bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and replication of gene‐by‐stress interaction associations with Alzheimer’s disease and related dementias
Authors: Singh Abanish , Arbeev Konstantin , Yashkin Arseniy Pavlovich , Mengel‐From Jonas , Schupf Nicole , Akushevich Igor , Yashin Anatoliy I 
Published: December 2023

AbstractBackgroundSeveral mechanisms have been hypothesized for the pathogenesis of Alzheimer’s disease and related dementias (ADRD); however, we are still far from effective prevention and treatment of the disease, thus more basic research is needed to understand the etiological neuropathogenesis. We hypothesized that a part of increased ADRD‐risk could be due to a complex interplay of genes and daily‐life psychosocial stress.MethodWe used the Health and Retirement Study (HRS) surveys and Medicare‐linked data for the discovery analysis and the Long‐Life Family Study (LLFS) dataset for replication analysis, creating a synthetic stress measure using the algorithm based on stress proxy‐indicators, as described in Singh et al., 2015. The two datasets were compared by evaluating samples’ stress levels and socioeconomic status. We performed the HRS gene‐by‐stress discovery GWAS analyses on age‐at‐onset of ADRD using linear regression with SNP, STRESS, SEX, and ancestry principal components as other terms in model. We fitted the same regression model in the LLFS replication analysis, adjusting it additionally with field centers and Huber–White familial clustering.ResultThe HRS GWASs resulted in associations at p‐value of order 10−8 in both Blacks and Whites. Although most of the top 25 significant SNPs were mapped to non‐coding regions, we identified four characterized genes (BCR, MCC, KCNQ5, and DCP2) in Whites and three genes (EMCN, DPYD, and INSYN2A) in Blacks. Published literature from human and experimental studies suggested that five out of the eight genes were known for their association with neurodevelopmental disorders including Autism, intellectual disability, but also for cancers including colorectal carcinoma, gastric carcinoma, and leukemia. Although LLFS samples presented higher socioeconomic status and lower stress levels compared to HRS samples, the associations of one‐third tested SNPs from HRS Whites replicated in LLFS samples.ConclusionOur findings suggest that daily‐life stress may contribute to the risk of ADRD via complex interactions with genes. The associations with non‐coding genetic variants may indicate their influence through gene‐regulatory roles. In addition, the associations observed with cancer genes may possibly point towards the involvement of a common mechanistic feature, e.g., angiogenesis, which needs to be investigated further.
Clinical and genetic characteristics of patients with very early onset frontotemporal dementia
Authors: Friedberg Adit , Ramos Eliana Marisa , Bonham Luke W. , Knudtson Marguerite V. , Castruita Ale , Lopez Lucia , Li Yi , Geschwind Daniel H. , Seeley William W. , Yokoyama Jennifer S. , Miller Bruce L 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) spectrum disorders may occur in patients who are under 45 years old, often posing a diagnostic challenge, yet little is known about the clinical presentation and underlying genetic causes in this age group.MethodAs part of a prospective study focused on FTD, 780 participants met the research criteria for an FTD spectrum disorder between 2002‐2021. Of these, 40 patients (5.1%, 18 females) presented with age at onset < 45 years and constituted the very early onset frontotemporal dementia (VEO‐FTD) group. Their research records were reviewed to delineate their clinical characteristics. A panel of 40 dementia and amyotrophic lateral sclerosis‐associated genes was screened for pathogenic genetic variation using standardized methods.ResultBehavioral variant of frontotemporal dementia was disproportionally represented in the VEO‐FTD group (n = 35, 87.5%) suggesting selective vulnerability of the social‐emotional brain networks to frontotemporal lobar degeneration underlying neuropathologies in this age range. The median age at first symptom was 39 (interquartile range (IQR) = 32‐42.2) years, and the median diagnostic delay from symptom onset was 4 (IQR 2‐8.25) years. Initial misdiagnosis with a primary psychiatric disorder was prevalent, occurring in 17 (42.3%) of patients, and was diverse including mood, psychotic, anxiety, and addictive disorders. In five patients (12.5%), positive psychotic symptoms were reported, mostly as a presenting symptom or arising within a year from the first symptom. Among the VEO‐FTD patients, 18 (45%) carried C9orf72, MAPT or UBQLN2 pathogenic variants.ConclusionFTD spectrum disorders may occur under the age of 45 and are often misdiagnosed. The high prevalence of monogenic causes in this age group warrants timely genetic testing, especially in the era of emerging gene‐specific therapies.
Cognitive and Socio‐Demographic Factors Related to Subjective Cognitive Decline in Native Americans
Authors: Dixon Bradley J. , Moll Allison C. , Woodard John L. 
Published: December 2023

AbstractBackgroundSubjective cognitive decline (SCD) is commonly reported in neuropsychological evaluation, but self‐reported SCD can be influenced by anosognosia and depressed mood. Cognitive decline reported by a close informant, such as a spouse, may be more predictive of objective cognitive decline than a patient’s self‐report (Bellaali et al., 2021). Recent research comparing how racial and ethnic groups report SCD found strong evidence that Native Americans and their close informants reported SCD more frequently than White and Black Americans (Dixon & Woodard, N.D.). This study investigates whether unique socio‐demographic or cognitive variables could account for this phenomenon.MethodParticipants were selected from the National Alzheimer’s Coordinating Center (NACC) database. Participants were cognitively healthy at baseline, at least 65 years of age, and had an informant who lived with or visited the participant weekly (N = 9355). Participant racial groups included White Americans (n = 7770), Black Americans (n = 1517), and Native Americans/Alaskans (n = 68). Pairwise comparisons compared objective cognitive performance on the Mini‐Mental State Examination (MMSE), clinician‐determined functional decline, level of independence, educational attainment, self‐reported anxiety, Geriatric Depression Scale (GDS), and history of tobacco and substance abuse between each racial group using Bayesian contingency tables and t‐tests to find reliable evidence supporting the null or alternative hypothesis.ResultGroup comparisons indicated no reliable differences between Native Americans and the other racial groups on clinician‐determined functional decline, level of independence, self‐reported anxiety, tobacco use, and substance abuse (BF10 < 3). White Americans had significantly higher educational attainment and performed better on the MMSE (BF10 > 100) than Black and Native Americans. Native Americans exhibited reliably higher GDS scores than White (BF10 = 5.5) and Black (BF10 = 10.4) Americans.ConclusionThe greater rate of SCD reported by Native Americans and their close informants compared with White and Black Americans may be related to significantly higher rates of depressive symptoms reported by Native Americans/Alaskans. Careful evaluation of mood symptoms may be particularly important for clinicians working with Native American/Alaskan patients to differentiate between SCD and objective cognitive impairment.
Suboptimal sleep efficiency and duration predict faster cognitive decline in cognitively unimpaired older adults
Authors: Pivac Louise N , Brown Belinda M , Doecke James D , Weinborn Michael , Sohrabi Hamid R , Gardener Samantha L , Bucks Romola S , Maruff Paul , Masters Colin L , Rowe Christopher C , Martins Ralph N , Rainey‐Smith Stephanie R 
Published: December 2023

AbstractBackgroundResearch indicates a role for suboptimal sleep, in cognitive ageing. An increasing, though inconsistent body of evidence has associated aspects of suboptimal self‐reported sleep quality with poorer cognitive performance. The current study investigated whether self‐reported sleep quality parameters predict the slope of domain specific cognitive performance.MethodParticipants were drawn from the Australian Imaging, Biomarkers and Lifestyle study of ageing. Linear mixed effect model (LMM) analyses were conducted on 525 cognitively unimpaired, older adults (M = 74.1, SD = 5.5, 56.4% female), characterised by apolipoprotein E (APOE) ε4 status, with baseline self‐reported sleep characteristics. Comprehensive cognitive assessments were conducted over a minimum 3 timepoints (range 29.64 ‐ 98.16 months). All models included random slopes, random intercepts, interaction effects for time, and APOE ε4 carriage, with each model adjusted based on the model of best fit for each cognitive outcome variable of interest.ResultFollowing Bonferroni correction, sleep duration <6 hours and sleep efficiency <65% in the whole cohort, and in APOE ε4 non‐carriers, forecasted accelerated decline in attention and speed of processing. In the same groups, greater sleep efficiency (%) forecasted greater preservation within the attention and speed of processing domain. No associations were observed for other sleep variables or cognitive domains of interest.ConclusionThese findings suggest a role for self‐reported suboptimal sleep efficiency and duration in the early stages of cognitive decline, represented by declining attention and speed of processing performance, in cognitively unimpaired individuals. Additionally, short sleep duration and poor sleep efficiency may increase future risk of cognitive decline independent of APOE ε4 carriage. Our findings also suggest the potential utility of self‐report screening for sleep efficiency and duration as a marker for increased risk of declining attention and speed of processing performance. Individuals with suboptimal sleep may benefit from an intervention to improve sleep efficiency and duration to lessen future risk of cognitive decline.
Tributyrin oral administration significantly attenuates the loss of intestinal butyrate‐producing bacteria and the ensuing cognitive dysfunction associated with Alzheimer’s Disease pathogenesis in 3xTg‐AD mice
Authors: Rao Aakarsha V. , Ghare Smita S. , Chilton Paula M. , Charpentier Benjamin T , Petrosino Joseph , Hoffman Kristi L , Greenwell J Caleb , Tyagi Neetu , Behera Jyotirmaya , Wang Yali , Sloan Lucy J , Zhang JingWen , Gobejishvili Leila , Whittemore Scott R , Shields Christopher B , Cooper Gregory , McClain Craig J. , Barve Shirish 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) development is linked to the loss of overall gut microbial diversity. However, the specific alterations are only beginning to be examined. In this regard, decreases in intestinal butyrate‐producing bacteria have been indicated by pre‐clinical and clinical studies in AD. The current work, employing the 3xTg‐AD mouse model examined the causal association of loss of butyrate‐producing bacterial communities with cognitive dysfunction associated with AD pathogenesis.MethodCecal samples from tributyrin (TB) treated and untreated female 3xTg‐AD mice were used to perform metataxonomic analysis by sequencing the 16S rRNA gene (V4 region) on a large‐scale Illumina MiSeq platform. Inferred metagenomics analysis was performed using the PICRUSt2 pipeline. TB treatment (oral gavage, 2mg/kg, twice a week) was initiated at 6‐months of age until 17‐months. Spatial and short‐term memory functions were tested using the Y‐maze and Novel Object Recognition Test (NORT).ResultMetataxonomic analysis showed an age‐dependent, significant decline in alpha diversity represented by measures of OTUs, Chao‐1 and Shannon Index from 2‐ to 18‐months. Additionally, age‐dependent changes in gut microbial composition were demonstrated by a significant decrease in the Firmicutes‐to‐Bacteroidota (F/B) ratio. Further analysis of specific features of the gut microbiome demonstrated an age‐dependent decrease in total butyrate‐producing families within the Firmicutes phylum; particularly, a significant loss of critical butyrate producing family Ruminococcacea was identified. Predictive functional analysis using PICRUSt2 also showed a significant reduction in the abundance of specific bacterial genes involved in butyrate synthesis. Importantly, these age‐dependent markers of gut microbial dysbiosis coincided with diminished measures of spatial and short‐term memory. Notably, administration of TB, a butyrate pro‐drug, significantly attenuated the age‐dependent (i) decline in gut microbial diversity & butyrate‐producing bacteria and (ii) loss of spatial and short‐term memory.ConclusionThe findings from this study identify that decline in total butyrate‐producing families is a key pathogenic feature of AD‐associated microbial dysbiosis and cognitive dysfunction. Importantly, these findings have the potential to inform the development of treatment strategies targeting gut microbial dysbiosis using TB, to prevent onset and development of cognitive decline in AD.
Investigating Alzheimer’s Disease‐Related Pathology in a Chronic Hyperglycemic Mouse Model
Authors: Ortiz Andrew Adonay , Hernandez Kimberly Stephanie , Suk Kyle Donghoon , Balsamo Brianna Michelle ,   Amanda Leisgang Osse, and Jefferson W Kinney
Published: December 2023

AbstractBackgroundDiabetes is a major risk factor for Alzheimer’s disease (AD). Hyperglycemia is the primary characteristic of diabetes. Hyperglycemia was induced in both young and aged mice. Following an incubation period, a hyperglycemic rescue was introduced to lower hyperglycemia, and to determine if hyperglycemia itself, or neuroinflammation as a result of hyperglycemia, increased AD pathology (i.e., hyperphosphorylated tau and reactive gliosis).MethodYoung (7‐month‐old; N = 24) and aged (18 month old; N = 24) C57BL/6J (wildtype) mice were injected with a low and staggered dose of streptozotocin (STZ) to induce sustained hyperglycemia. After a 9‐week incubation period of hyperglycemia (e.g., +250mg/dl), a group of mice were treated with Phloridzin (PZ) ‐ a drug that reduces hyperglycemia by preventing renal and intestine glucose uptake ‐ for two consecutive weeks to determine if hyperglycemia itself or the subsequent neuroinflammation, is what increase the risk for AD.ResultSTZ increased hyperglycemia levels; PZ lowered hyperglycemia levels. Both young and aged STZ, PZ, and STZ+PZ mice showed significantly differences in P‐S396‐tau/total, P‐T181‐tau/total, proinflammatory cytokines, and increases reactive microglia and astrocytes compared to controls.ConclusionPZ did not rescue hyperglycemic‐induced AD pathology.
Sleep‐mediated cognitive assessment and sleep architecture associations for real‐world diagnostic phenotyping of neurocognitive disorders
Authors: Karageorgiou Elissaios , Sykara Konstantina , Andronas Nikolaos , Alexoudi Athanasia , Devenopoulou Zoe , Pitman Julie , Karageorgiou Klimentini E 
Published: December 2023

AbstractBackgroundSleep disorders precede cognitive deficits by an average of four years in Alzheimer’s disease, and disrupted sleep has been associated with worse cognitive performance. We examined the association of a novel sleep‐mediated cognitive assessment to sleep architecture in people with and without cognitive impairment, towards earlier diagnosis of cognitive impairment.MethodForty‐three participants from the Sleep & Memory Center at the Neurological Institute of Athens cohort underwent a comprehensive evaluation that included polysomnography and pre‐ and post‐ sleep cognitive assessments of a novel short term verbal memory test as well as phonemic fluency testing. We examined the correlation of sleep‐mediated cognitive performance to sleep metrics of total sleep time, NREM/REM sleep, as well as respiratory metrics of Apnea‐Hypopnea Index and oxygen saturation during sleep.ResultSleep‐mediated spontaneous recall and phonemic fluency metrics were not associated to sleep architecture metrics. Instead, sleep‐mediated cued recall and recognition was positively associated to REM metrics of sleep time and relative REM/NREM ratio (R > 0.39; p < 0.039). On individual metrics, pre‐sleep verbal learning was positively associated to total sleep time (R > 0.30; p<0.05) as well as a larger REM/NREM ratio (R 0.52; p = 0.003). Finally, higher levels of oxygen during sleep, especially REM sleep, were associated with better pre‐sleep verbal learning (R > 0.39; p < 0.44).ConclusionOur results on people across a spectrum of cognitive abilities suggest that sleep‐mediated cognitive performance is significantly affected by shorter sleep times, and to a large extent these effects are dependent to the integrity of REM sleep. It is possible that both late evening learning abilities and sleep‐mediated memory reflects a person’s cholinergic capacity, as represented in subsequent REM sleep.
Vitamin D deficiency may increase the risk of developing cognitive impairment especially for APOE e4 non‐carriers
Authors: Kim Jiwon 
Published: December 2023

AbstractBackgroundVitamin D has been reported to play a role for neural protection and anti‐inflammation. However, its effects on the risk of cognitive decline has been inconsistent. Apolipoprotein E (APOE) could be a possible modulator of such influences as it takes part in the transport of cholesterol sharing a synthetic pathway with vitamin D and APOE e4 isoform is a well‐known significant risk factor of cognitive impairment. This study aimed to demonstrate the effects of vitamin D on incident cognitive impairment including mild cognitive impairment (MCI) and dementia and to explore its associations according to APOE e4 allele presence.MethodWe enrolled 1,271 cognitively normal community‐dwelling adults aged 60 years or older from the participants in the Korean Longitudinal Study on Cognitive Aging and Dementia. They were evaluated every two years from 2010 to 2018. We measured serum 25‐hydroxyvitamin D [25(OH)D] level and administered diagnostic assessment on MCI and dementia at every evaluation. We grouped the serum 25(OH)D into three levels as sufficient (> 30 ng/mL), insufficient (20 – 29.9 ng/mL), and deficient (< 20 ng/mL). We examined the associations of serum 25(OH)D level with the risks of incident MCI and dementia using Cox proportional hazard models adjusting for potential confounders. Then we also analyzed these effects in the APOE e4 non‐carriers and carriers separately.Result221 subjects showed a progression to MCI or dementia while 1,050 remained unchanged or improved cognitive function during follow‐up period. Participants who had deficient vitamin D concentration showed significant associations with a higher risk of cognitive decline (HR = 2.945, 95% CI = 1.088 – 7.970, p = 0.033) compared to sufficient 25(OH)D level group. APOE e4 non‐carriers who were vitamin D deficiency at baseline were 3.3‐fold more likely to suffer progression of cognitive impairment (HR = 3.308, 95% CI = 1.050 – 10.426, p = 0.041), whereas APOE e4 carriers did not show significant correlations of 25(OH)D levels with such progression (p > 0.05).ConclusionThese results indicate that vitamin D deficiency may increase the risk of developing cognitive impairment and the effects would be greater for APOE e4 non‐carriers compared to APOE e4 carriers.
The influence of everyday acoustic environments on the challenging behaviour in dementia: a participatory observation study in Nursing Homes
Authors: Vriendt Patricia De , Talebzadeh Arezoo , Decoutere Ine , Mynsbrugge Tara Vander , Botteldooren Dick , Devos Paul , Aletta Francesco , Van de Velde Dominique 
Published: December 2023

AbstractObjectiveDementia is a progressive illness characterized by cognitive and functional decline and often co‐occurs with a behaviour change. ‘Challenging behaviour’ (CB) is a group of behaviours, reactions and symptoms due to dementia, which can be challenging for the (professional) caregivers. The study aims to research the influence of acoustic on CB in people with dementia (PwD).DesignAn ethnographic design was used to study the daily life of PwD in their nursing homes with a specific focus on how people react to everyday environmental sounds.Setting/participantsThirty‐five residents were included in the sample based on a purposeful, homogeneous group characteristics sampling. Empirical data were collected using 24/7 participatory observations. The collected data were analyzed using a phenomenological‐hermeneutical Method: a naïve understanding, a structural analysis, and a comprehensive understanding.ResultsThe onset of CB depends on whether the resident feels safe and is triggered by an excess or lack of stimuli. The excess or shortage of stimuli and whether and when it affects a person is highly personal. It depends on various factors, such as the person’s state and the time of day. In addition, the nature of the stimuli, familiarity or strangeness is also a determining factor for the onset and progression of CB.ConclusionCB is an indirect consequence of something that threatens the well‐being of the PwD. This unsettling feeling can find its cause in the acoustic environment. The results can form an essential basis for developing soundscapes to make the PwD feel safe and reduce CB.
Strategic Multimodal Intervention in at‐risk Elderly Indians for Prevention of Dementia (SMRUTHI INDIA): A cohort multiple randomised controlled trial (cmRCT)
Authors: Vishnu Venugopalan Y , Sinha Abhik , Gupta Anu , N Nilima , Srivastava MV Padma ,   SMRUTHI INDIA CONSORTIUM
Published: December 2023

AbstractBackgroundThe major burden of dementia will be falling on Low and middle‐income countries in the next few decades. One of the major strategies to counter the rise in dementia burden is primary prevention, especially in at‐risk elderly individuals.MethodStrategic Multimodal Intervention in at‐risk Elderly Indians for Prevention of Dementia (SMRUTHI INDIA) is designed as a Cohort Multiple Randomised Controlled Trial (cmRCT) under a prospective community‐based cohort in rural India with long‐term follow‐up over many years. The rural cohort will be established in four zones of India, under the Indian Council of Medical Research (ICMR), Model Rural Health Research Units (MRHRUs) at Himachal Pradesh (North), Tripura (East), Rajasthan (West) and Karnataka (South). We plan to recruit 10000 participants with age > = 55 years and CAIDE score > = 6. SMRUTHI INDIA will be established in 2 phases. Phase 1 involves establishing a cohort (phase 1a) and development, followed by validation of the multimodal care bundle (phase 1 b). The care bundle preparation will have a development phase, acceptability and adaptability phase followed by feasibility testing involving a pilot RCT in a single centre. Phase 2 involves testing multiple interventions in cmRCT, and the first intervention to be tested will be the multimodal care bundle. The primary outcome will be the incidence of all‐cause dementia.ResultSMRUTHI INDIA will establish in parallel a large prospective rural cohort of at‐risk elderly in India and develop a culturally adapted and context‐specific multimodal care bundle. At the end of Phase 1, we will have the results of the pilot RCT on the feasibility of multimodal care bundle.ConclusionSMRUTHI INDIA is a landmark cohort multiple randomised controlled trial (cmRCT) which will assess multiple interventions for the primary prevention of dementia for the first time in India.Funding: Department of Health Research, Indian Council of Medical Research (ICMR)