bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep duration in relation to dementia risk in the UK Million Women Study
Authors: Wong Angel TY , Reeves Gillian K , Beral Valerie , Floud Sarah 
Published: December 2022

AbstractBackgroundSleep is often disrupted in people with dementia. To help assess whether any association between sleep duration and dementia may be the consequence of pre‐clinical disease or causal we examined dementia risk in relation to follow‐up time after reporting sleep duration in a large UK prospective study of women.MethodAbout 1.3 million women were recruited in median year 1998 (IQR 1997‐1999) in England and Scotland; in 2001 (IQR 2000‐2003), ∼830,000 reported their usual hours of sleep per 24 hours. They were followed for any mention of dementia in hospital records, the first mention of which was the main outcome. Cox proportional hazards regression was used to estimate dementia detection risk ratios (RRs and 95% confidence intervals [CI]) for <6, 6, 9, and >9 hours of sleep, compared to 7‐8 hours, respectively, during follow‐up periods of 0‐4, 5‐9, 10‐14 and 15+ years after sleep duration was reported. Adjustment was made for sociodemographic factors, lifestyle factors, and other characteristics.ResultWomen most commonly reported sleeping for 7‐8 hours (67%), with substantially fewer women reporting short sleep duration (<6 hours [5%], 6 hours [18%]) or long sleep duration (9 hours [7%], >9 hours [3%]). Over a mean 17 years of follow‐up (with <2% lost to follow‐up) ∼34,000 women had at least one hospital record of mentioning dementia. Compared to 7‐8 hours, there was no clear and consistent association between short sleep duration (<6, 6 hours) and dementia detection risk throughout the follow‐up periods. Long sleep duration (9, >9 hours) was associated with higher dementia detection risk in the first 5 years of follow‐up (e.g. RR for >9 vs 7‐8 hours sleep: 2.78 [95% CI, 2.22‐3.48]), but these RRs declined rapidly as follow‐up time increased and had largely disappeared 15+ years of follow‐up (1.18 [1.08‐1.28]), suggesting that the short‐term associations are the consequence of pre‐clinical disease. Associations by follow‐up period did not notably differ for Alzheimer’s disease, vascular dementia, and unspecified dementia.ConclusionIncreased sleep duration appears to be a consequence of pre‐clinical dementia but there is little to suggest a long‐term causal association of sleep duration with dementia risk in women.
Nighttime behaviors, but not insomnia, correlates with cognition and biomarkers of dementia
Authors: Zawar Ifrah , Quigg Mark S , Mattos Meghan K , Manning Carol A 
Published: December 2022

AbstractBackgroundWhile sleep disturbances appear to be risk factors in the progression of Alzheimer’s disease (AD) and other dementias, little is known about the prevalence across dementia severity and the potential influence on the trajectory of cognitive decline.MethodWe used the prospective National Alzheimer Coordinating Center Uniform Data Set to evaluate the hypotheses that the prevalence of insomnia differs by definition and by stage of cognitive impairment, that certain sleep features track with established biomarkers of AD, and that longitudinal changes in sleep disorders affect cognition and AD biomarkers. We conducted cross‐sectional analyses to determine the prevalence of clinician‐determined insomnia and nighttime behaviors (nighttime restlessness, agitation, daytime sleepiness) in normal, mild cognitive impairment (MCI), and demented individuals, as defined by Montreal Cognitive Assessment (MoCA) cut‐off scores obtained during the patient’s first visit. We evaluated mean MoCA scores, hippocampal volumes, and CSF phosphorylated tau:beta amyloid ratios obtained near the first visit using Analysis of Variance (ANOVA) with age as a covariate. In longitudinal evaluations, we classified changes in insomnia and nighttime behaviors as “none”, “remitted”, “acquired”, or “steady” between the first and last visits. Similar changes in MoCA scores and hippocampal volumes were assessed with repeated‐measure ANOVA.ResultThe prevalence of clinician‐identified insomnia at initial visits was 15%, 17%, and 13% for normal, MCI, and dementia groups respectively. Prevalence of clinician‐identified nighttime behaviors was 13%, 19%, and 27% respectively. Insomnia was significantly associated with higher MoCA scores, larger hippocampal volumes, and higher pTau:Beta values, indicating those with clinician‐identified insomnia had better cognition and less neurodegeneration than individuals who clinicians identified to be without insomnia. In contrast, the presence of nighttime behaviors were associated with significantly worse cognition, smaller hippocampal volumes, and lower pTau:Beta. Similar findings were seen between longitudinal associations of sleep disorders and cognition and hippocampal volumes.ConclusionOur findings suggest that the clinician determination of insomnia may be under‐recognized in patients with cognitive impairment seen in memory disorders clinics, and that nighttime behaviors especially when reported by family members may better reflect sleep disturbances, the biological underpinnings of AD, and have diagnostic specificity in AD over insomnia.
Substantia nigra integrity is associated with poorer recognition memory for novel stimuli in early Alzheimer’s disease
Authors: Krohn Friedrich , Sarkar Mousumi , Schütze Hartmut , Yakupov Renat , Spottke Annika , Hämmerer Dorothea , Schneider Anja , Heneka Michael T. , Fließbach Klaus , Kilimann Ingo , Teipel Stefan , Jessen Frank , Duzel Emrah , Betts Matthew 
Published: December 2022

AbstractBackgroundThe substantia nigra/ventral tegmental area (SN/VTA), the brain’s most prominent dopamine source, is involved in novelty exploration and episodic memory. Using a novelty detection task combined with neuromelanin‐sensitive MRI, this work aimed to investigate the relationship between SN integrity, neural novelty response and subsequent recognition memory performance in individuals with early Alzheimer’s disease.Method79 healthy subjects, 54 participants with subjective cognitive decline (SCD), 18 with mild cognitive impairment (MCI), and 10 individuals with ADD from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study performed a previously published scene novelty and encoding task (“FADE”) using 3T fMRI. Additional 3D T1‐weighted FLASH images were collected to visualize and quantify the volume and MRI contrast in the SN.Linear regression models were generated to assess for associations between either SN volume and median MRI contrast, considered as proxy integrity measures, with functional activity during novelty and subsequent recognition memory performance (dprime). We used site, gender, age and years of education as covariates. We assessed AD pathology in a subsample of individuals with CSF biomarkers (n = 71).ResultWe observed a significant decline in SN volume (p = 0.003) but not MRI contrast in ADD compared to healthy controls. The SN volume in the whole sample correlated positively with recognition memory for novel stimuli (r = 0.35; p = 0.02,). This association held in the CSF subsample (r = 0.31; p = 0.034) and also after correcting for levels of both tau (phosphotau, r = 0.57; p = 0.0284,) and amyloid (Abeta 42/40 ratio, r = 0.46; p = 0.03,). Additionally, SN median MRI contrast significantly correlated with novelty responses in the hippocampus in the CSF subsample and also in amyloid positive but not negative (Abeta 42/40 ratio<0.08, n = 26) individuals. Finally, recognition memory (p<0.001) was significantly decreased in Abeta positive compared to negative individuals.ConclusionWe show that significant degeneration to the SN in AD dementia and pathological Abeta 42/40 levels are associated with poorer recognition memory for novel stimuli. Moreover, associations between SN median MRI contrast and novelty responses differed between amyloid positive and negative individuals. These results indicate that degeneration to the SN may contribute to memory dysfunction in AD dementia which may be linked to pathological amyloid levels.
Plasma glial fibrillary acidic protein is associated with reactive astrogliosis assessed via 18F‐SMBT‐1 PET
Authors: Chatterjee Pratishtha , Dore Vincent , Pedrini Steve , Krishnadas Natasha , Thota Rohith N , Bourgeat Pierrick , Rainey‐Smith Stephanie , Burnham Samantha C , Fowler Christopher , Taddei Kevin , Mulligan Rachel S , Ames David , Masters Colin L. , Fripp Jurgen , Rowe Christopher , Martins Ralph N , Villemagne Victor L 
Published: December 2022

AbstractBackgroundReactive astrogliosis is an early event along the Alzheimer’s disease (AD) continuum. We have shown that plasma glial fibrillary acidic protein (GFAP), reflecting reactive astrogliosis, is elevated in cognitively unimpaired individuals with preclinical AD (Chatterjee et al., 2021). We reported similar findings using 18F‐SMBT‐1, a PET tracer for monoamine oxidase B (MAO‐B) (Villemagne et al., 2022). To provide further evidence of their relationship with reactive astrogliosis we investigated the association between GFAP and 18F‐SMBT‐1 in the same participants.MethodPlasma GFAP, Aβ42 and Aβ40 levels were measured using the Single Molecule Array platform in 71 participants comprising 54 healthy controls (12 Aβ+ and 42 Aβ‐), 11 MCI(3 Aβ+ and 8 Aβ‐) and 6 probable AD(5 Aβ+ and 1 Aβ‐) patients from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing cohort. These participants also underwent 18F‐SMBT‐1 and Aβ PET imaging. Aβ imaging results were expressed in Centiloids (CL; ≥20 CL classified as Aβ+). 18F‐SMBT‐1 Standard Uptake Value Ratio (SUVR) were generated using the subcortical white matter as reference region. Linear regression analyses were carried out using plasma GFAP levels as the dependent variable and regional 18F‐SMBT‐1 SUVR as the independent variable, before and after adjusting for age, sex, soluble Aβ (plasma Aβ1‐42/Aβ1‐40 ratio) and insoluble Aβ (Aβ PET).ResultPlasma GFAP was significantly associated with 18F‐SMBT‐1 SUVR in brain regions of early Aβ deposition, such as the supramarginal gyrus (SG, β=.361, p=.002), posterior cingulate (PC, β=.308, p=.009), lateral temporal (LT, β=.299, p=.011), lateral occipital (LO, β=.313, p=.008) before adjusting for any covariates. After adjusting for covariates age, sex and soluble Aβ, GFAP was significantly associated with 18F‐SMBT‐1 PET signal in the SG (β=.333, p<.001), PC (β=.278, p=.005), LT (β=.256, p=.009), LO (β=.296, p=.004) and superior parietal (SP, β=.243, p=.016). On adjusting for age, sex and insoluble Aβ, GFAP was significantly associated with SMBT‐1 PET in the SG (β=.211, p=.037) however only a trend towards significance was observed in the PC (β=.186, p=.052) and LT (β=.171, p=.067) (Figure 1).ConclusionThere is an association between plasma GFAP and regional SMBT‐1 PET that is primarily driven by brain Aβ load.
Increased incidence of dementia following herpesvirus infection in the Korean population
Authors: Shim YongSoo 
Published: December 2022

AbstractBackgroundHerpesviruses affect the development of dementia. We investigated the association between herpes infection and subsequent diagnoses of dementia.MethodData from the National Health Insurance Service of South Korea were used. Patients aged ≥ 50 years with the relevant diagnostic codes in the reference year 2009 were included and prospectively reviewed from January 2010 to December 2018. All study participants were followed from the index date until the onset of dementia, death, or the study endpoint.ResultThe three cohorts comprised 92,095 patients with herpes simplex virus (HSV) infections, 97,323 patients with varicella‐zoster virus (VZV) infections, and 183,779 controls. During the follow‐up period, 15,831 (17.19%) subjects with HSV infection and 17,082 (17.55%) VZV‐infected subjects, compared to 27,028 (14.17%) control subjects, were subsequently diagnosed with dementia (all, P<0.001). The adjusted hazard ratio for developing dementia was found to be 1.18 (95% confidence interval [CI]; 1.16‐1.20) in HSV and 1.09 (95% CI; 1.07‐1.11) in VZV patients (all, P<0.001). HSV1 infections such as oral or ocular subtypes, but not HSV2, anogenital subtype, were associated with dementia, including several subtypes such as Alzheimer’s disease (AD), vascular dementia, and dementia with Lewy bodies. VZV infection is also associated with AD.ConclusionIn this Korean nationwide population‐based cohort study, both HSV and VZV infections were associated with a higher risk of dementia, particularly AD. Among the subtypes of HSV infection, HSV1 is associated with a risk of dementia. Further studies including appropriate public health interventions could evaluate the causality of these relationships.
Positive Aspects of Caregiving Moderates the Relationship between Family Functioning and Caregiver Burden in Dementia
Authors: Zammitti Melissa G , Chapman Kimberly R , Tremont Geoffrey 
Published: December 2022

AbstractBackgroundWorse family functioning may predict greater caregiver burden for families dealing with dementia. However, experiencing positive aspects of dementia caregiving could mitigate this relationship. The current work explored whether the relationship between family functioning and caregiver burden depends on positive aspects of caregiving. We hypothesized that greater endorsement of positive aspects of caregiving would attenuate the relationship between family functioning and caregiver burden.MethodCross‐sectional baseline data from dementia caregivers enrolled in a caregiver intervention study were analyzed (n = 163). Dementia caregivers self‐reported demographic data. Family functioning, caregiver burden, and positive aspects of dementia caregiving were captured, respectively, using a brief version of the Family Assessment Device (FAD; Epstein et al., 1983), the Zarit Burden Interview (ZBI; Zarit et al., 1986), and the Positive Aspects of Caregiving scale (PAC; Tarlow et al., 2004). Linear regression was used to determine if PAC moderated the relationship between FAD and ZBI controlling for caregiver relationship.ResultThe overall model (R2 = 0.28, F(4, 158) = 15.6, p<.001) and interaction term (b = ‐0.06, 95%CI [‐0.10, ‐0.03] were significant. At low and average levels of PAC there was a significant negative relationship between FAD and ZBI such that worse family functioning predicted greater caregiver burden. At high levels of PAC there was no relationship between FAD and ZBI.ConclusionConsistent with expectation, the relationship between family functioning and caregiver burden depended on positive aspects of caregiving. Dementia caregivers who do not strongly identify with the positive aspects of their caregiver role may be particularly susceptible to experiencing increased burden in the face of low family support. Both the individual and the family of the caregiver may benefit from intervention strategies that assist in recognizing and cultivating the positive aspects of dementia caregiving.
Scaffold morphing and in silico studies of potential BACE1 (β‐secretase) inhibitors: A hope for newer dawn in anti‐Alzheimer therapeutics
Authors: Singh Manjinder , Bhatia Shiveena , Sharma Pratibha , Kaur Maninder , Singh Thakur Gurjeet 
Published: December 2022

AbstractBackgroundAD (Alzheimer’s disease) is the prime causes for 65‐85% cases of senile dementia occurs due to the plaques aggregation and tangles formation in various parts of brains neurons (cortical and hippocampal) leading to brain cell death. The major cause of AD is the extracellular plaques accretion made of β‐amyloid protein. The β‐secretase enzyme also known as BACE‐1 is the key player behind this phenomenon catalyzing the rate determining step of the reactions generating β‐amyloid. Therefore, efforts are being applied for research and development of novel entities that can inhibit the BACE‐1 enzyme and thus halting the plaque build‐up.MethodIn our study, we analyzed some of the analogues of Elenbecestat, which is a β‐secretase inhibitor currently in clinical trials designed by using scaffold morphing and structure‐based designing approach with a superior therapeutic profile, followed by in silico screening i.e. pharmacokinetics and docking methodologies.ResultThe designed molecules showed good interactions with the active pockets (Asp32 and Asp228, catalytic dyad residues) of β‐secretase protein and having drug likeliness properties.ConclusionHenceforward, molecular dynamic studies are required to fully establish their possible utility as the promising BACE1 inhibitors.
Plasma biomarkers for Alzheimer's disease: from amyloid to CNS derived extracellular vesicles, overview of changes through age, sex and risk factor in control and AD populations
Authors: Boyer Emilien , Kienlen‐Campard Pascal , Hanseeuw Bernard J 
Published: December 2022

AbstractBackgroundHallmark proteins pathogenic in Alzheimer's disease (AD), amyloid and tau, can now be quantified in plasma samples using single‐molecule array (SIMOA). However, proteins are not only circulating in plasma, but are also present in nervous system‐derived extracellular vesicles (NDBEs) secreted by neurons in the plasma. We aim to quantify plasmatic NBDEs to evaluate whether their number or content are modified in symptomatic AD.MethodPlasma samples were obtained in clinically normal (CN) participants (N = 76, sex ratio F/M = 1.5, mean age 57.5 ± 16.3, Apoε4 positive n=31, Apoε4 negative n=43) and in patients with symptomatic AD (N=17, sex ratio F/M = 0.7, mean age 70.1 ± 7.6). Quantification of amyloid 42 – 40 peptides and Tau protein was achieved with SIMOA multiplex analysis. For relative quantification of NDBEs circulating in plasma, we used DELFIA ELISA immunoassay with anti‐neuronal cell adhesion molecule (NCAM1) antibody. Normalization to the total number of vesicles was done using an antibody targeting CD81, a ubiquitous vesicle marker.ResultWe observed a significant decrease of Aβ42 in AD patients (p < 0.05), and in CN carrying an Apoε4 allele (p < 0.05). The ratio Aβ42/40 was lower in AD patients (p < 0.05) and the ratio Tau/Aβ42 was higher (p < 0.05). In CN, the relative amount of NDBEs in plasma was correlated with circulating Aβ42 (p < 0.0001, R² 0.2699) and Tau (p < 0.0001, R² 0.2753) such that greater numbers of NBDEs were associated with lower concentrations of proteins in circulating plasma. Amount of NDBEs do not seem to change with age, Apoε4 status or in AD patients.ConclusionLevels of Ab42, ratios Aβ42/40 and Tau/Aβ42 in plasma are significantly different in patients with symptomatic AD, and between ApoE4 carriers and non‐carriers among CN individuals. However, the number of NBDEs is negatively associated with the concentrations of these proteins, suggesting that these proteins are encapsulated in NBDEs. Future work will analyze the content of the vesicles to confirm that hypothesis.
APOE4 exacerbates α‐synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy Body pathology
Authors: Jin Yunjung 
Published: December 2022

AbstractBackgroundAccumulating evidence demonstrates that 40‐50% of Alzheimer’s disease (AD) brains present with concomitant Lewy pathologies at autopsy, suggesting that α‐synuclein (α‐SYN) aggregation is likely involved in the pathogenesis of AD. Interestingly, the genome‐wide association study (GWAS) revealed that the ε4 allele of APOE (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying the important role of APOE4 in both amyloid β (Aβ) and α‐SYN pathogenesis. However, how APOE4 modulates the α‐SYN aggregation in AD is still unclear.MethodWe performed biochemical analyses measuring α‐SYN levels on a pathologically confirmed human AD cohort (N = 469) obtained from the Mayo Clinic Brain Bank, wherein 54.4% of our cohort presented with co‐morbid α‐SYN pathology upon diagnosis of AD with Lewy Body pathology (hereinafter referred to as AD+LB), which was subdivided into APOE4 non‐carriers (APOE4−) and carriers (APOE4+). To determine the seeding activity of α‐SYN, we performed Real‐time quaking‐induced conversion (RT‐QuIC) assays with the soluble TBS protein fractions of the brain lysates. The cytotoxicities of the amplified α‐SYN seeds were tested with MTT assay for cell viability and neuronal outgrowth measurement by immunofluorescence staining with human induced pluripotent stem cells (iPSC)‐derived neurons.ResultWe found that AD+LB cases showed the significantly higher seeding activity of α‐SYN compared to AD cases without LB pathologies. Furthermore, APOE4+
AD+LB brains had the highest α‐SYN seeding activity compared to AD+LB APOE4−
cases. The α‐SYN seeding activity was associated with the level of α‐SYN, tau, or APOE aggregates, but not Aβ. Finally, we showed that the amplified α‐SYN aggregates derived from AD+LB APOE4+
had highest protease resistance and cytotoxicities in iPSC‐derived neurons.ConclusionThese findings suggest that APOE4 modulates the conformation of α‐SYN seeds which leads to high seeding activity and toxicity of α‐SYN in AD.
Development and Evaluation of a Natural Language Processing Annotation Tool (NAT) to Facilitate Phenotyping of Cognitive Status in Electronic Health Records
Authors: Magdamo Colin G. , Noori Ayush , Liu Xiao , Tyagi Tanish , Li Zhaozhi , Kondepudi Akhil , Alabsi Haitham , Rudmann Emily , Wilcox Douglas , Brenner Laura , Robbins Gregory K. , Moura Lidia Maria V. , Hsu John , Zafar Sahar F. , Benson Nicole , Serrano‐Pozo Alberto , Dickson John , Hyman Bradley T. , Blacker Deborah , Westover M Brandon , Mukerji Shibani , Das Sudeshna 
Published: December 2022

AbstractBackgroundElectronic Health Records (EHR) with large sample sizes and rich information offer great potential for dementia research, but current methods of phenotyping cognitive status are either not scalable or suffer from inaccuracies. Our objective is to evaluate whether deep learning Natural Language Processing (NLP)‐powered semi‐automated annotation can improve the speed and reliability of chart reviews for phenotyping cognitive status.MethodIn this study we developed and evaluated a semi‐automated NLP‐powered annotation tool (NAT) to facilitate phenotyping of cognitive status. Clinical experts adjudicated the cognitive status of 627 patients at Mass General Brigham (MGB) Healthcare using NAT or traditional chart reviews. Patient charts contained EHR data from two datasets: (1) Records from January 1, 2017 to December 31, 2018 for 100 Medicare beneficiaries from the MGB Accountable Care Organization (ACO), and (2) Records from 2‐years pre‐COVID diagnosis to the date of COVID diagnosis for 527 MGB patients. All EHR data from the relevant period were extracted; diagnosis codes, medications, and laboratory test values were processed and summarized. Clinical notes were processed through a deep learning NLP algorithm and a web tool was developed to present an integrated view of all data. Cognitive status was rated as cognitively normal, cognitively impaired, or undetermined. Assessment time and interrater agreement of NAT compared to manual chart reviews for cognitive status phenotyping was evaluated.ResultNAT adjudication provided higher interrater agreement (Cohen k = 0.89 vs. k = 0.80) and significant speed up (time difference mean [SD]: 1.4 [1.3] minutes, P < 0.001; ratio median [min, max]: 2.2 [0.4, 20]) over manual chart reviews. There was moderate agreement with manual chart reviews (Cohen k = 0.67). In the cases that exhibited disagreement with manual chart review, NAT adjudication was able to produce assessments that had broader clinical consensus due to its integrated view of highlighted relevant information and semi‐automated NLP features.ConclusionNAT adjudication improves the speed and reliability for phenotyping cognitive status compared to manual chart reviews. This study underscores the potential of an NLP‐based clinically adjudicated method to build large‐scale dementia research cohorts from EHR.