bluuebunny/crossref_metadata_2025_split huggingface dataset:
Facilitating the use of the target product profile in academic research
Authors: Ibnidris Aliaa , Streffer Johannes , Rea Mike , Gold Michael , Bot Sjaak , Teipel Stefan , Gardiol Alex , Boccardi Marina 
Published: December 2023

AbstractBackgroundTarget product profiles (TPP) were first defined by industry and supported by FDA to address user needs and guide communication in all phases of drug development. However, heterogeneity in practical use hurdles uptake in academic research. Our study aims to facilitate uptake by outlining a reference template to be adapted to dementia research.MethodsWe conducted a systematic review to extract structural characteristics, along with differences and commonalities across TPPs used in different product development (e.g., drugs vs diagnostics). We included data from peer‐reviewed publications on TPPs
content
(i.e., developing, revising, or mentioning a TPP),
product
type (drug, diagnostics, vaccine, medical device, other),
disease category
(infectious, non‐infectious diseases),
specific disease
, TPP
features
of the target profile, and
levels of compliance
for each feature.Results327 of 1297 identified records were eligible for full‐text review. Preliminary data extraction from 20 papers shows that:
Content
: 45% (n = 9) developed a new TPP, 10% (n = 2) revised a predefined TPP; 45% only mentioned TPPs (n = 9).
Product
: of the nine papers that developed a new TPP, 77.8% (n = 7) were for drug and 22.2% (n = 2) for diagnostics development.
Disease category
: 70% (n = 14) used TPPs in infectious diseases while 30% (n = 6) were in non‐infectious diseases. So far, no publication reported using TPPs in dementia. TPP
features
for different product types from the 11 publications that developed or revised TPPs: 39 features were extracted from TPPs for diagnostic development, 11 of which (28%) were in common. We extracted 35 features from TPPs for drug development, 9 of which (27.5%) were in common.
Levels of compliance
ranged between one (n = 5, 45.5%) to two (n = 5, 45.5%) levels, corresponding to conservative and optimistic levels. One (9%) did not report targeted levels of compliance.ConclusionTPPs are not frequently used by academic researchers. Despite being a useful tool enhancing product development, its considerable heterogeneity in structure renders its adaptation challenging. Completing data extraction and comparing the outcome with opinion leader’s assessment and formal guidance (e.g., from WHO) will facilitate drawing a comprehensive picture of common TPP features to derive a consistent and comprehensive template and facilitate its use in academic dementia research.
Relationship between metabolic disease and Alzheimer’s disease
Authors: Arvanitakis Zoe 
Published: December 2023

AbstractBackgroundDiabetes is an enormous and growing global public health problem, associated with poor health outcomes including dementia. Mechanisms underlying the relationship of diabetes to dementia are less well understood.MethodsWe leveraged several large, ongoing community‐based cohorts of older women and men with and without diabetes, taking part in longitudinal, clinical‐pathologic studies of aging at the Rush Alzheimer’s Disease Center. Participants undergo annual clinical evaluations including detailed neuropsychological testing, and brain autopsy at time of death. We examined the relation of diabetes and related clinical variables (e.g., medications, body mass index [BMI], hypertension), and blood and brain biomarkers of insulin resistance and other measures (e.g., epigenetics), to brain outcomes. Level and change in global cognition and five cognitive domains were based on neuropsychological tests, and dementia status was classified. Postmortem human brain specimens of deceased persons were systematically evaluated for neuropathology, including neurodegenerative (e.g., Alzheimer’s disease [AD]) and cerebrovascular disease (e.g., infarcts).ResultsDiabetes, present in 15‐20% of our cohorts, is associated a two‐fold increased risk of dementia and relates to cognitive decline (particularly in some cognitive domains more than others), and these observations are found in both Black and White participants. Some diabetes‐related clinical variables (e.g., BMI) are associated with faster cognitive decline, while others such as medications (metformin) are associated with slower cognitive decline. Regarding human postmortem neuropathologic outcomes, diabetes is associated with cerebrovascular pathologies, and small subcortical infarcts in particular. But, while we have not found clear associations of diabetes with neurodegenerative pathologies such as AD, some brain molecular markers in the insulin signaling pathway (AKT1) are associated with AD (including amyloid‐beta and tau tangles) and cognition (memory). Recently, using blood and brain specimens, we show that genome‐wide 5‐hydroxymethylcytosine profiling uncovers epigenetic features and biologic pathways related to nucleotide sugar metabolism linking diabetes to diabetes‐associated AD.ConclusionDiabetes is a potentially‐modifiable risk factor for dementia and cognitive decline. Clinical, neuropathologic, and epigenetic factors are at play in the underlying mechanisms. A better understanding of mechanisms will inform future research and offer opportunities for precision medicine and dementia prevention (supported by NIH: R01NS084965, RF1AG059621, RF1AG074549, R01AG022018, P30AG10161, P30AG072975, R01AG15819, R01AG17917).
The role of the blood‐brain barrier in brain insulin signaling
Authors: Calon Frederic 
Published: December 2023

AbstractBackgroundDefects in central response to insulin is suspected to play a role in AD. However, to act on the brain, pancreas‐secreted insulin must interact first with the blood‐brain barrier (BBB). The insulin receptor (INSR) consists in 2 insulin‐binding extracellular α chains, either short (INSRα‐A) or long (INSRα‐B) isoforms, as well as 2 intracellular β‐chains (INSRβ) containing auto‐phosphorylation sites. The aim of the present study was to better understand the role of INSR located on the BBB in AD.MethodWe used microvessel‐enriched brain samples from individuals classified as Controls, MCI or AD and from 3xTg‐AD mice from different ages. In situ cerebral perfusion was used to directly assess the interaction between circulating insulin and the BBB.ResultsWe first show that INSR in human and mouse brains are concentrated in blood microvessels, with INSRα‐B being almost absent from the parenchymal fractions. Lower levels of INSRα‐B were observed in microvessel extracts from the parietal cortex of AD persons, associated with cognitive decline. The resulting shift toward a higher INSRα‐A:INSRα‐B ratio is consistent with insulin resistance situated on the BBB. Intracarotid infusion of insulin induced a rapid phosphorylation of INSRβ retrieved from cerebrovascular extracts, but not from parenchymal extracts of the mouse brain. In the 3xTg‐AD mouse model of AD neuropathology, lower levels of cerebrovascular INSRα‐B were observed whereas activation of INSRβ was blunted upon intracarotid administration of insulin. Finally, we provide some insights on a possible association between BACE1 activation and the reduction of cerebrovascular INSR.ConclusionOverall, data gathered from postmortem AD brains and an animal model of AD neuropathology suggest that brain insulin resistance in AD may occur at the level of INSR located on microvessels. These results also indicate that INSR and its downstream signaling within endothelial cells of the BBB are systemically accessible drug targets in AD.
Effect modification of the association between BMI and cognition in India
Authors: Nichols Emma , Deal Jennifer A , Gross Alden L. , Lee Jinkook 
Published: December 2023

AbstractBackgroundHigh body‐mass index in midlife is an established risk factor for poor cognition and dementia. While most evidence supporting the association between high BMI and dementia comes from high‐income countries, 60% of global dementia cases are expected to be in low‐ and middle‐income countries by 2050. Existing evidence from India suggests higher BMI is associated with better cognition and lower odds of dementia. We sought to replicate these findings and investigate effect modification by age, rurality, and education to better contextualize results.MethodWe used cross‐sectional data from the Longitudinal Aging Study in India (N = 57,164). We used weighted linear regression models to assess associations between latent cognitive functioning, estimated from confirmatory factor analysis models, and BMI category. We compared unadjusted models to models controlling for age, sex, rurality, state, literacy, education, per capita consumption quintile, parental education, smoking, and depressive symptoms. We investigated effect modification by age, rurality, and education.ResultCompared to unadjusted models, estimated associations from multivariable models were substantially attenuated but remained statistically significant. Underweight BMI was associated with lower cognitive scores and overweight and obesity were associated with higher cognitive scores (underweight = ‐0.16 SD units [‐0.18‐ ‐0.14]; overweight = 0.10 [0.09‐0.12]; obese = 0.13 [0.11‐0.16]). For participants in urban settings or with higher educational attainment, associations between cognition and overweight and obesity were smaller and not statistically significant for those with tertiary education. A global ANOVA test for effect modification was statistically significant for rurality (p<0.01), trending towards significance for education (p = 0.09), but not significant for age category (p = 0.31).ConclusionCounter to findings in high‐income settings, but consistent with prior findings in India, high BMI was associated with higher cognitive performance. Lack of evidence for effect modification by age and the association between low BMI (underweight) and lower cognition, indicate reverse causation due to weight loss in early disease stages is unlikely to explain results. Instead, strong attenuation of effects with confounder control and effect modification by rurality and education indicate that associations could be due to the clustering of access to fat‐enriched foods with other factors that are beneficial for health, such as higher education and access to healthcare.
Carnosine supplementation improves delayed recall: a systematic review and meta‐analysis
Authors: Bell Simon M , Hariharan Rohit , Laud Peter , Majid Arshad , Courten Barbora 
Published: December 2023

AbstractBackgroundCarnosine is a histidine‐containing dipeptide found in human muscle tissue and other organs like the brain. Data in rodents and humans indicate that administration of exogenous carnosine improved cognitive performance. However, RCTs results RCTs vary.MethodsWe searched OVID Medline, Medline, EBM Reviews, Embase, and Cumulative Index to Nursing and Allied Health Literature databases from 1/1/1965 to 1/6/2022 for all RCT of carnosine and other histidine‐containing dipeptides. 2653 abstracts were screened, identifying ninety‐four full‐text articles which were assessed for eligibility. 11 articles reporting use of carnosine supplementation were meta‐analysed. The random effects model has been applied using the DerSimonian‐Laird method.ResultsCarnosine treatment significantly increased performance on Wechsler Memory Scale (WMS) ‐2 Delayed recall (Z = 3.28, p<0.01). Treatment with carnosine had no effect on Alzheimer’s Disease Assessment Scale‐Cognitive (Weighted mean difference (WMD) (95% CI) = ‐0.2 (‐1.1, 0.7), P = 0.65, I2 = 0%), Mini‐Mental State Examination (WMD (95% CI) = 0.7 (‐0.2, 1.5), P = 0.14, I2 = 42%), The Wechsler Adult Intelligence Scale (WAIS) Digit span Backward (95% CI) = 0.1 (‐0.3, 0.5), P = 0.51, I2 = 0%), WAIS digit span Forward (WMD (95% CI) = 0.0 (‐0.3, 0.4), P = 0.85, I2 = 33%) and the WMS‐1 Immediate recall (WMD (95% CI) = 0.7 (‐0.2, 1.5), P = 0.11, I2 = 0%). The effect on delayed recall remained in subgroup meta‐analysis performed on studies of patients without mild cognitive impairment (MCI), and in those without MCI where average age in the study was above 65.ConclusionsCarnosine supplementation improved scores on the Delayed recall examination, a neuropsychological test affected early in Alzheimer’s disease. Further studies are needed in people with early cognitive impairment with longer follow‐up duration and standardisation of carnosine doses to delineate the true effect.
INVOKE‐2: Phase 2 trial of a TREM2 mAb in Early AD
Authors: Romano Gary , Mayorga Arthur , Simmons Adam , Burgess Brady , Grundman Michael , Gao Jinjing 
Published: December 2023

AbstractAL002 is an investigational, humanized monoclonal antibody that targets triggering receptor on myeloid cells 2 (TREM2) and is currently under development for the treatment of early Alzheimer’s disease. The INVOKE‐2 trial is an ongoing global Phase 2 randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of AL002 in participants with early Alzheimer’s disease. This presentation will provide an update on AL002 clinical development.
Symptomatic Alzheimer’s Disease Therapy Utilization in 3 National Cohorts
Authors: DiBello Julia R , Zhong Wenjun , Ma Jiemin , Goto Daisuke , Liu Xinyue 
Published: December 2023

AbstractBackgroundAlthough the positive results of the first disease modifying therapies is anticipated to moderately slow disease progression, significant need remains for cognitive enhancers to address AD symptoms and improve quality of life. Despite potential benefits of current treatments, the literature suggests that a large percentage (40‐60%) of AD patients do not use symptomatic treatments for AD and treatment patterns may have considerable geographic variation.MethodPatients with AD (ICD‐10 code G30 or READ code for AD) in 2018‐2019, with ≥1‐year baseline period before index date (first AD diagnosis date during 2018‐2019) and ≥1‐year follow‐up after the index date were selected from the US Humana Research Database (Humana) and the UK Clinical Practice Research Datalink GOLD (CPRD). Patients with an AD diagnosis during the baseline period were excluded. Within the Japan Medical Data Vision (MDV) database, an ICD‐10 code for AD (G30) was required prior to/on the same date as the first provider visit with an associated prescription for a specified AD medication during the 2018‐2020 study period (defined as the index date). Patients with AD medication visits ≤6 months before the index date were excluded. Percentages of patients initiating donepezil, rivastigmine, galantamine, and memantine, median time on first therapy, and use of a second therapy were calculated.ResultAD therapy was initiated by 35,459, 8,901, and 51,115, patients in the US, UK, and Japan, respectively. Sixty‐three percent were female, in the US and UK, and 59% in Japan; mean age ranged from 81‐82 years. Donepezil was used most frequently (69%, 61%, and 50%), followed by memantine monotherapy (19%, 28%, and 22%) in the US, UK, and Japan, respectively. Median time on first therapy was 213, 334, and 111 days, and a second treatment was used by 30%, 12%, and 10%, respectively.ConclusionIn contemporary cohorts of US, UK, and Japanese individuals newly initiating symptomatic AD therapy, donepezil was the most frequently used therapy followed by memantine monotherapy. Time on first therapy was relatively short (<1 year) and the majority of patients did not utilize a second therapy. These results underscore the unmet need for additional therapies to alleviate the significant burden of AD.
The relationship between ApoE4 and lipid dysregulation in glia of the PS19 mouse model of tauopathy
Authors: Litvinchuk Alexandra 
Published: December 2023

AbstractBackgroundApolipoprotein E4 (apoE), the major lipoprotein in the brain, plays an essential role in brain`s lipid homeostasis; furthermore, the presence of the apoE4 allele is the strongest genetic risk factor for developing late‐onset AD compared to most common apoE3 and protective apoE2 alleles. Recent studies in iPSC microglia and astrocytes demonstrate that apoE modulates cholesterol dysfunction and inflammatory responses in an isoform‐specific fashion. However, it is not known if lipid accumulation in glia mediates toxic effects in vivo in the context of tauopathy and neurodegeneration.MethodIn this work we used the combination unbiased lipidomics coupled with immunostainings to dissect the role of apoE and apoE isoforms in glial lipid metabolism of tauopathy P301S tau transgenic mice with a targeted replacement of murine apoE with human ApoE4, ApoE3, or ApoE KO. We further treated the P301S/ApoE4 mice with the LXR agonist GW3965 to test if promoting cholesterol efflux in P301S mice would reduce tau pathology and neurodegeneration in this model.ResultsBy performing unbiased lipidomic analysis of forebrain samples, we demonstrate that P301S/ApoE KI mice accumulate significant amounts of specific cholesteryl esters, oxidized sterols and endolysosomal BMP lipids in an ApoE‐isoform and Tau‐dependent manner. We further show that microglia from aged 9.5 months old P301S/ApoE4 mice accumulate significant amounts of neutral BODIPY‐positive lipid inclusions within lysosomes. Next, we demonstrate that the oral administration of the LXR agonist GW3965 for 3 months significantly reduces p‐tau‐positive AT8 immunostaining in cortex and hippocampus, protects from associated brain neurodegeneration, and improves nesting behavior in 9.5 months old P301S/ApoE4 mice. Using bulk RNA sequencing and immunostaining, we show that LXR agonist diet induces changes in cholesterol biosynthesis and metabolism that result in a significant reduction of neuroinflammatory responses in aged P301S/ApoE4 mice. Lastly, using unbiased lipidomics of forebrain tissues we demonstrate that P301S/ApoE4 mice on LXR diet exhibit significantly lower levels of cholesterol esters when compared to tau transgenic animals on control diet.ConclusionsTogether, we demonstrate that ApoE4 promotes lipid accumulation in glia in the setting of tauopathy and that reducing the accumulation of these lipids by LXR activation is neuroprotective.
COVID‐19 Infection and Dementia: Analyses of time‐varying risk, subtypes, and subpopulations from the UK Biobank
Authors: Cao Yaying , Feng Chengwu , Chen Jing , Liu Yunman , Sheng Aili , Li Shuai , Hu Yonghua , Yuan Changzheng , Xie Junqing , Zong Geng 
Published: December 2023

AbstractBackgroundAlthough COVID‐19 patients were suggested to experience worse cognitive outcomes, there is a paucity of evidence on time‐varying risk of dementia, especially the subtypes, as well as among critical subpopulations.MethodOut of over 50,000 individuals from a general population in the UK Biobank, SARS‐COV‐2 infected patients between March 1, 2020, and July 31, 2021 and maximally 5:1 propensity score matched contemporary non‐infected individuals were selected, with baseline dementia cases excluded. Matching was done on demographic characteristics, lifestyle, and comorbidities. Dementia was captured according to primary care, inpatient records, and death registry, with the follow‐up ending at the earliest of outcome occurrence, death, or August 31, 2021. Associations were evaluated using time‐varying hazard ratios (HRs) and odds ratios (ORs).ResultWith a mean age of 65.0 years for 18,032 COVID‐19 patients and 83,008 controls, participants were followed for a median of 247 (IQR: 204‐305) days and 255 dementia cases occurred, including 90 Alzheimer’s disease (AD) cases and 42 vascular dementia cases. Compared with matched controls, COVID‐19 infection was associated with increased risks of dementia during the acute phase (first 30 days), with HRs (95% CIs) being 12.77 (6.77, 24.08) for all‐cause dementia, 9.21 (2.77, 30.59) for AD, 5.53 (1.69, 18.11) for vascular dementia, and 25.35 (8.74, 73.56) for other dementia. Dementia risk declined drastically after COVID‐19 infection and sustained for all‐cause dementia, vascular dementia, and other dementia, while became non‐significant for AD. Among those not hospitalized during the acute phase, elevated dementia risk in the follow‐up remained for all‐cause dementia, vascular dementia, and other dementia, with ORs being 1.82, 4.55, and 1.64, respectively. Among most of the subpopulations classified by demographic characteristics, APOE genotype, and comorbidities (except for those with baseline chronic obstructive pulmonary diseases), COVID‐19 infection was associated with an elevated all‐cause dementia risk and no modification effect was detected.ConclusionDeclined yet sustained elevated dementia risk since COVID‐19 infection was found, with differential trends for dementia subtypes. Increased dementia risk from COVID‐19 infection also applied for the non‐hospitalized during the acute phase and most subpopulations. The potential dementia risk associated with Omicron variants warrants further evaluation.
Mitigating risks of online engagement; considering the contexts and mechanisms of cybercrime among older adults
Authors: Burton Alexandra , Tripathi Kartikeya , Cooper Claudia 
Published: December 2023

AbstractBackgroundThis talk will explore how benefits of remote interventions can be realised for older people with cognitive impairments alongside risk mitigation, drawing on a realist review of how and in what circumstances older people become victims of cybercrime. We aimed to identify factors leading to older adults' victimisation, and review theory and evidence for interventions to reduce victimisation risks.MethodWe conducted a realist review synthesising published literature and gathering stakeholder experiences via an online workshop to understand how, why and in what circumstances older adults are at risk of financial cybercrime victimisation. We used the evidence to develop a programme theory and Context, Mechanism, Outcome Configurations (CMOCs) to explain the mechanisms by which older adults become victims of financial cybercrime in different contexts, and to inform the development of interventions to produce desired outcomes of reducing and preventing cybercrime.ResultWe analysed 52 primary and secondary data sources and consulted with 21 stakeholders from across health, social, legal, and financial sectors. Our programme theory comprised 16 CMOCs describing how social isolation, cognitive decline, physical and mental health problems; wealth status, limited cyber security skills or awareness, societal attitudes and content of scams led to increased risk of victimisation. Only evidence for interventions to enhance cyber security awareness and skills of potential older victims was identified. Targeting offender motivation, redesign of security software to increase usability by older people and training programmes for professionals and family members are rational, yet untested interventions. A shift in societal attitudes, conveying positive messages, of older people’s rights to be safely active online, is needed too.ConclusionProtection from cybercrime is instrumental to supporting ageing in a digital world. Incorporating cyber security awareness into future interventions that promote social connectedness, cognition and healthy lifestyles, alongside legal structural protections, and measures to improve societal attitudes towards financial cybercrime victimisation will help older adults navigate online spaces safely. Training programmes targeting older adults, or their supporters should be deliverable by a range of professionals for greatest reach; and be co‐designed with end users to ensure that if they are useful, they are acceptable and used.