dysregulation as the male APOε4 carriers but less than the female groups. These analyses provide rationale to develop risk factor‐specific therapeutics for the prevention and treatment of LOAD by considering the interaction between biological sex and APOE genotype.
Dysphagia in people with dementia
Authors: Opritoiu Bianca , Ungureanu Larisa , Ciopleias Bogdan , Diaconu Stefania , Irincu Laura , Despa Irina , Falup‐Pecurariu Oana , Kakucs Cristian , Cusnir Malina , Falup‐Pecurariu Cristian 
Published: December 2023

AbstractBackgroundDysphagia is a common complication in multiple neurodegenerative disorders, influencing quality of life and long term prognosis. In dementia, data regarding prevalence of dysphagia and secondary complications such as aspiration pneumonia is not well understood.Aim of the study: to assess the prevalence of dysphagia and aspiration pneumonia in patients with dementia.MethodCross‐sectional study that included patients previously diagnosed with dementia, evaluated in the outpatient clinic or admitted in the Department of Neurology, County Clinic Hospital Brasov. We evaluated the patients using a standardized protocol that included the MMSE, MoCA scale, Gugging Swallowing Screen, fiberoptic evaluation of swallowing and FEDSS scale.Resultthere were 42 patients with dementia included in the study (57,14% females) with a mean age of 69.7 ±9,1 years. The mean MMSE score was 16.8 ± 4.4. Dysphagia was present in 9 patients (21.42%). Pneumonia was encountered in 33.3% of the dysphagic patients, and it was associated with high mortality. The major secondary risk factors for pneumonia were older age, obesity, smoking and diabetes. Patients with a lower score on the MMSE/MoCA scale had a higher risk of developing dysphagia and aspiration pneumonia. Mortality in the dysphagic group was higher when compared with the non‐dysphagic group (44.2% vs. 21.2%).ConclusionDysphagia has an important impact on the clinical outcome of the patients with dementia, increasing the risk of institutionalization and mortality and being associated with dependency and poor quality of life.
Esya AD360: A multi‐parametric platform for establishing a novel lysosome‐based biomarker for Alzheimer’s Disease
Authors: Connolly Owen , Deivasigamani Senthilkumar , Wahdan Malak , Venkat Dhivya , Krishnan Yamuna , Modi Souvik 
Published: December 2023

AbstractBackgroundBiomarker development in Alzheimer’s Disease (AD) relied on techniques such as neuroimaging, and proteomics to investigate tauopathy and amyloidosis (Musiek & Holtzman, 2015). However, multiple studies show that lysosomal dysfunction is associated with Alzheimer’s disease (AD) by regulating both the formation and degradation of Aβ (van Weering & Scheper, 2019). To leverage this paradigm shift in our understanding of AD pathology, we describe a method using lysosomal two ion‐mapping (2‐IM) technology in addition to RNA panel for early detection of AD.MethodEsya’s diagnostic (Esya AD360) is a multiparameter platform incorporating 1) 2‐IM probes that ratiometrically measure concentrations of ions such as H+ and Ca2+ with single lysosome resolution 2) ApoE genotyping and, 3) a panel comprising 12 RNA targets identified through RNA‐Seq. The diagnostic utility of Esya AD360 was assessed through application to fibroblasts from a clinically diagnosed cohort comprising healthy individuals and patients diagnosed with AD, frontotemporal dementia (FTD), Parkinson’s, and Huntington’s disease. A model probability score of predicting AD was calculated using a logistic binary regression.ResultThe diagnostic power of Esya AD360 is improved by addition of a custom RNA panel and ApoE genotyping to our pre‐existing 2‐IM model. Logistic regression demonstrates that the assay is >96% accurate in differentiating AD from HI (specificity of >99% and sensitivity of 92.3%). This was further validated using a small validation sample set comprising 12 autopsy confirmed AD samples. Esya AD360 successfully identifies all 12 samples as AD patients, independently validating assay accuracy. After combining the validation data, we find the specificity of Esya AD360 to be >99%, and 96% sensitive. We also demonstrate that Esya AD360 can successfully differentiate between AD and non‐AD dementias (FTD, Huntington’s and Parkinson’s), with an AUC of 0.99 between HI and AD, and an AUC of 0.99 between AD and non‐AD dementias.ConclusionThe incorporation of three independent features has resulted in an accurate, specific, and sensitive assay at identifying AD and differentiating it from healthy and non‐AD dementias. This technology can be further optimised and applied to other neurological disorders and will allow Esya to develop a more accurate platform for personalized medicine in neurology.
Understanding the protective effect of the PLCG2 P522R variant in human microglia
Authors: Frik Jesica , Robert Aiko , Koppes Sascha , Erlebach Lena , Kronenberg‐Versteeg Deborah , Giera Martin , Kant Rik 
Published: December 2023

AbstractBackgroundAlthough recent advances in the field suggest significant involvement of the shared pathway between the proteins ApoE and TREM2 in the pathogenesis of late onset Alzheimer’s disease (LOAD), the direction that disease‐modifying interventions targeting this pathway should take are still under debate.Interestingly, a variant of the Phospholipase C Gamma 2 (PLCG2), a downstream effector of the TREM2 receptor, has been associated with a reduced risk of developing dementia. This variant results in a single amino acid change, which was reported to increment enzyme activity. However, mutations in this same enzyme (S707Y, L848P), which also result in hyperactivity, were found to lead to auto‐inflammatory immune diseases or increased AD risk (M28L), suggesting that there may be specific modulatory effects of the P522R variant. Alternatively, the existence of diverging downstream signaling pathways may explain its protective potential.MethodWe have generated a complete set of human isogenic iPSCs derived from the Bioni037A parental line using Crispr/Cas9 edition to introduce the mutations for the different PLCG2 variants. We obtained homozygous and heterozygous clones with the protective P522R mutation, the immune disease related S707Y or L848P. We also acquired ApoE4 isogenic iPSCs. Microglia differentiation was induced from these iPSCs using a protocol involving embryoid bodies. Our approach includes lipidomics and proteomics analyses, with focus on microglial lipid metabolism.ResultsHere, we show the generation of new human isogenic iPSC lines to study PLCG2 mutations. Preliminary results from the characterization of human iPSC‐derived ApoE4 microglia employing this multi‐omics approach shows a reduced expression of TREM2 pathway components including the tyrosine kinases SYK and BTK. Since BTK and SYK are both PLCG2 kinases that result in enzyme activation, we are expanding this analysis to PLCG2 mutants and base our working hypothesis on the possibility that PLCG2 hyperactive variants show a reverse phenotype compared to ApoE4 microglia.ConclusionWe present new tools and a rationale to explore the protective effect of the PLCG2 P522R variant against LOAD in human microglia.
To Assess Mediation Effects of BIN1 Risk Variant rs6733839 and APOE4 on Alzheimer’s disease Pathology
Authors: Hooli Basavaraj , Rathore Saima , Wang Jian , Morris Amanda , Lu Ming , Sabourin Jeremy , Shcherbinin Sergey 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) patients carrying T‐allele in the single nucleotide polymorphism rs744373 show higher levels of misfolded tau protein levels, as well as faster accumulation of neurofibrillary tangles (Franzmeier‐2019; Franzmeier‐2022), in addition to established risk gene apolipoprotein E (APOE4). Here we conduct pathway analysis to understand the direct and indirect effects, mediated through amyloid levels, of the rs6733839 T‐allele and APOE e4‐allele on tau.MethodAmyloid‐positive (florbetapir PET) placebo‐arm patients with a clinical diagnosis of AD dementia from four clinical trials (NCT01900665, NCT02791191, NCT02245737, NCT02016560, Table.1) underwent baseline (N = 547) and follow‐up (N = 230) flortaucipir PET scans. Tau burden was assessed using standardized uptake value ratio (SUVr) in AD‐specific region (MUBADA; Devous‐2018) with respect to cerebellum‐crus. We tested direct and indirect effects of BIN1 (rs6733839) and APOE4 on baseline SUVr and change‐from baseline (CFB) in tau‐PET mediated by baseline florbetapir signal. Unstandardized indirect effects were computed for each of 1,000 bootstrapped samples, and the 95% confidence interval was computed by determining the indirect effects at the 2.5th and 97.5th percentiles.ResultBIN1 and age showed significant association with the baseline tau‐PET level (BIN1: ßeta = 0.05, P = 0.05; Age: ßeta = ‐0.03, P<0.001), whereas APOE4 association with the baseline tau‐PET levels was not statistically significant (ßeta = 0.006, P = 0.81). The bootstrapped unstandardized indirect effect of BIN1, age, and APOE4 mediated via baseline amyloid levels was insignificant (BIN1: ßeta = 0.0002, P = 0.92; Age: ßeta = 3.82e−05, P = 0.74; APOE4: ßeta = ‐0.0003, P = 0.86). When evaluated on longitudinal tau measures, the direct effect of APOE4 on CFB in tau‐PET SUVr was significant (ßeta = 0.02; P = 0.01). The direct and indirect effects (mediated via baseline amyloid levels) of BIN1 (Direct: ßeta = ‐0.007, P = 0.215; Indirect: ßeta = ‐0.0007, P = 0.58) and Age (Direct: ßeta = ‐0.0009, P = 0.26; Indirect: ßeta = 0.0001, P = 0.32) were insignificant.ConclusionBIN1 showed significant association with the baseline tau‐PET level whereas APOE‐e4 allele directly affected longitudinal tau buildup independent of amyloid levels. These observations require additional validation using larger datasets and further optimization of the applied methodology is warranted.