bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐term nicotine treatment of mild cognitive impairment (The MIND Study): Baseline characteristics and study progress
Authors: Newhouse Paul A , Raman Rema , Saykin Andrew J. , Dumas Julie , Levin Edward , Kellar Kenneth , Aisen Paul S. 
Published: June 2023

AbstractBackgroundCognitive decline in AD/MCI is related to loss of cholinergic neurons. However, inhibition of acetylcholine degradation has not slowed progression. Treatment directly targeting nicotinic cholinergic receptors may be more helpful. We have shown proof of concept in a 6‐month multicenter trial that transdermal nicotine provides significant improvement in attention, episodic memory, and global ratings of functioning with minimal side effects in MCI. A larger and longer (2‐year) trial is underway to determine the persistence of improvement and attenuation of cognitive decline.MethodMCI participants were randomized 1:1 to either transdermal nicotine, beginning at 3.5 mg/day, increasing to 21 mg/day or matching placebo by 5 weeks. Participants were assessed at 0, 3, 6, 12, 18, and 24 months, with a subset undergoing MRI scans at 0, 12, and 24 months, and CSF collection at 0 and 24 months. Primary cognitive outcomes included reaction time standard error change‐from‐baseline (Connors CPT) for attention and delayed word recall (Cogstate) for memory. Primary clinical outcome is the CGIC. Secondary clinical measures include behavioral/functional scales and the CDR‐SOB. An MRI substudy is examining possible neural mechanisms.ResultTo date, 663 participants were screened and 309 were randomized including 133 females (43%) and 176 males (57%). Mean age was 73.7±7.1, education 16±2.8 years. Mean MMSE was 27.4±1.8 and CDR Global was 0.5. Randomization of ethnoracial underrepresented populations (URPs) was 9.4% (Black/African‐American 4%, Asian 2%, Hispanic/Latinx 3%). Treatment/Study discontinuations were higher than expected at 29% due in part to pandemic‐related disruptions. There are 87 completers thus far. Baseline MRI scans are 59 and LPs are 37. Safety results show that treatment has been generally well tolerated with no SAEs definitively or probably tied to study participation or investigational product thus far.ConclusionIf the hypotheses are validated, this will support a novel, broadly available, and inexpensive repurposed intervention for MCI and would encourage early treatment to improve symptoms, attenuate progression of cognitive impairment, and lead to combined trials with agents that interact with Aβ, tau or other mechanisms. Low URP recruitment and higher dropout rate remain challenging and will be specifically addressed in recruitment/enrollment/retention efforts moving forward.
Decoding the gene subnetworks prioritized in prediction with GLRP in Alzheimer’s Disease
Authors: Varathan Pradeep , Xie Linhui , He Bing , Nho Kwangsik , Risacher Shannon L. , Saykin Andrew J. , Yan Jingwen 
Published: June 2023

AbstractBackgroundAlzheimer’s disease is the leading cause of brain dementia, along with which substantial failure of organs and mental issues arise. The abundance of AD related data in the current decade has allowed for much advancement in the field using modern machine learning and deep learning techniques to decrypt pathology. Though diagnostic tools have been modeled over such large expanses of data, the black box problem of decoding the significant biological components contributing to the prediction has been overlooked in the research field.MethodGLRP is a method to decode the final predictions of a deep learning method. Since Graph‐CNN are best suited for using the gene expression data modeled over an established whole human PPI network. The usage of GLRP allows us to build the relevance that we need to interpret how the genes contribute to the prediction based on proven PPI network topology as the basis. From the relevance’s obtained of correctly predicted ROSMAP AD subjects and controls, important genes were extracted to be analyzed for functional annotations and pathway analysis with HPRD PPI.ResultThe graph‐CNN model was able to predict between AD subjects and controls with an AUC of 76.58% and test accuracy of 79.167% while the highest accuracy of machine learning models capped at 75% with an AUC of 72.95% from SVM as seen in Table 1. Having found a threshold of 550 genes to have the highest connected component in graph before noisy genes are added to the network as seen in Fig 1, the average relevance of AD subjects and controls provided us with 214 common genes with 181 genes in the largest connected component as seen in Fig 2.ConclusionAlong with tackling the black box problem of the deep learning model using GLRP which has allowed us to gather the important genes from the network view at a higher efficiency than the machine learning models. The top 214 common genes and the network relating to the negative regulation of organelle organization, hypoxia and oxygen level response, and cellular response to tumor necrosis factors could have potential impact on the pathology of AD and its progression.
Serum total tau, neurofilament light, and glial fibrillary acidic protein are associated with overall and cardiovascular mortality in a biracial longitudinal population‐based cohort
Authors: Halloway Shannon , Evans Denis A , Desai Pankaja , Rajan Kumar B 
Published: June 2023

AbstractBackgroundSerum cytoskeletal biomarkers may indicate greater risk of poor outcomes in age‐related conditions, including mortality. Total tau (t‐tau), neurofilament light (Nf‐L) and glial fibrillary acidic protein (GFAP) are neuronal cytoskeletal biomarkers that are measurable in biofluids. Our objective is to examine separate and combined associations of serum t‐tau, Nf‐L, and GFAP with overall and cardiovascular mortality in a biracial population‐based sample.MethodData came from 1,327 older participants who were either of Black or White racial background from the Chicago Health and Aging Project (CHAP), a longitudinal population‐based study of chronic conditions of aging. An ultrasensitive immunoassay was used to measure the concentration of t‐tau, Nf‐L, and GFAP in blood serum. Mortality based on age at death included overall mortality and cardiovascular mortality. A series of Cox proportional hazard regression models were used to examine associations between biomarker(s) and outcomes (overall and cardiovascular mortality), adjusting for age, gender, education, the APOE‐e4 allele, global cognitive function, and physical functioning.ResultIn univariate models, 5‐fold higher concentrations of serum t‐tau (HR = 1.46, 95% CI: 1.28, 1.68), Nf‐L (HR = 2.14, 95% CI: 1.79, 2.57), and GFAP (HR = 1.39, 95% CI: 1.07, 1.81) were separately associated with increased risk of overall mortality, with higher risk in participants of Black race versus White in models with t‐tau or Nf‐L. In combined models with all three biomarkers, t‐tau (HR = 1.38, 95% CI: 1.09, 1.75) and Nf‐L (HR = 3.05, 95% CI: 2.35, 3.95) were associated with risk of overall mortality, with racial differences in t‐tau only. In univariate models, higher concentrations of t‐tau (HR = 1.32, 95% CI: 1.03, 1.68), Nf‐L (HR = 2.11, 95% CI: 1.56, 2.88), and GFAP (HR = 1.74, 95% CI: 1.13, 2.69) were separately associated with risk of cardiovascular mortality, with racial differences in t‐tau or Nf‐L. In combined models, only Nf‐L was associated with cardiovascular mortality (HR = 2.84, 95% CI: 1.84, 4.38).ConclusionSerum t‐tau, Nf‐L, and GFAP were associated with increased risk of overall and cardiovascular mortality, with racial differences among associations, in a biracial population‐based sample. Our findings suggest that serum t‐tau, Nf‐L, and GFAP may serve as a potential biomarker for overall and cardiovascular mortality among older adults.
Herpes Simplex Virus‐1 Proteins as Drivers for Alzheimer’s Disease Pathologies
Authors: Shemesh Or A. , Reis Roberta , ` Hyde Vanesa 
Published: June 2023

AbstractBackgroundDNA and RNA of Herpes Simplex Virus 1 (HSV‐1) were found in the brains and serological samples of Alzheimer’s disease (AD) patients. Such molecular presence of HSV‐1 in AD patients is especially intriguing as HSV‐1 virions are rarely detected in AD brains.MethodTo follow the molecular footsteps detected, we imaged viral proteins in postmortem human AD brains at superior resolution using expansion microscopy, a tissue manipulation method that physically expands the samples by a factor of 4.5x, allowing a 40 nm imaging resolution, and immunolabeled herpetic proteins, AD pathologies and cell markers.ResultWe found an abundance of herpetic proteins, previously undetectable with standard methods, across large brain areas. Importantly, we found that HSV‐1 proteins strongly co‐localized with AD pathologies. Consequently, we hypothesized that expression of HSV‐1 proteins during latency may be linked to AD pathology. We are now in the process of characterizing the HSV‐1 proteome in AD brains by imaging key proteins in expanded AD brain slices and examining their colocalization with AD pathologies across brain areas and disease stages. As a complementary system to the fixed human brain slices, we are exposing live human brain organoids, to HSV‐1, and imaging the relationships between viral proteins and the formation of AD pathologies via expansion microscopy.ConclusionPathogens may be triggers of immune responses driving AD; this study would shed light on one common pathogen, HSV‐1, while serving as a framework to unveiling molecular causation between infectious agents and AD hallmarks.
A citation network analysis of the rural dementia literature
Authors: Prusaczyk Beth , Huo Rani 
Published: June 2023

AbstractBackgroundThere are key differences between urban and rural areas in terms of dementia risk, diagnosis, treatment, and service availability and utilization. Despite the unique and important context of rural areas, there has been relatively little research on dementia in rural areas. A broad yet comprehensive understanding of the existing rural dementia literature is an important step in grounding future dementia research in the existing literature and field.MethodIn June 2021, we conducted a citation network analysis of articles on rural dementia. Articles were identified using Web of Science and inclusion criteria included having “rural” and “Alzheimer’s” or “dementia” in the title. The abstracts of articles meeting these criteria were then reviewed manually by two researchers to ensure the primary focus was on rural dementia. Bibliographic data for the final sample of articles was downloaded from Web of Science and imported into VOS Viewer, a software tool for constructing and visualizing bibliometric networks.ResultThree hundred articles were included for analyses. Using time‐adjusted number of citations as a measure of prominence, 142 (47.3%) articles had been cited more than 10 times. An analysis of these 142 articles revealed twelve clusters. We found no patterns among the clusters based on publication year but found that publications tended to cite others originating from countries in close geographic proximity. Text citation analysis revealed three sub‐themes among the articles based on keywords: long‐term care studies, epidemiological studies, and community‐based and caregiver services studies, with few citations between the last two sub‐themes.ConclusionThere are three key findings from this analysis that help elucidate the rural dementia literature. First, authors publishing on rural dementia are citing older and newer articles at the same rate, suggesting the field is actively growing. Second, many countries are contributing to the literature base but authors still tend to cite articles originating from their own country or those close to them, suggesting there is a missed opportunity to learn from the global community. Third, there are three sub‐themes dominating the literature with little citations across sub‐themes, which suggests a need for more interdisciplinary research.
Overall and sex‐specific AT(N) biomarker prevalence in a low SES community: A population‐based study
Authors: Shaaban C. Elizabeth , Fang Fang , Cohen Ann D. , Chang Chung‐Chou H , Lopresti Brian J. , Laymon Charles M , Aizenstein Howard J , Klunk William E , Villemagne Victor L , Ganguli Mary , Snitz Beth E. 
Published: June 2023

AbstractBackgroundMost previous studies of amyloid[A], tau[T], and/or neurodegeneration[(N)] prevalence have been completed in highly selected samples, leaving low SES older adults from medically underserved areas underrepresented in research. Furthermore, women consistently have greater T and sometimes greater A accumulation than men, but clear characterizations of AT(N) biomarker positivity overall and by sex in different populations are lacking.MethodsNeuroimaging (NI) sub‐study participants in a population‐representative study of older adults from a low SES, medically underserved US Rust Belt area underwent PET and MRI. We calculated overall and sex‐specific AT(N) biomarker positivity within the NI sub‐study (Table 2) and population‐representative prevalence (Table 3) with inverse probability of selection weighting (IPSW). We calculated age and education adjusted odds ratios (ORs) for women vs men.ResultsThe overall sample (N = 1226) was 61% female, 94% white, and 98% dementia‐free. NI study participants (N = 115) were older, likelier to be from the parent study’s original (vs. replenishment) cohort, and less likely to report diabetes than non‐NI participants (N = 1111; Table 1). IPSW based on variables associated with AT(N) biomarkers (age, cohort, sex, race, education, hypertension, diabetes, and number of medications) successfully balanced these characteristics across NI and non‐NI samples. Population‐weighted prevalence of the A‐T‐(N)‐ profile was 18.8%. Based on 2018 NIA‐AA Research Framework terminology, prevalence of AD continuum biomarkers (any A+) was 24.4%; about 2/3 of these cases were specifically due to AD (A+T+ biomarkers). Prevalence of any T+ was 34.7%, and any (N)+ was the most common at 63.0%. Prevalence of A‐ with T+ and/or (N)+ was 56.8%. Any T+ and AD continuum/AD+ biomarkers were non‐significantly more common in women than men (weighted ORs ranging from 1.20 to 1.69, Table 3).ConclusionsCompletely normal AD biomarkers (A‐T‐(N)‐) were comparatively rare in older participants in this community, while any N+ and A‐ with T+ and/or (N)+ were quite common. Women trended toward a greater prevalence of AD+ biomarkers than men. These results are more applicable to other primarily white, low SES, and medically underserved populations than results from highly selected samples. Characterizing brain health across varying cohorts is essential to advance precision medicine and population health.
Cognitive function and brain structure correlates in individuals with subjective cognitive decline: Voxel‐based morphometry results from a lifestyle intervention to prevent Alzheimer’s disease (PENSA study)
Authors: Lorenzo Thais , Cuenca Aida , Operto Grégory , Falcon Carles , Puig‐Pijoan Albert , Forcano Laura , Piera Iris , Boronat Anna , Knezevic Iva , de Toma Ilario , Soldevila‐Domenech Natalia , Fauria Karine , Molinuevo Jose Luis , Gispert Juan Domingo , Torre Rafael de la ,   PENSA Study Group
Published: June 2023

AbstractBackgroundInterventions based on the modification of several lifestyle factors have provided promising results to maintain cognitive function in late/middle‐aged individuals at higher risk of developing Alzheimer’s disease (AD). Framed under the WW‐FINGERS network, the PENSA clinical trial is focused on the prevention of cognitive decline in individuals with subjective cognitive decline who are also APOEε4 carriers. It consists of a 12‐month multimodal lifestyle intervention supplemented with EGCG, a natural flavonoid from green tea. In this study, we looked for the brain structure correlates of cognitive performance for PENSA participants at baseline.MethodsOne hundred thirty‐one (N = 131) participants of the PENSA study at baseline [Table 1] with valid T1w, T2w and FLAIR MRI scans were included. They underwent a neuropsychological assessment battery consisting of the modified Alzheimer Disease Cooperative Study ‐ Preclinical Alzheimer Cognitive Composite (ADCS‐PACC‐Plus‐exe) that includes MMSE, Free and Cued Selective Reminding Test (FCSRT), Delayed Recall Logical Memory (DRLM), Five Digits Test, Digit Symbol Substitution Test, and Stroop. Additional cognitive measurements were obtained from semantic verbal fluency (SVF), Boston Naming Test, digit span subtest, visual puzzle subtest (VPT) and the Montreal Cognitive Assessment. FLAIR images were used to segment white matter hyperintensities and perform a lesion filling procedure in T1w and T2w images. These two later modalities were then entered into a multimodal segmentation in the SPM12 voxel‐based morphometry pipeline. Associations between test scores and grey matter volumes (GMv) were sought (p<0.001) including age, sex, education, and total intracranial volume as confounders.ResultsA positive association was found (p uncorr <0.001; k>200) between GMv and ADCS‐PACC‐Plus‐exe composite [Figure 1] in the bilateral hippocampus, amygdala, entorhinal and parahippocampal gyri. Additionally, positive correlations (p uncorr <0.001; k>200) were found between GMv and FCSRT, DRLM, VPT and SVF tests albeit in less consistent regional patterns. No associations were found between GMv and the remaining tests.ConclusionIn a sample at high risk of developing AD, the ADCS‐PACC‐Plus‐exe composite is associated with GMv in brain areas known to be affected in AD. These results suggest that the ADCS‐PACC‐Plus‐exe composite might be sensitive to detect subtle cognitive changes in cognitively unimpaired at‐risk individuals.
Longitudinal body weight dynamics in relation to cognitive decline over 18 years: A prospective cohort study
Authors: Zhou Tianjing , Chen Hui , Huang Yuhui , Wang Binghan , Zheng Yan , Wang Liang , Rong Shuang , Ma Yuan , Yuan Changzheng 
Published: June 2023

AbstractBackgroundWeight loss and body weight variability have been related to cognitive decline in old adults, respectively. However, the long‐term and independent associations of the two measures of body weight dynamics with cognitive decline remain unclear.MethodIn the Health and Retirement Study (HRS), we included 10,258 participants (58.4% women; mean age ± standard deviation (SD), 68.0 ± 9.8 years) free from memory‐related diseases in 1998. Body weight was reported biennially from 1993/1994 to 2016. Linear regression of the longitudinal body mass index for each individual was used to estimate body weight change (BWC, slope, kg/m2·year) and body weight variability (BWV, root mean squared error, kg/m2). Both measures were categorized by tertiles, with participants being classified as stable weight, weight loss, and weight gain (median = 0.0, ‐0.3, and 0.2 kg/m2·year, respectively), and small, moderate, and large BWV (median = 0.5, 1.1, and 2.0 kg/m2, respectively). Cognitive function was measured biennially from 1998 to 2016 using the Telephone Interview for Cognitive Status (TICS). We investigated the associations of BWC and BWV with annual rate of cognitive decline using linear mixed models.ResultDuring a median (IQR) follow‐up of 12 (4‐18) years, the average rate of cognitive decline was ‐0.052 z‐score/year. When adjusted for basic demographics, average BMI, and major lifestyle factors, we observed no significant associations of weight gain and moderate BWV with cognitive decline, whereas both weight loss and large BWV were associated with faster cognitive decline in the same model. Compared to those with stable weight, participants with weight loss experienced faster cognitive decline by ‐0.012 (95%CI, ‐0.015, ‐0.009) z‐score/year. Large BWV was also related to faster cognitive decline (β = ‐0.003, 95% CI: ‐0.006, ‐0.001) compared with small BWV. The associations were similar for both episodic memory and working memory, and across prespecified study subgroups.ConclusionWeight loss and large body weight variability were associated with faster cognitive decline in old adults. Our findings suggest the importance of dynamic body weight monitoring and management as a potential strategy to prevent age‐related cognitive decline.
Training caregivers to make meaningful connections with persons living with dementia: Telehealth strategies from the Pacific island of Guam
Authors: Twaddle Iain K. B. , Hattori‐Uchima Margaret Perez , Gutierrez Nikolas Jude , Orallo Rhoda Gaba 
Published: June 2023

AbstractBackgroundAlzheimer’s Disease and Related Dementias (ADRD) are not only characterized by a decline in memory and cognition, but also by marked difficulties in language, communication, and social functioning. As ADRD progresses, it becomes increasingly challenging for persons living with dementia to participate in social interactions with family, friends, and caregivers, adversely impacting their well‐being and quality of life. Despite impairment in social functioning, persons with dementia still enjoy interaction with others and respond positively to social contact even in advanced stages. Thus, there is a need to develop effective strategies for interacting with persons living with dementia in a meaningful way.MethodA telehealth dementia care training initiative was developed in the Pacific island of Guam focused on teaching family and professional caregivers to make meaningful connections with persons with ADRD through a wide range of stimulating, culturally responsive activities adapted to meet their unique needs, interests, and abilities. Activities were designed to provide opportunities for social engagement and simultaneously to help persons with dementia remain mentally and physically active. Examples include: (1) making meaningful connections with persons with dementia during activities of daily living; (2) rediscovering Guam’s history and culture through family‐based virtual museum tours; (3) embracing the oral storytelling traditions of Pacific island cultures by sharing family memories; (4) employing culturally responsive bibliotherapy by reading indigenous stories and picture books together; (5) stimulating the mind through collaborative readings of poetry; (6) soothing the aches and pains that come with aging by providing therapeutic massage; and (7) integrating music, dance, and movement into each day. All trainings were conducted in virtual family caregiver support group sessions as part of a comprehensive telehealth outreach program designed to provide improved access to dementia care support services for persons with dementia and their caregivers in Guam.ResultApproximately 60‐100 family and professional caregivers participate in the program each month.ConclusionProgram outcomes indicate that telehealth training in activity‐based dementia care can be an effective way to help caregivers learn to make meaningful connections with persons living with dementia.