bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of comprehensive, individualized, person‐centered care on the relative risks of hospitalization and emergency department visits in community‐dwelling persons with advanced Alzheimer’s Disease in a 52‐week randomized controlled trial
Authors: Kenowsky Sunnie , Shao Yongzhao , Heller Sloane , Dafflisio Gianna , Vedvyas Alok , Marsh Karyn , Romero Arelis , Talbeh Mahmoud , Sadowski Martin J. , Masurkar Arjun V. , Reisberg Barry 
Published: December 2023

AbstractBackgroundRates of hospitalization are 3 times higher for community‐dwelling Alzheimer’s disease (AD) persons than non‐affected, age‐matched persons (Rudolph et al., J Am Geriatr Soc. 2010). These investigators reported that hospital outcomes were significantly worse for AD patients regarding delirium, prolonged length of stay, institutionalization and death. They concluded, “Given the frequency of hospitalization in …[AD]… patients, an intervention to prevent or shorten hospitalization would potentially save Medicare billions of dollars per year.” We conducted 28‐week, controlled, clinician‐blind, parallel group and 24‐week extension studies in which advanced AD persons were randomized to receive a comprehensive, individualized, person‐centered management program (CI‐PCM) developed by Sunnie Kenowsky and memantine or usual community care (UCC) and memantine (Reisberg…Kenowsky, Dement Geriatr Cogn Disord., 2017). Herein, we investigate the occurrence of hospitalization and emergency department visits (EDV) in the two groups at 52‐weeks.MethodsEach occurrence of death, hospitalization and EDV was documented. Investigators blind to group assignment analyzed occurrences. Any fraction of a hospital stay or EDV occurring on or between the baseline and week 52 visit days was recorded as one incident. Relative Risk Reduction (RRR) was calculated for the incidence of hospitalization and EDV.Results40% of UCC subjects experienced EDV, 40% were hospitalized and 10% died. Comparatively, only 10% of CI‐PCM subjects experienced EDV and 10% were hospitalized. UCC subjects were hospitalized for C. difficile infection, a fall and subsequent pelvic fracture, syncope and gastrointestinal disease. One CI‐PCM subject was hospitalized for a fall and hip fracture secondary to osteoporosis. UCC subject falls were attributed to neuropsychiatric symptoms of dementia. A CI‐PCM subject had C. difficile successfully treated by their physician. The RRR for utilization of the CI‐PCM program was 0.75 for EDV and 0.75 for hospitalizations (Tables 1&2).ConclusionsCI‐PCM subjects had a 75% decreased risk of EDV and a 75% decreased risk of hospitalization. Given the 5.8 million USA AD persons and the current high cost of hospitalization, the CI‐PCM program could potentially, significantly decrease the costs of care for AD persons, Medicare, and Medicaid while greatly increasing the AD person’s quality of life and alleviating their caregiver’s burden.
Patient and caregiver views on participating in clinical trials for behavior problems with Alzheimer’s disease
Authors: Velayudhan Latha , Dugonjic Marta , Pisani Sara , Seath Paige , Aarsland Dag , Sagnik Bhattacharyya 
Published: December 2023

AbstractBackgroundAlong with memory problems and functional impairment, people with Alzheimer’s dementia often suffer from behavioural and psychological symptoms of dementia (BPSD), such as hallucinations, delusions, anxiety and agitation. Current used medications have modest benefits and significant side effects. Promising evidence suggests that cannabidiol (CBD) a non‐psychoactive and non‐addictive substance present in the cannabis plant extract may be useful in treating these symptoms. We conducted a randomised, double‐blind, placebo‐controlled trial of CBD for AD patients with BPSD. However, it is also important to seek to explore the views of potential participants through qualitative research methods about their acceptance of such interventions and participating in such trials especially during the COVID‐19 pandemic period.MethodsAD patients with BPSD were recruited within a single site, South London and Maudsley NHS trust, UK. We carried out semi structured quality interview for participants and their carers who were randomised and received treatment within the feasibility trial. The purpose of the qualitative interviews was to explore participants’ experiences of taking part in the trial including what encouraged them to take part, their views on the intervention and how they are finding the trial in general.ResultsBoth AD participants (n = 15) and their carers (14) were interviewed. Only five AD participants could reasonably participate due to their symptoms. All the carers completed the interview. The key motivator for participating in the trial identified was to derive health benefits from the intervention (100% carers), and 43% also had altruistic motivation to help other people and research. Of the 5 AD patients, 4 had altruistic motivation and one said for health benefits. There were no concerns taking CBD orally in little capsule form. All the participants expressed positive experience with adequate information, thorough and flexible assessments (face to face and virtual), being visited at home or taxis arranged for hospital visits.ConclusionsThe findings demonstrate good acceptability and compliance for CBD among elderly with AD and BPSD. Health benefit was the key motivator for enrolling in the clinical trial facilitated by appropriate arrangements for participation. Learnings from this study would help plan further trials for this cohort.
Exploring the relationship between genetic patterns and brain properties using the Allen Human Brain Atlas
Authors: Hobbs Diana A. , McCullough Austin A. , Millar Peter R , Flores Shaney , Keefe Sarah J. , Benzinger Tammie L.S. , Gordon Brian A. 
Published: December 2023

AbstractBackgroundImaging transcriptomics is a rapidly developing field that combines neuroimaging with genomics to study mechanisms that influence the organization and activity of the nervous system. Using whole‐brain microarray mRNA expression data from the Allen Human Brain Atlas (AHBA), we examined spatial gradients of gene expression in the brain. We then related these gradients to known spatial patterns of brain function.MethodWe mapped regional mRNA expression data from more than 21,000 genes to the 200‐parcel Schaeffer atlas. Principle components analysis (PCA) was used to reduce the dimensionality of the data to ten principle components (PCs). This was done for all genes for the whole brain (WBExp) as well as those specific to Alzheimer Disease (ADExp). We additionally mapped eight other properties: functional connectivity gradients (Fig. 2A), myelin, cortical thickness, cerebral blood volume, cerebral blood flow, glucose consumption, and evolutionary expansion (Fig. 2B) to this atlas to explore their relationships with genetic patterns. Region weights from the PCs were predicted from these eight maps.ResultThe majority of variance for both WBExp (Fig. 1A & 1C) and ADExp (Fig. 1B & 1D) expression was explained by three PCs. Functional connectivity gradients one (β = ‐0.38, β = 0.14), two (β = 0.33, β = ‐0.45), and five (β = ‐0.44, β = 0.32) were moderately related to the first PC of WBExp (Fig. 3A) and ADExp (Fig. 3C) expression patterns (p < 0.05), respectively. Cortical thickness (β = ‐0.32, β = 0.19), cerebral brain volume (β = 0.10, β = ‐0.13), cerebral blood flow (β = 0.42, β = ‐0.52), and evolutionary expansion (β = 0.08, β = ‐0.20) were additionally moderately related to the the WBExp PC1 (Fig. 3B, p < 0.05) and the ADExp PC1 (Fig. 3D, p < 0.05), respectively.ConclusionOur results highlighted that gradients in genetic expressions are related to functional gradients seen using rs‐fMRI as well as biological properties such as cortical thickness, cerebral blood volume, cerebral blood flow, and evolutionary expansion. These findings shed light on mechanisms that influence the structure and function of the brain. Understanding the relationship between genetic patterns and these properties can give insight into healthy and diseased‐brain states such as Alzheimer disease.
Exploring Brain Functional Connectivity in Cognitively Healthy Individuals with Pathological CSF Amyloid/Tau
Authors: Al‐Ezzi Abdulhakim Abdullah A , Molloy Cathleen , Arakaki Xianghong , Fonteh Alfred N. , Buennagel David P , Aguda Shelly , Rising Shant , Spezzaferri Mitchell , Sin Caleb , Nolty Anne 
Published: December 2023

AbstractBackgroundDisrupted brain connectivity precedes cognitive impairment in Alzheimer’s disease (AD), affects self‐regulation and executive functions, and can be revealed by quantitative electroencephalography (qEEG). Neuroimaging research on AD progression has demonstrated structural and functional abnormalities in specific brain regions and connections. However, little is known about the changes in directional functional connectivity in pre‐symptomatic AD. We aim to explore the information flow in pre‐symptomatic AD during cognitive flexibility challenge.MethodDuring a task‐switching challenge, 21‐head channel EEG was recorded from 55 cognitively healthy individuals classified into two groups (9 were excluded from artifacts or suboptimal performance): with an abnormal (CH‐PAT, n = 27) versus normal (CH‐NAT or controls, n = 19) ratio of cerebrospinal fluid (CSF) amyloid/total‐tau. In the task‐switching paradigm, each trial included two stimuli, and participants were required to either name the ink color or read the word when color words were printed in different colors of ink. Only correctly responded trials were analyzed. Directed functional connectivity between brain regions was estimated with Partial Directed Coherence (PDC) in frontal, central, parietal, temporal, and occipital regions in alpha frequency band (8‐12 Hz) during word‐color trials. Two‐sided t‐tests were conducted, with p<0.05 considered the level for significance. No multiple comparison correction was used for this exploratory study.ResultPilot analysis shows significant differences between CH‐PATs and CH‐NATs: CH‐PATs has shown decreased information flow from the temporal and occipital regions compared to CH‐NATs with p‐values of 0.001 and 0.04, respectively. In addition, frontal brain regions have shown enhanced information flow in the CH‐PATs compared to CH‐NATs (p = 0.02) (Figs 1&2). Moreover, greater information flow between the medio‐frontal cortex and occipital regions was observed in CH‐PATS than CH‐NATS (Fig 1).ConclusionCompared to CH‐NATs, the enhanced connectivity in frontal regions in CH‐PATs suggests that their frontal brain regions are compensating for the damage caused by the amyloid/tau pathology. The decreased information flow from temporal and occipital regions in CH‐PATs may indicate a loss of relative functional importance of these regions. Our exploratory findings provide a novel and alternative approach for connectivity‐based analysis to identify the effects of amyloid/tau pathology in CH participants.
Lower locus coeruleus integrity in older COVID‐19 survivors: initial findings from an international 7T MRI consortium
Authors: Jacobs Heidi I.L. , Ibrahim Tamer , Vahidy Farhaan S , Girard Timothy D. , Hosseini Akram A. , Alkateeb Salem , Bowtell Richard , Penny Gowland , Habes Mohamad , Karmonik Christof , Mougin Olivier , Roman Gustavo C , Masdeu Joseph C. , Li Karl , Garbarino Valentina R. , Goss Monica , Nair Rejani R , Patel Vibhuti N , Snyder Heather M , Tannous Jonika D , de Erausquin Gabriel A. , Snitz Beth E. , Seshadri Sudha 
Published: December 2023

AbstractBackgroundThe SARS‐CoV‐2 coronavirus has been associated with structural brain changes, consistent with its neurological manifestations. Recent studies showed a specific predilection for brainstem glial activation and hypometabolism, possibly indicating involvement of the locus coeruleus. The locus coeruleus (LC) modulates many cognitive functions and behaviors and its norepinephrine projections regulate both immune responses and vascular reactivity. We aimed to examine differences in LC integrity between COVID‐19 survivors and controls.MethodParticipants are enrolled across 3 US and 1 UK sites using harmonized cognitive and 7T MR‐imaging protocols. Here, we analyzed data from 18 participants enrolled at Houston Methodist (12 COVID‐19 survivors, 6 controls; Figure 1). COVID‐19 survivors were required to have had a positive antigen test and an illness syndrome consistent with COVID‐19. Healthy controls were required to have no significant pre‐existing medical, neurologic, or psychiatric illness and no illness requiring hospitalization in the last 2 years. LC imaging was performed using a dedicated 7T MT‐TFL sequence (0.4×0.4×0.5mm). A site‐specific normalized template was constructed using ANTs/FSL. The entire average LC integrity as well as voxel‐wise integrity values were compared between COVID‐19 survivors and controls using a robust linear regression (age‐controlled and threshold free cluster enhancement corrected). LC integrity was correlated with age, sex, ethnicity and cognition using Spearman’s rank correlation.ResultAverage LC integrity was not correlated with age, sex, or Hispanic ethnicity (p>0.3). COVID‐19 survivors did not differ from Controls when examining the entire LC (p = 0.54). Voxel‐wise analyses revealed a small cluster (19 voxels) in the middle portion of the left LC where COVID‐19 survivors exhibited lower LC integrity than controls (p = 0.005; Figure 2). Integrity of this cluster was not related to age or Hispanic ethnicity (p = 0.9). LC integrity did not correlate with cognitive performance within the COVID‐19 survivors (Trail Making Test B: p = 0.43; Craft Story delayed recall p = 0.47; MoCA p = 0.84).ConclusionConsistent with previous animal and human studies, our initial findings provide evidence for neuroinvasive potential of SARS‐CoV‐2 localized in the middle LC. In the future, we aim to expand our sample and link these observations to the neurocognitive sequelae of COVID‐19.
Association of APOE with Alzheimer’s disease in Mexico, Caribbean‐Hispanics, Peruvian and Mexican Americans
Authors: Barral Sandra , Rentería Miguel Arce , Reyes‐Dumeyer Dolly , Arango Silvia Mejia , Obregon Alejandra Michaels , Samper‐Ternent Rafael , Wong Rebeca , Barber Robert , Phillips Nicole , O'Bryant Sid E. , Montesinos Rosa , Soto‐Añari Marcio F. , Custodio Nilton , Tosto Giuseppe 
Published: December 2023

AbstractBackgroundThe Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Late Onset Alzheimer’s disease (LOAD). However, its genetic effect is heterogeneous across different ethnicities. We investigated the association of APOE with LOAD in five different Hispanic studies: Mexicans in the Mexican Health and Aging Study (MHAS), Caribbean Hispanics in the Washington Heights Inwood Aging project (WHICAP), Peruvians in the Genetics of Alzheimer’s disease In Peruvian Populations (GAPP) and Mexican Americans from The Health & Aging Brain among Latino Elders (HABLE) and the Texas Alzheimer’s Research and Care Consortium (TARCC).MethodA total of 7,832 participants were included in the analysis. APOE genotypes were generated by direct genotyping or imputation. SNPs associations with LOAD were assessed using multivariate logistic regression models in PLINK. Analyses were adjusted for age (≥60 years old), sex, and education. Global ancestry proportions, Native Americans, European, African were estimated with ADMIXTURE software using the Human Genome Diversity Project as the reference panel. Genetic ancestry specific secondary analyses were conducted using the same models.ResultThe genetic ancestral composition was significantly different across cohorts. Peruvians and Mexicans showed a predominant native ancestry, Caribbean‐Hispanics appeared to have a major contribution of European ancestry, and Mexican Americans exhibited similar proportions of both European and Native ancestries. We observed a significant association with e4 allele dosage in all the cohorts, except for MHAS. The genetic effect of at least one copy of the e4 allele on LOAD risk was very similar in GAPP and HABLE (OR = 3.42, SE = 0.39 and OR = 3.33, SE = 0.33, respectively), while attenuated in TARCC (OR = 2.81, SE = 0.28) and WHICAP (OR = 1.82, SE = 0.16). Among MHAS participants with a predominant European ancestry, APOE association achieved statistical significance with an increased disease risk (OR = 3.42, SE = 0.55) for homozygous carriers. Within the native‐prevalent ancestry subsample, the increased LOAD risk among APOE_ e4 heterozygous carriers were similar in both GAPP and HABLE cohorts (OR = 3.61, SE = 0.44 and OR = 3.64, SE = 0.43, respectively).ConclusionOur results showed a differential risk for LOAD from the APOE_ e4 allele across populations with admixed genetic ancestry.
A genome‐wide association study in Puerto Ricans suggests new risk loci for Alzheimer disease
Authors: Rajabli Farid , Feliciano‐Astacio Briseida E. , Hamilton‐Nelson Kara L. , Rivero Joe , Akgun Bilcag , Adams Larry D. , Mena Pedro R. , Tejada Sergio J. , Celis Katrina , Sanchez Jose Javier , Feliciano Nereida I , Whitehead Patrice , Prough Michael B. , Gardner Olivia K. , Acosta Heriberto , Chinea Angel ,   The Alzheimer’s Disease Sequencing Project (ADSP), McInerney Katalina , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W. , Pericak‐Vance Margaret A. 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) is the fourth leading cause of death in Puerto Rico. The Puerto Rican (PR) population has a high proportion of older adults (18%, over > 65), with 12.5% of them suffering from ADThese statistics highlight the need to investigate the genetic risk factors underlying AD in the PR population, as it could lead to the development of targeted treatments and therapies. Moreover, the ancestrally admixed makeup of the PR population provides an opportunity to assess the role of the European (∼67%), African (∼20%) and Amerindian (∼13%) ancestry in AD risk. We performed genome wide association analysis (GWAS) using whole genome sequence data to identify genetic risk/protective factors associated with AD in the PR population.MethodThe PR dataset includes WGS and phenotype data from 640 individuals, comprising 335 AD and 305 cognitively unimpaired (CU) controls. To account for the population substructure, we calculated the global ancestry (principal components) using EIGENSTRAT. We performed GWAS analyses with a generalized linear mixed‐model using the SAIGE software. The model included genotype, sex, age, and principal components (population substructure) as fixed effects and genetic relationship matrix as a random effect. The genetic relationship matrix was calculated based on genomic data and accounted for the relatedness among the individuals in the dataset.ResultWe identified four suggestive significant loci (P<1×10−6) associated with the risk of AD in PRs: NACC2 (pv = 4.8×10−7) on chromosome 9, SCN8A (pv = 9.3×10−7) on chromosome 12, FOXK2 (pv = 9.9×10−7) on chromosome 17, and APOEe4 (pv = 6.8×10−8) on chromosome 19. Eight additional AD loci with the same lead marker from European GWAS study (Bellenquez et al.) showed nominal significance: FERMT2 (pv = 6.2×10−3), TREM2 (pv = 8.0×10−3), CLU (pv = 1.8×10−2), RASGEF1C (pv = 2.4×10−2), ADAM17 (pv = 3.5×10−2), DOC2A (pv = 4.3×10−2), GRN (pv = 4.4×10−2) and SORL1 (pv = 5.1×10−2).ConclusionThis study identified three suggestive novel significant loci (NACC2, SCN8A, and FOXK2) associated with AD risk in PRs. In addition, GWAS study on PRs with a high proportion of European ancestry was able to replicate nine AD loci previously identified in European studies. These findings provide new insights into the genetic architecture of AD in the PR population.
Association between antipsychotics and all‐cause mortality in elderly patients diagnosed with dementia with different patterns of BPSD
Authors: Rogani Sara , Calsolaro Valeria , Coppini Giulia , Lemmi Bianca , Taverni Irene , Bianchi Elena , Pullia Rosanna , Carlo Ludovica Di , Okoye Chukwuma , Virdis Agostino , Monzani Fabio 
Published: December 2023

AbstractBackgroundduring the dementia time course Behavioral and Psychological Symptoms of Dementia (BPSD) may arise. Despite their use is still off‐label and they are associated with several side effects, antipsychotics represent the main pharmacological strategy to alleviate BPDSMethodaim of this retrospective study was to evaluate the correlation between antipsychotics use and all‐cause mortality. BPSD were classified in three clusters: “mood/apathy”, “psychosis” and “hyperactivity”. ANOVA for repeated measures was used to evaluate the functional/cognitive changes over three time points (baseline, 6 months and 12 months follow‐up). Chi‐Square test was carried out to verify the correlation between antipsychotic drug use and mortality. Logistic regression and stepwise regression method were used to analyze the relationship between mortality and other potential influencing factors, including ADL, IADL, CFS, in addiction of antipsychotics drugs use.Resulta total of 209 patients with a clinical diagnosis of dementia were enrolled (71.3% women; mean age = 83.24±4.98 years). The results of the ANOVA indicated a significant worsening of ADL and IADL over time [ADL Wilks’ Lambda = 0.744, F(2,80) = 13.75, p<0.001, η2 = 0.256, IADL Wilks’ Lambda = 0.71, F(2,80) = 16.3, p<0.001, η2 = 0.29, respectively], a significant progression of cognitive impairment as measured with MMSE and a significant worsening in frailty at CFS at 6 and 12 months follow up [MMSE Wilks’ Lambda = 0.751, F(2,73) = 12.11, p<0.001, η2 = 0.249, CFS Wilks’ Lambda = 0.749, F(2,79) = 13.224, p<0.001, η2 = 0.241]. Patients on antipsychotic therapy reported a higher mortality rate, although there is no statistically significant association between antipsychotic use and mortality. We found no significant correlation between mortality and antipsychotic drug use within the different BPSD cluster (“mood/apathy” p = 0.464, “psychosis” p = 0.569, “hyperactivity” 0.528), and no statistically significant association between mortality and other potential influencing factors. Using a stepwise regression, the loss of independence in IADL survived as factor associated to mortality (p = 0.002).Conclusionpatients on antipsychotic therapy reported a higher mortality rate, although there is no statistically significant association between antipsychotic use and mortality. Further work is needed to establish the relationship between antipsychotics and mortality in elderly patients with dementia.