bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recruitment and Retention in the Puerto Rico Alzheimer’s Disease Initiative
Authors: Feliciano‐Astacio Briseida E. , Rajabli Farid , Prough Michael B. , Hamilton‐Nelson Kara L. , Adams Larry D. , Mena Pedro R. , Tejada Sergio J. , Sanchez Jose Javier , Celis Katrina , Silva‐Vergara Concepcion , Whitehead Patrice , Acosta Heriberto , Feliciano Nereida I , Chinea Angel , McInerney Katalina , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W. , Pericak‐Vance Margaret A. 
Published: December 2023

AbstractBackgroundPuerto Ricans, the second largest US Latino group, are underrepresented in genomic studies of Alzheimer disease (AD). We describe a multi‐source ascertainment approach, networking with community and governmental stakeholders, as part of the Puerto Rico (PR) Alzheimer Disease Initiative (PRADI) whose goal is to increase recruitment and retention of PR individuals in genomic research.The National Alzheimer’s disease Action Plan 2015‐2025 served as a framework for PRADI group that aims to fill two of the goals of the plan: increase research and education.MethodWe developed collaborative relationships with community and governmental organizations that serve the elderly and AD patients from 37/78 (47%) municipalities of PR to identify potential research participants. Trust and transparency were central to our interactions with community groups. We educated patients and caregivers about AD and their possible contribution to science. Bringing academia to the community encouraged participation. Additionally, we established relationships with multiple neurologists across PR caring for AD patients and their families. For recruitment and enrollment PRADI team members visited families in the homes, daycare facilities and clinics. All participants were assigned diagnoses by a clinical adjudication committee comprised of neurologists and neuropsychologists with expertise in AD and related dementias (ADRD)ResultSince 2016 we have enrolled 1, 281 individuals. Among these 752 are unrelated individuals (193 AD, 170 mild cognitive impairment (MCI), 306 cognitively unimpaired (CU) and 83 with other diagnoses (OD). 529 individuals (195 AD, 76 MCI, 178 CU and 80 OD) were part of 155 multiplex AD families. Most families are from Eastern and Northern PR regions, reflecting dense population areas with large cities. Longitudinal follow‐up of the first 167 participants for diagnostic updates is complete. 64 individuals were ascertained in the continental US (cUS). Of the 167 individuals in the longitudinal follow‐up (3‐5 years), 7.2% progressed from either CU to MCI or AD, or MCI to AD.ConclusionThe PRADI group multisource ascertainment approach enabled recruitment and retention of participants both in PR and the cUS. Longitudinal clinical data across the cohort further enriches the impact of genomic studies in a diverse population.
The effect of our physical or cognitive program for the elderly with mild cognitive impairment: the eighteen months’ follow‐up after intervention, third version, showed an improvement in RBMT story retention delayed and Raven’s colored progressive matrices
Authors: Kanemaru Akiko , Kato Takayuki , Kawaji Yoshie , Honda Takuya , Makita Ayaka , Uno Shizuna , Higuchi Wakana , Shimizu Aya , Enomoto Yoji , Kanemaru Kazutomi 
Published: December 2023

AbstractBackgroundTo prevent or slow down a cognitive decline in the elderly is an important issue. Therefore we have conducted an intervention study with our rehabilitation training program of physical or cognitive rec‐xercise (the made‐up word from recreation+exercise) (REPCREC) for the elderly with mild cognitive impairment (MCI).MethodThis study design is a non‐randomized controlled trial. The ninety‐one individuals have been enrolled and eighty‐seven those have undergone our study, where they have been divided into four groups: the cognitive (group A: n = 22), physical (group B: n = 27), both cognitive and physical (group C: n = 30) training and control (group D: n = 8). The three training groups received the each session once per week up to twelve times. Before and after the intervention, and 3, 6, 12 & 18‐months after the intervention, we have evaluated the following items: physical function, GDS and neuropsychological tests [MMSE, RBMT, TMT, Ravenʼs Colored Progressive Matrices (RCPM), Rey‐Osterrieth Complex Figure Test (ROCF), story retention, coding and Miyake’s paired verbal associate learning test (MPVALT)]. A one‐day booster program has been provided at the time of evaluation. For statistical analysis, Fisher’s exact test and Kruscal‐Wallis test for the baseline data, and linear mixed model (LMM) analysis have been performed.ResultAt the baseline, no difference between groups except RCPM (p = 0.017). LMM analysis revealed the significant time‐course differences in RBMT Story Retention Delayed (RBMT‐SRD), RCPM, ROCF recall, coding and MPVALT related words (MPVALT‐RW) (p = 0.003, 0.001, 0.000, 0.000 and 0.001, in order). Furthermore, LMM analysis showed the interaction effects in RBMT‐SRD and RCPM. Therefore, we have conducted the LMM analysis of each group, where groups A and B showed improvements in RBMT‐SRD (p = 0.003 and 0.040, in order) and where group A and C showed improvements in RCPM (p = 0.001 and 0.016, in order).ConclusionThe improvement in RBMT‐SRD and RCPM may have shown that our program REPCREC can have the better effects on non‐verbal intelligence, visuospatial abilities, memory, attention, working memory etc. for the elderly with MCI. However, in ROCF recall, coding and MPVALT‐RW, all the groups have shown the similar time‐course, which might suggest merely an interventional effect of the evaluation using those neuropsychological tests.
Larger hippocampal and temporal lobe volume may associate with early rapid forgetting in cognitively healthy individuals with a predisposition to Alzheimer’s disease
Authors: Rising Shant , Woo Rachel , Nolty Anne , Chui Helena C , Butler Ryan , Kang Jimmy , Spezzaferri Mitchell , Sin Caleb , Buennagel David P , Aguda Shelly , Minazad Yafa , Kim Sung , Kloner Robert A , Fonteh Alfred N. , Arakaki Xianghong 
Published: December 2023

AbstractBackgroundGrowing need exists to link volumetric brain analysis to functional cognitive performance in early prediction of Alzheimer’s disease.MethodIn cognitively healthy older adults (N = 40; M age = 71.7±7.7 years), we established amyloid/tau ratios from cerebrospinal fluid, thus finding a small group with pathological amyloid/tau ratios (PAT, n = 11) and normal ratio (NAT, n = 29). Approximately 40% of the PAT group were expected to convert to mild cognitive impairment within 4 years. It was hypothesized that reduced performance on the California Verbal Learning Test‐II (CVLT‐II) Short Delay Free (SDFR) and Cued Recall (SDCR) task would be associated with smaller hippocampal and temporal lobe volume (obtained via NeuroQuant).ResultHippocampal total, left, and right percentiles were found to be negatively associated with SDFR in the PAT group, r(38) = ‐.67*, ‐.66*, and ‐.63*, but not in the NAT group, r(38) = ‐.21, ‐.04, and ‐.35, such that a larger hippocampus was associated with fewer remembered words after a short delay on a list learning task in those with pathological amyloid/tau ratios. Temporal lobe volume was also found to be negatively associated with SDFR and SDCR in the PAT group, r(38) = ‐.67* and ‐.69*, but not in the NAT group, r(38) = ‐.36 and ‐.34, such that a larger temporal lobe was associated with fewer remembered words after a short delay on a list learning task (even when cued) in those with smaller amyloid/tau ratios. Two hierarchical multiple regression analyses, one including amyloid/tau ratio and the other including amyloid only, found that age and sex associate with ∼20.4% variance of the performance on the CVLT‐II SDFR task while temporal lobe volume increased associative value by 16.1% in the former [F (1, 35) = 8.871, p < .05] and by 15.4% in the latter [F (1, 35) = 8.430, p < .05].ConclusionOur findings suggest there may be early compensation in brain structures among cognitively healthy individuals whose CSF biomarker suggest increased risk for the development of symptomatic Alzheimer’s disease, such that hippocampi and temporal lobes increase in size during early pre‐Alzheimer’s stages despite reduced performance on memory tasks.
Further Preclinical Development of a Bio‐therapeutic Against Porphyromonas gingivalis for the control of Systemic and Neuro‐inflammation related Dementia and Alzheimer’s Disease
Authors: Nara Peter Lloyd 
Published: December 2023

AbstractAddressing novel mechanisms and effective therapeutic treatments for cognitive decline, Dementia and Alzheimer’s Disease is a major public health need. Keystone Bio have identified that specific virulent strains of Porphyromonas gingivalis (Pg) and the release of specific virulence factors/toxins in the oral cavity as the primary driver/causation of systemic/neuro‐vascular inflammation/degenerative diseases i.e., cognitive decline/dementias/Alzheimer’s disease (Nara et. al 2021). A recent landmark finding was reported in a sub‐cohort analysis from a Phase 2/3 GAIN trial (n = 238) demonstrated that lowering the load of Pg in the mouth leads to a significant improvement of cognitive slowing at both 24 and 48 weeks in participants with mild to moderate AD. Another study showed lowering the load of Pg in the mouth had a favorable effect on AD‐related brain atrophy (https://doi.org/10.1002/alz.12378). Pg OMVs and systemic system diseases has many well‐defined examples such as: cardiometabolic diseases‐ Pg OMVs attenuate insulin induced Akt/GSK‐3_ signaling in hepatic HepG2 cells, thereby causing changes in glucose metabolism in the liver and promoting the development of diabetes and increase vascular permeability by cleaving endothelial cell connexins such as PECAM‐1, thereby promoting cardiovascular diseases.Keystone Bio has further developed both a companion diagnostic (CDx) and a clinical, proof‐of‐concept tested, first generation, safe, efficacious, precision, bio‐therapeutic murine monoclonal antibody (KB‐001) for the diagnosis, treatment and monitoring against the oral bacteria and major virulent factor/toxin of Pg. The antibody engagement is with the later stages of the complex virulent factor/toxin secretion containing outer membrane vesicles from the bacteria thereby interfering/stopping all necessary metabolic, host defense, energy‐producing sources, adherence and biofilm formation and integrity (Nara et. al 2021). The talk will review what now seems like a solid case for causation in the role of virulent/toxin secreting strains of in neuro‐inflammation leading to cognitive decline, dementia, Sporadic Alzheimer’s disease and possibly Parkinson’s.
Virulent Porphyromonas gingivalis as the root cause of chronic inflammation‐a Chronic Oral Health Perspective
Authors: Sindelar Dan 
Published: December 2023

AbstractOral health professionals are the forefront of preventing and treating not only dental and periodontal diseases, but also a growing list of systemic conditions associated with specific periodontal pathogens such as P. gingivalis (Pg). The oral‐systemic connection offers dental professionals an opportunity to positively influence patients’ overall health. Armed with the ability to transform its own environment and the entire periodontal microbiome, as well as modify the host response, the influence of Pg extends beyond the oral cavity. Beyond the neuroinflammatory effects discussed in this session it is capable of both releasing complex virulence factors/toxins and translocating and invading distant tissues and organs and is involved in the pathogenesis of systemic diseases including cardiovascular disease, atherosclerosis, hypertension, myocarditis, and myocardial infarction. This periodontal pathogen also impacts autoimmune diseases including rheumatoid arthritis; neurodegenerative diseases such as Alzheimer’s disease and AD‐related brain atrophy; several cancers‐oral, esophageal, and pancreatic; and metabolic diseases such as diabetes mellitus. Pg by limiting the complement cascade and restraining leukocyte death by activating and exploiting the C5a‐receptor signaling pathway. Another viable conduit in systemic dysbiosis and immune dysfunction is the translocation of Pg with its microbiome‐altering abilities and its coaggregation pathobiont actions found in the gut flora. Studies on murine models that introduced Pg into the gut demonstrated an altered intestinal microflora and increased manifestation or aggravation of liver disease, arthritis, including an increase in the production of proinflammatory cytokines observed at both the intestinal and extra‐intestinal levels. Dental professionals will most likely be one of the major healthcare delivery systems to bring a paradigm shift in healthcare and medicine using novel companion diagnostics and treatments to early screening and treatment of virulent Pg infections in the general population thereby greatly reducing the onset of multiple major systemic inflammatory driven chronic diseases. Dental professionals will most likely be one of the major healthcare delivery systems to bring a paradigm shift in healthcare and medicine by using novel companion diagnostics and treatments to early screening and treatment of virulent Pg infections in the general population thereby greatly reducing the onset of multiple major systemic inflammatory driven chronic diseases.
Memory alteration test (M@T) is correlated with CSF biomarkers and neurodegeneration in patients with aMCI and AD in a low‐and‐middle‐ income country
Authors: Custodio Nilton , Malaga Marco , Montesinos Rosa , Chambergo‐Michilot Diego , Baca Fiorella , Carbajal Juan C , Huilca Jose , Herrera‐Perez Eder , Lira David , Diaz Monica M , Lanata Serggio 
Published: December 2023

AbstractBackgroundAs new therapies become available, early detection of Alzheimer’s disease (AD) becomes increasingly important. However, the use of biomarkers or advanced imaging has not been fully implemented in low‐ and ‐middle income countries (LMICs), especially in Latin America. Given that brief cognitive tests (BCTs) are widely available and easy to administer, we evaluated the capacity of the AD‐focused BCT, the Memory Alteration Test (M@T), to detect AD, neurodegeneration markers in MRI, and its correlation with CSF biomarkers.MethodThis is a secondary analysis from a previously published cohort of 63 controls, 53 amnestic MCI (aMCI), and 69 AD patients. They underwent testing with the M@T and a complete neuropsychological battery. Total‐tau (t‐tau), phosphorylated tau (p‐tau) and β‐amyloid in CSF were measured in all included patients. Neurodegeneration was determined by Medial Temporal Atrophy (MTA) score in MRI. We used Receiver‐Operator Curves to determine the discriminative capacity of the total M@T score as well as its subdomains. We used the Pearson coefficient and performed a linear regression between total score and CSF biomarkers.ResultThe M@T score had an AUC of 0.994 to discriminate between controls and cognitively impaired (aMCI or AD) patients, and an AUC of 0.98 to differentiate between aMCI and AD patients. Free‐recall and cued recall had the highest AUCs of all subdomains. Total score was strongly correlated with t‐tau (‐0.77) and p‐tau (‐0.72), and moderately correlated with β‐amyloid (0.66). The AUC for discrimination of neurodegeneration was 0.87.ConclusionThe M@T brief cognitive test had excellent discrimination of MCI and AD patients in an LMIC. It was also strongly correlated with CSF biomarkers and had good discrimination of Neurodegeneration. The recall sub‐domains presented the highest diagnostic capacity. Its use as a screening tool could allow LMICs to enrich samples of patients who may benefit from new available therapies.
Chronic traumatic encephalopathy in former college football playing brain donors
Authors: Hong Cindy , Abdolmohammadi Bobak , Martin Brett M , Palmisano Joseph N , Alvarez Victor E. , Huber Bertrand R. , Tripodis Yorghos , Stein Thor D. , Alosco Michael L , McKee Ann C. , Mez Jesse B. 
Published: December 2023

AbstractBackgroundChronic traumatic encephalopathy (CTE) is neurodegenerative disease associated with a history of repetitive head impacts (RHI). The majority of CTE cases have been reported in former contact sport athletes, including American football players. In 2017, a case series from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank reported that 48 of the first 53 donors with college football as their highest level of play had CTE. Here we present updated numbers of former college football players with CTE in the UNITE Brain Bank and compare them to former college football players without CTE. We hypothesized that increasing CTE stage would be associated with dementia and increasing scores on clinical scales of informant reported symptoms.MethodBrain donors from the UNITE Brain Bank with college football as their highest level of play were included. CTE neuropathological diagnosis and staging (0‐IV; 0 = no CTE, IV = most severe) were assessed using validated criteria. Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS), activities of daily living (Functional Activities Questionnaire, FAQ), and neurobehavioral dysregulation (BRIEF‐A Behavioral Regulation Index, BRI). Consensus dementia diagnoses were made by expert clinicians. Multivariable regression models examined associations between CTE stage, dementia, and each clinical scale, controlling for age at death, racial identity, education, and duration of football play in years.ResultAmong 319 donors with college football as their highest level of play (median age at death = 64.0; IQR = 47‐77), 222 (69.5%) had CTE. Among those with CTE, 44 (19.8%) were stage I, 47 (21.2%) were stage II, 79 (35.6%) were stage III and 52 (23.4%) were stage IV. Among those with CTE, 122 (55.0%) were demented and 123 (61.5%) and 131 (70.8%) had clinically meaningful elevations on the FAQ and BRI respectively. CTE stage was significantly associated with having dementia (OR = 1.37; 95%CI:1.08‐1.72) and with more symptoms on the CDS (beta = 5.04; 95%CI:1.41‐8.66) and FAQ (beta = 1.12; 95%CI:0.38‐1.86), but not the BRI. Effect estimates were larger after removing donors with non‐CTE neurodegenerative pathology.ConclusionAmong former college football playing brain donors, CTE pathology was very common. CTE stage was significant associated with dementia history and symptoms on clinical scales.
Epigenetic Modulation Through KAT5/HDAC2 Regulates Synaptic Genes in a Disease‐State Specific Manner
Authors: Wiley Jesse C , Yeboah Fred , Cary Gregory A. , Frankowski Harald , Heath Laura M , Levey Allan I. , Greenwood Anna K , Carter Gregory W , Young Jessica E. 
Published: December 2023

AbstractBackgroundThe balance between histone acetylation and deacetylation by lysine acetyltransferases (KATs) and histone deacetylases (HDAC) plays a central role in neurodegeneration. In this work, we leverage the informatics infrastructure developed for TREAT‐AD, to align epigenetic regulation from two different models: the KAT5 knockout mouse and HDAC2 knockdown iPSC‐derived neurons of control and FAD genetic lineages.MethodThe KAT5 knockout mouse differential expression data derived from the CA1 of the hippocampus was compared to three groups: 1) human late onset Alzheimer’s disease (LOAD), 2) the 5X FAD mice and 3) human FAD patient transcriptomic data. In each comparison, the data was assessed in the context of the biological domains (19 core AD endophenotypes computationally defined for the TREAT‐AD bioinformatics pipeline). The KAT5 data are compared to the differential expression data derived from WT and FAD lines of iPSC‐derived neurons with or without HDAC2 knockdown (KD) post‐differentiation.ResultThe biological domain focused analysis found a consistent modulation of synaptic and immune genes across models. Interestingly, there is a statistically significant correlation between down‐regulated synaptic genes in the KAT5 knockout mouse data and human LOAD differential expression observed in the 1700 brains of transcriptomic data and 1100 brains of proteomic data analyzed for TREAT‐AD and concomitantly identified in early stage pseudotemporal models of AD. Not surprisingly, there is better correlation between the KAT5 KO mouse and the 5X FAD mice, with the human FAD data falling in between these comparisons. The examination of the FAD and WT iPSC‐derived neurons with and without HDAC2 KD, demonstrates that HDAC2 KD ameliorates the down‐regulation of synaptic genes in the FAD neurons, but appears to have the opposite effect in WT human neurons.ConclusionThe comparison of the two systems of epigenetic regulation suggest that KAT5 and HDAC2 exert opposite effects upon synaptic gene expression. However, the observation that decreasing HDAC2 levels increases synaptic gene expression in FAD neurons but decreases synaptic gene expression in normal healthy neurons suggest that there is an optimal chromatin state associated with maximal synaptic gene expression, and that too much or too little histone acetylation may impair synaptic homeostasis.
[18F]‐D3FSP amyloid‐β PET imaging in elderly adults and Alzheimer’s disease
Authors: Li Anqi , Zhao Ruiyue , Zhang Mingkai , Sun Pan , Cai Yue , Liu Lin , Lan Guoyu , Zhu Yalin , Chen Xuhui , Guo Lizhi , Zhou Yajing , Sun Kun , Zhu Lin , Kung Hank F. , Wang Qingyong , Xu Linsen , Han Ying , Wang Xinlu , Guo Tengfei 
Published: December 2023

AbstractBackgroundN‐methylderivative of Amyvid (18F‐D3FSP) displayed very similar β‐amyloid (Aβ) targeting properties to the 18F‐florbetapir tracer, but it is not well established about the performance of 18F‐D3FSP Aβ positron emission tomography (PET) imaging in Alzheimer’s disease (AD).MethodIn this study, we recruited 142 Greater‐Bay‐Area Healthy Aging Brain Study (GHABS) participants from the community and completed Simoa plasma biomarkers, MRI imaging, 18F‐D3FSP Aβ PET imaging, and cognitive assessments. MRI images were segmented using FreeSurfer (v7.2.0) according to the Desikan–Killiany atlas. 18F‐D3FSP Aβ PET images were coregistered with their corresponding MRI scans, and intensity‐normalized to the mean uptakes in the whole cerebellum, cerebellar gray matter (cerebellar GM), brain stem (PONs), white matter, and big reference separately (Figure 1A). A cortical summary COMPOSITE 18F‐D3FSP standardized uptake value ratio (SUVR) in AD typical cortical regions was calculated. We used Gaussian Mixture Model to estimate 2 gaussian distributions of low and high Aβ for COMPOSITE SUVRs, and the threshold was defined as an SUVR corresponding to a 90% probability of belonging to the low‐Aβ distribution. COMPOSITE SUVRs were compared between Aβ‐ and Aβ+ groups. Finally, we investigated the association of COMPOSITE SUVR with plasma biomarkers, including age and sex as covariates.Result18F‐D3FSP Aβ PET imaging was capable of detecting fibrillary Aβ plaques in AD, and the Aβ+ group showed substantial Aβ deposition compared to the Aβ‐ group (Fig.1B). The dementia patients had more Aβ burden than the CU, SCD, and MCI individuals (Fig.1C), and the preclinical AD individuals (Aβ+/CU) showed significantly higher Aβ SUVRs than the Aβ‐/CI and Aβ‐/CU groups (Fig.1D). The comparisons of COMPOSITE SUVR between Aβ‐ and Aβ+ had a very high effect size, particularly in the brain stem reference region (Fig.2). Higher COMPOSITE SUVRs were related to lower plasma Aβ42/40 and higher plasma p‐Tau, GFAP, NfL concentrations, especially based on the composite big reference region (Fig.3).Conclusion[18F]D3FSP is an effective Aβ tracer to detect Aβ deposition in AD. Using the big reference may be optimal for calculating SUVR by considering the Aβ positive effect size and its correlation with Aβ, tau, neurodegeneration, and neuroinflammation measured in plasma.