bluuebunny/crossref_metadata_2025_split huggingface dataset:
“I would constantly watch myself”: Individual Attitudes and Needs towards Dementia Risk Prediction and Risk Disclosure in Interviews (PreTAD)
Authors: Baumeister Annika , Hübner Constanze , Schwegler Carolin , Gerards Michelle , Cantero‐Fortiz Yahveth , Marquié Marta , Ribaldi Federica , Wittrock Julia , Boada Mercè , Frisoni Giovanni B , Jessen Frank , Rostamzadeh Ayda , Schmitz‐Luhn Björn , Woopen Christiane 
Published: December 2023

AbstractBackgroundResearch on medical risk profiles and early detection progresses rapidly. With the early knowledge of individual health risks comes, so the hope, the possibility of tailored prevention. Potential users and healthcare providers are facing new challenges in terms of decision‐making for risk prediction, education and counselling, as well as dealing with the risk information obtained. If, as in the case of Alzheimer’s disease, there are hardly any therapy and no healing options so far, risk prediction has an existential relevance and social impact, the extent of which has been little investigated yet. Therefore, supporting a self‐determined decision for or against dementia risk prediction, taking into account individual attitudes, needs and expectations, is of major importance. As part of the PreTAD‐project (The Predictive Turn in Alzheimer’s Disease: Ethical, Clinical, Linguistic and Legal Aspects), we aim to explore the attitudes, needs and expectations regarding early dementia prediction and risk disclosure in the general population, first‐degree relatives of persons with Alzheimer’s dementia or APOE4 allele carriers, and individuals with subjective cognitive decline (SCD).MethodIn the work package ethics, we (1) conduct an online‐survey within the general population and (2) carry out 40 narrative interviews with a) individuals from the general population, b) individuals with AD family history, and individuals diagnosed with SCD (either c) ≤ 4 weeks or d) > 4 weeks ago) to get an in‐depth view of individual attitudes and needs regarding early dementia prediction, the reasons for its approval or rejection, and to examine whether personal characteristics play a role in the decision‐making process. We analyze the interviews using type‐building qualitative content analysis (Kuckartz & Rädiker 2022).ResultPreliminary results of the first interviews (n = 5), accompanying the quantitative study, showed that participants tended to confuse the terms prediction and diagnosis in the context of Alzheimer’s. The driving reasons for or against prediction were 1) the anticipated impact on self‐determination and 2) self‐awareness, and 3) the anticipated psychological burden of risk knowledge.ConclusionHealthcare providers should carefully consider individual attitudes and expectations regarding dementia risk prediction as risk disclosure may have serious implications on individuals’ self‐determination, self‐awareness and mental health.
iPSC‐derived hindbrain spheroids to evaluate drug responses targeting neuropsychiatric symptoms in Alzheimer’s disease
Authors: Zivko Cristina , Sagar Ram , Xydia Ariadni , Lyketsos Constantine G. , Machairaki Vasiliki 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD), a neurodegenerative disorder, is the most common cause of dementia. The gradual deterioration of brain function eventually leads to death. Almost all AD patients eventually suffer from neuropsychiatric symptoms (NPS; e.g., agitation, depression) whose emergence correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain spheroids containing serotonergic neurons using induced Pluripotent Stem Cells (iPSCs) from healthy volunteers or AD patients with and without NPS. The spheroids can be used to study AD, NPS, and to evaluate individual differences in disease progression, NPS development, and/or pharmacological treatment response.MethodHuman peripheral blood mononuclear cells from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain spheroids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of serotonin (5‐HT) secreted in the extracellular environment. To assess patient‐specific treatment effects, spheroids were treated with different concentrations of escitalopram oxalate, a medication widely prescribed for the treatment of NPS.ResultHindbrain spheroids containing serotonergic neurons were successfully generated and characterized from these 6 individual iPSC lines. Changes in 5‐HT levels before and after treatment with escitalopram were dose‐dependent and variable across patients.ConclusionIt is possible to generate hindbrain spheroids from human iPSCs to study inter‐patient variability using a precision medicine approach. Since hindbrain spheroids from different people respond differently to the application of escitalopram in vitro this may reveal subgroups of AD patients who may be more or less likely to benefit from the drug in vivo. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment with escitalopram.
Amyloid‐beta (Aβ) load in the post‐mortem brain correlates with APOE genotype and ante‐mortem cognitive performance in centenarians
Authors: Rohde Susan K , Fierro‐Hernández Patricia , Rozemuller Annemieke J.M. , Bank Netherlands Brain , Lorenz Linda M.C. , Sikkes Sietske A.M. , Hoozemans Jeroen , Holstege Henne 
Published: December 2023

AbstractBackgroundThe prevalence of amyloid‐beta (Aβ) pathology increases at higher ages in non‐demented individuals1. With anti‐amyloid‐beta therapies on the horizon and the growing number of elderly in our population, a clear perception of the association between accumulated Aβ pathology, APOE genotype and cognitive performance in the oldest‐old is warranted.MethodsIn 93 post‐mortem brains donated by participants of the Dutch 100‐plus Study, who self‐reported to be cognitively healthy at inclusion, we evaluated: 1) the spatiotemporal Aβ spread using Thal phases2; and 2) Aβ load in frontal, parietal, temporal and occipital cortices using a quantitative image analysis method. Spread and load of Aβ pathology were compared between different APOE groups (ɛ2/2 and ɛ2/3 (n = 20); ɛ3/3 (n = 65); ɛ2/4 and ɛ3/4 (n = 8)). Post‐mortem Aβ measurements were correlated to ante‐mortem test scores on a comprehensive neuropsychological test battery3 and a composite z‐score for global cognitive performance. Median age at death was 103.3 (interquartile range (IQR): 102.3‐104.9) and median time between neuropsychological assessment and brain donation amounted 0.61 years (IQR: 0.28‐0.93).ResultsNotably, only 10% of the centenarians had not accumulated Aβ pathology. APOE ɛ2/2 and ɛ2/3 carriers had lower Aβ load (median frontal AB load = 0.30%, IQR: 0.02‐6.15), but not spread, compared to APOE ɛ2/4 and ɛ3/4 carriers (median frontal AB load = 5.08%, IQR: 2.13‐30.71) (p = 0.041), but not compared to ɛ3/3 carriers (median frontal AB load = 2.19%, IQR:0.23‐7.54) (p = 0.245). Higher Aβ load in all four analyzed regions associated with lower performance on the Digit Span Backward test (rfrontal = ‐0.29, rparietal = ‐0.29, rtemporal = ‐0.28, roccipital = ‐0.32, FDR corrected p<0.05) and the Clock Drawing test (rfrontal = ‐0.40, rparietal = ‐0.29, rtemporal = ‐0.29, roccipital = ‐0.33, FDR corrected p<0.05), which assess executive‐ and visuospatial‐functioning. Moreover, higher Aβ load in the frontal cortex correlated with lower performance on the Mini Mental State Examination (MMSE) (r = ‐0.24, p = 0.049) and a seperate composite score of global cognitive performance (r = ‐0.28, p = 0.019).ConclusionAlthough Aβ pathology seems nearly inevitable at extreme ages, our results suggest that Aβ load, rather than Aβ spread, affects cognitive performance in the oldest‐old1 https://doi.org/10.1002/alz.12899
2 https://doi.org/10.1212/wnl.58.12.1791
3 https://doi.org/10.1007/s10654-018-0451-3
APOE4 impairs microglia‐astrocyte response in Alzheimer’s disease by inducing TGFβ‐mediated checkpoints
Authors: Butovsky Oleg , Yin Zhuoran , Rosenzweig Neta , Kleemann Kilian , Zhang Xiaoming , Brandao Wesley N , Margeta Milica , Schroeder Caitlin M , Silveira Sebastian , Gauthier Christian , Mallah Dania , Pitts Kristen , Durao Ana , Herron Shawn , Shorey Hannah , Cheng Yiran , Barry Jen‐Li , Wakelin Sam , Rhee Jared , Yung Anthony , Aronchik Michael , Wang Chao , Jain Nimansha , Bao Xin , Gerrits Emma , Brouwer Nieske , Deik Amy , Tenen Daniel G. , Ikezu Tsuneya , Santander Nicolas G. , McKinsey Gabriel L. , Baufeld Caroline , Sheppard Dean , Krasemann Susanne , Eggen Bart , Clish Clary , Tanzi Rudolph E. , Madore Charlotte , Arnold Thomas D. , Holtzman David M. 
Published: December 2023

AbstractBackgroundAPOE ε4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD).MethodGeneration of CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl: APP/PS1 and APOE‐KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI, and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.ResultHere we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD‐astrocyte crosstalk associated with b‐amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex‐dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4‐mediated induction of ITGB8‐TGFb signaling impairs MGnD response via upregulation of TGFb‐mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD‐astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8‐TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice.ConclusionWe identify the microglial APOE4‐ITGB8‐TGFb pathway as a negative regulator of microglia‐astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8‐TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.
RNA‐seq study on the effect of MAPT rs242557 deletion in HMC3 cells
Authors: Das Rueben , Kuska Pavel P. , Lee Wan‐Ping , Choi Eirene , Jiang Ming , Dombroski Beth A. , Schellenberg Gerald D. 
Published: December 2023

AbstractBackgroundMicrotubule associated protein tau (MAPT) is associated with neurodegenerative diseases including Frontotemporal dementia (FTD), Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Multiple GWAS on AD, PD, PSP and CBD have identified strong signal in MAPT intronic region (SNP, rs242557). Being part of FANTOM5 enhancer in eye and brain, we are interested in the effect of this region in HMC3 (human microglial clone 3) cell line.MethodUsing CRISPR‐Cas9 genome editing, a clone was isolated having homozygous 309 bp deletion encompassing rs242557 and its flanking sequences in HMC3. Sanger sequencing confirmed the deletion while whole genome sequencing corroborated the same and also confirmed no off‐target effects. To identify gene transcripts whose expression was altered due to the deletion, paired‐end RNA‐seq was performed using total RNA extracted from rs242557 KO and wild type (WT) clones.ResultThere were 272 up‐ and 861 down‐regulated transcripts (p< = 0.01) between WT and KO cells. Down‐regulated transcripts include AD risk genes ICA1, EPDR1, PTK2B, SORL1, DOC2A, and TSPOAP1, and PD candidate gene, SNCA. Notable among up‐regulated transcripts was AD risk gene, CASS4. Enrichment analyses revealed biological processes and pathways that are related to structural constituents and organization of neurons and synapses. Currently, we are validating the transcript data.ConclusionOur preliminary data suggests that the genomic region encompassing rs242557 might affect multiple AD risk genes.
Prevalence of Mild cognitive impairment (MCI) in a rural Indian population and its association with hypertension, diabetes and depression
Authors: Partha Ajith , Stezin Albert , L Abhishek M , Mallikarjun Divya N , Hameed Shafeeq K Shahul , Narayanasamy Rajitha , R Meghana , Menon Meenakshi , M Amitha C , Arvind Prathima , Velavarajan Goutham , Singh Sadhana , HS Sunitha , Kommaddi Reddy Peera , Diwakar Latha , Malo Palash Kumar , Sundarakumar Jonas S. , Issac Thomas Gregor , Ravindranath Vijayalakshmi 
Published: December 2023

AbstractBackgroundMild cognitive impairment (MCI) is a transitional phase between normal cognitive ageing and dementia. The prevalence of MCI in rural populations is an understudied area. Risk factors such as hypertension, diabetes, and depression are more prevalent in rural areas, which can contribute to the development of MCI (Longfei et al, 2020). The purpose of this study is to find out the prevalence of MCI amongst a rural cohort and to study the relationship between MCI and hypertension, diabetes and depression.MethodCross sectional analysis on the subset of data taken from ongoing longitudinal study on dementia named Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) (Sundarakumar et al, 2020), which has a target of 10000 participants. MCI was diagnosed in the subject whose Clinical Dementia Rating (CDR) score was 0.5, as per the NIA‐AA (National Institute on Aging‐Alzheimer’s Association) criteria, 2011. Presence of hypertension and diabetes were collected through a structured clinical questionnaire. Depression was assessed using the Geriatric Depression Scale 30 (GDS‐30) and a score above 9 was considered as depression. Chi‐square analysis(χ2) was used to study the association between MCI and hypertension, diabetes and depression.ResultA total of 3789 participants were examined amongst which 293 had a CDR score of 0.5, indicating presence of MCI in 7.7% of the study group. Prevalence of depression in non‐MCI and MCI subjects was 14.91% and 30.73% respectively and depression was found to be significantly associated with MCI(χ2 =24.522, p< 0.001). Hypertension was seen in 13.83% of non‐MCI subjects and in 17.76% of subjects with MCI. Diabetes was seen in 16.93% of non‐MCI subjects and in 18.25% of subjects with MCI. Both hypertension (χ2 =2.086, p = 0.149) and diabetes (χ2=0.195, p = 0.659) were not significantly associated with MCI.ConclusionDepression was significantly associated with MCI. It is known that late onset depression, which is diagnosed above the age of 50, may be a predisposing factor for dementia in later life. Our results may indicate this relationship between depression and cognitive impairment. However, further longitudinal studies are necessary to evaluate causal relationship.
Cognitive Function based on Theta‐Gamma Coupling vs. Clinical Diagnosis in Older Adults with Mild Cognitive Impairment with or without Major Depressive Disorder
Authors: Brooks Heather , Wang Wei , Zomorrodi Reza , Blumberger Daniel M. , Bowie Christopher R , Daskalakis Zafiris J. , Fischer Corinne E. , Flint Alastair , Herrmann Nathan , Kumar Sanjeev , Lanctôt Krista L. , Mah Linda , Mulsant Benoit H. , Pollock Bruce G. , Voineskos Aristotle N. , Rajji Tarek K. ,   PACt‐MD Study Group
Published: December 2023

AbstractBackgroundWhether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase‐gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cut‐off is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC‐based groups than diagnostic groups.MethodWe analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N‐back task. An optimal TGC cut‐off was determined during performance of the 2‐back. This TGC cut‐off was used to classify participants into low vs. high TGC groups. We then compared the Cohen’s d of the difference in global cognition between the high and low TGC groups to the Cohen’s d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen’s d values using the whole sample.ResultAs hypothesized, Cohen’s d for the difference in global cognition between the TGC groups was larger (0.64 [0.32,0.88]) than between the diagnostic groups (0.10 [0.004,0.37]) with a difference between these two Cohen’s d’s of 0.54[0.10, 0.80].ConclusionOur findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline.
Subjective Cognitive Decline And Inflammation Among The Elderly
Authors: Gonçalves Eduardo C Q , Buchain Patricia Cardoso , Ribeiz Salma Rose Imanari , Kahtalian Lais Lundstedt , Marques Fernanda Mariotti , Filho Geraldo Busatto 
Published: December 2023

AbstractBackgroundSubjective cognitive decline (SCD) is a state of self‐perception of cognitive worsening compared to the normal state, without abnormalities on objective neuropsychological assessments. Since its definition in 2014, this condition has raised considerable interest, once those patients are at higher risk for developing objective cognitive decline, Alzheimer disease and other types of dementia (JESSEN 2020). The inflammatory cytokine network is associated with aging‐related diseases, and changes in the release of these substances may impact higher brain functions, such as mood and cognition (NG 2018).MethodUsers of basic healthcare units aged 60 years and over without dementia (MMSE≥14) and non‐depressed (CES‐D<16) from a community sample in São Paulo were assessed with a questionnaire about perceived memory problems (“have you had memory problems lately?”) and for sociodemographic data, cognitive and depression screening. Serum samples were collected for dosages of C‐reactive protein (RCP), interferon gamma (IG) and interleukines (IL) 1, 4 and 10.ResultOut of the 529 elderly evaluated in the study, 286 were women, of which 112 (39,1%) had SCD, and 243 men, with 89 (36,6%) having SCD. The SCD group had a mean age of 69.8 years old and a mean of 8.4 years of education, contrasting with 68.3 years of age and 5.07 years of education among those without SCD. The mean age difference was statistically significant. The SCD group had a slightly lower mean dosage of IL‐1 and higher mean dosages of IL 4 and 10, IG and RCP, but only the latter reached statistical significance.ConclusionOur study represents a step further towards understanding the pathophysiology of SCD, as this preclinical condition could be a target of future early interventions for Alzheimer’s disease and other dementia syndromes.References:Jessen F, Amariglio RE et al. The characterisation of subjective cognitive decline. Lancet Neurol. 2020 Mar;19(3):271‐278. https://doi.org/10.1016/S1474-4422(19)30368-0.Ng A et al. IL‐1β, IL‐6, TNF‐ α and CRP in Elderly Patients with Depression or Alzheimer’s disease: Systematic Review and Meta‐Analysis. Sci Rep. 2018 Aug 13;8(1):12050. https://doi.org/10.1038/s41598-018-30487-6.
Effect of APOE ε4 and its modification by sociodemographic characteristics on cognitive measures in South Asians from LASI‐DAD
Authors: Wang Yi Zhe , Zhao Wei , Dey Aparajit Ballav , Lee Jinkook , Smith Jennifer A , Kardia Sharon L R 
Published: December 2023

AbstractBackgroundThe ε4 allele of the apolipoprotein E (APOE) gene is the most significant genetic risk factor for dementia in nearly all human populations. However, the effects of APOE ε4 on late‐life cognitive function and its potential modification by sociodemographic factors have not been extensively studied in South Asians. We investigated the effects of APOE ε4 and its interaction with sociodemographic characteristics on cognitive measures in 2,607 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI‐DAD).MethodWe determined APOE ε4 carrier status from rs429358 and rs7412 genotypes in whole genome sequencing data. We first examined the main effects of APOE ε4 on seven cognitive measures, including five broad cognitive domain scores, a general cognitive function summary score, and the Hindi Mental State Examination (HMSE) score using linear regression models. Model 1 adjusted for age, sex, state of residence, and the first 10 genetic principal components (PCs). Model 2 additionally adjusted for education level, literacy, and urban/rural residence. We then tested for interaction between APOE ε4 and sociodemographic factors (age, sex, and education) through cross‐product terms, and further evaluated significant interactions (p<0.05) using stratified analysis.ResultAPOE ε4 was inversely associated with all cognitive measures except visuospatial function in the full sample in Model 1 after Bonferroni correction (p<0.007), all of which remained nominally significant in Model 2 (p<0.05). For example, APOE ε4 carrier status was associated with a decrease in the HMSE score of 0.77 points (p = 1.6×10−4) and a decrease in general cognitive function score of 0.09 standard deviations (p = 0.001) in Model 2. Furthermore, interaction tests showed that the effect of APOE ε4 was stronger in females than males for memory (ßAPOE ε4_male = ‐0.121, βAPOE ε4_female = ‐0.177) and language/fluency (βAPOE ε4_male = 0.075, βAPOE ε4_female = ‐0.125), and stratified analysis indicated that the APOE ε4 effects were significant only in females (p<0.05).ConclusionAPOE ε4 is associated with lower cognitive function in older South Asians from India. For memory and language/fluency, this association is stronger in females than males.