bluuebunny/crossref_metadata_2025_split huggingface dataset:
The international network of scholars of the US‐based Living Alone with Cognitive Impairment Project: advantages, methods, and lessons learned
Authors: Portacolone Elena 
Published: December 2023

AbstractBackgroundEstablishing international networks allows researchers of Alzheimer’s disease and related dementias (ADRD) to draw lessons from foreign best practices in terms of policies, programs, interventions, and study design, thus broadening perspectives. A broad perspective is essential to design studies efficiently. Furthermore, international comparisons spurred by international networks can point to the advantages oand shortcoming of national policies and programs. Despite the importance of developing international networks and collaborations, researchers often do not leverage the opportunity to develop international research networks of scholars with comparable research interests. This session will draw from the expertise gained by the research team of the 5‐year US‐based Living Alone with Cognitive Impairment Project to develop and establish an international advisory group advising on the design of their mixed‐method study.MethodIn the first year of the 5‐year project (2021) we convened an International Advisory Group and then 4 plenary meetings with its 15 members which include scholars from all continents, plus an officer of the World Health Organization.ResultRegular interactions between the research team and the International Advisory Group led to: 1) systematic review of the international literature on services available to older adults living alone with cognitive impairment; 2) a seminar series of work‐in‐progress seminars; 2) a grant submission to fund an international conference; 3) enhanced design of the US‐based project (e.g., unplanned new research questions).ConclusionThe oversight, and regular engagement, of an International Advisory Group has allowed the Living Alone with Cognitive Impairment Project to better understand the advantages and shortcoming of US‐policies and programs to support older adults living alone with cognitive impairment. The practice of establishing an international advisory group can be easily replicated by researchers in studies supporting underserved populations with cognitive impairment.
Statin therapy reduces the risk of AD: Clinic to bench translation for protective mechanism
Authors: Torrandell‐Haro Georgina , Chen Shuhua , Brinton Roberta Diaz 
Published: December 2023

AbstractBackgroundCholesterol dysregulation is a well‐documented factor involved in the pathophysiology of Alzheimer’s Disease (AD). APOE4, which is involved in cholesterol transport, is recognized as the strongest genetic risk factor for late‐onset AD. In a previous study using clinical data, we showed that exposure to statins, a first‐line cholesterol lowering therapeutic, was associated with a reduced risk of developing AD. Another study showed the risk reduction associated with statins was greater in APOE4 carriers. Although the effects of statins in the periphery are well documented, the mechanisms by which statins act in the brain remain poorly understood.MethodThis study aimed to identify potential mechanisms by which statins impact AD pathology at a cellular level and the different response by APOE genotype. Humanized APP/APOE3 and APOE4 mouse neurons and astrocytes were co‐cultured and treated with vehicle or atorvastatin at clinically relevant concentrations. Metabolic flux analysis was used to determine the impact of statins on mitochondrial bioenergetics and dynamics. Multi‐electrode array (MEA) was used to conduct electrophysiological recordings on hippocampal neurons. Lipid droplet burden in astrocytic cells was determined using LipidTOX staining and confocal microscopy. qPCR and Western Blot were used to determine the expression of key proteins involved in cholesterol transport.ResultIn this study, hippocampal neurons treated with atorvastatin in the presence of astrocytic cells induced a significant increase in the number of spikes and spike frequency, as well as the number of bursts and number of spikes within a burst. In contrast, in the absence of astrocytes atorvastatin exposure in neurons did not exhibit a significant difference compared to vehicle. Electrophysiological properties were increased in a dose‐dependent manner and the effect was greater 24‐hours following treatment. Atorvastatin also increased astrocyte mitochondrial respiration whereas it did not in neurons or in neurons co‐cultured with astrocytes.ConclusionOutcomes of these analyses indicated that atorvastatin acts primarily on astrocytes. Specifically, atorvastatin increased mitochondrial respiration in astrocytes and increased synaptic activity on neurons which was astrocyte dependent. These results provide evidence of a neuroprotective role of atorvastatin by regulating lipid metabolism deficits in a cell‐specific manner.Acknowledgments: NIA P01AG026572 and R01AG057931 to RDB.
Computational identification of precision therapeutics for Alzheimer’s disease specific to endocrine and APOE genotype status
Authors: Vitali Francesca , Zhang Jessica , Wang Tian , Brinton Roberta Diaz 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) affects 6.5 million people in the US, two‐thirds of which are women. Despite extensive research, there are currently no highly effective treatments for AD. The greatest risk factors for AD are age, chromosomal female sex and APOEε4 genotype. A key driver of chronological and endocrinological aging is the activation of innate and adaptive immune systems occurring in midlife female brain. To effectively prevent and treat AD, it is crucial to develop computational methods that take into account these factors and screen for personalized therapeutics.MethodRNAseq data of 15‐month acyclic vs 9‐month regular APOEε3/ε3 and APOEε4/ε4 female mouse models were analyzed to identify APOE‐specific Differentially Expressed Genes (DEGs, pvalue<.01). STRING Protein‐Protein Interaction (PPI) database was used to extract protein interactors for the two APOEε3/ε3 and APOEε4/ε4 DEG lists and construct two APOE‐specific AD PPI networks. Target Proteins (TPs) candidates in each network were identified using the DrugBank database by selecting only proteins targeted by at least one FDA‐approved drug. A score of drug synergy was developed to rank FDA‐approved drugs based on the number of target proteins in‐ vs out‐ of the APOE‐AD specific networks and their distance to DEG nodes.ResultFrom RNAseq analyses, we identified a total of 265 DEGs for APOEε3/ε3 and 452 DEGs for APOEε4/ε4 genotype. The APOE‐AD‐specific PPI networks resulted in 1,711 nodes (proteins) and 21,445 edges (PPIs) for the APOEε3/ε3 genotype and 2,841 nodes and 35,493 edges for APOEε4/ε4 genotype. Using the DrugBank database, 342 and 568 potential therapeutic targets were identified in the APOEε3/ε3 and APOEε4/ε4 networks, respectively. Finally, drug synergy score enabled ranking 99 therapeutics for APOEε3/ε3 network and 102 drugs for APOEε4/ε4 network, of which 19 resulted in both lists.ConclusionThis study presents a network‐based approach for identifying personalized therapeutics for AD based on endocrine transition changes and APOE genotype. The results suggest that there is greater transcriptomic dysregulation in female APOEε4/ε4 brains compared to APOEε3/ε3 brains. The proposed computational approach has the potential to advance precision medicine for the prevention and treatment of AD, and future research will focus on identifying the most effective combinations of therapeutics.
One scale, different apathy? Specific neuroanatomical substrates of apathy in dementia
Authors: Mariano Luciano Inácio , Oliveira Maciel Thiago , Caramelli Paulo , Souza Leonardo Cruz 
Published: December 2023

AbstractBackgroundApathy is a multidimensional neuropsychiatric feature that affect behaviour, cognition, and emotional reaction. Hence exploring its neuroanatomic substrates offers the possibility of understanding the variability of this symptom.Method20 Healthy Controls (HC), 19 patients with AD and 20 patients with bvFTD, matched for age, sex, education, and time of disease were included. Participants underwent a full clinical and neuropsychological assessment and a 3T MRI acquisition. Neuroimaging was processed in the FreeSurfer software, and cortical thickness (CTh) was obtained for 68 cortical regions (34 per hemisphere) for each participant. An index was calculated by dividing the raw volume for the intracranial total volume (ITV) to account for individual variability. This index was then correlated with each group’s Starkstein Apathy Score (SAS). A linear regression model controlled for general cognition, executive function, memory function, and social cognition function.ResultAD and bvFTD had a worse cognitive performance, with bvFTD presenting a slightly more dysexecutive profile than AD. The regression model showed that the apathy in AD is associated with the CTh of the Left Entorhinal cortex (F(1,31) = 5,165; p = 0.030; R2 = 0.527). For bvFTD, the regression model found that SAS correlated with the Right Lateral Orbitofrontal cortex (F(1,30) = 5.69319; p = .009; R2 = .804); the Right Rostral Anterior Cingulate (F(1,29) = 4.95855; p = .003; R2 = .856); the Left Lateral Orbitofrontal (F(1,28) = 4.67979; p = .042; R2 = .877); the Left Precentral cortex (F(1,27) = 4.34826; p = .027; R2 = .897); and the Left Postcentral cortex (F1,26) = 3.98166; p = .019; R2 = .917).ConclusionsOur results show that apathy is associated with specific cortical regions according to each disorder. For AD, apathy is related to the entorhinal cortex, even when controlling for mnemonic performance. In contrast to the single cortical region found in AD, bvFTD had several, indicating how more complex it is in the condition and possibly explaining why apathy is harder on bvFTD than AD. Generally, regions associated with apathy in bvFTD relate to social cognition, inhibitory control, behavioural activation and somatosensorial processing. The different pattern of cortical regions associated with apathy maps how plural apathy is and the need to consider its differences for each disease.
Indigenous individuals present distinct modifiable risk factors of dementia than white individuals: an ELSI‐Brazil study
Authors: Formoso Carolina Rodrigues , Borelli Wyllians Vendramini , Rosa‐Neto Pedro , Ferreira Pamela C.L. , Pascoal Tharick A. , Castilhos Raphael Machado , Zimmer Eduardo R 
Published: December 2023

AbstractBackgroundRisk factors for dementia have distinct frequency and impact according to racial origins. Our aim was to identify differences of modifiable risk factors of dementia related to Indigenous and White individuals, estimate their Population Attributable Fraction (PAF) and highlight the differences between races.MethodsAn epidemiological cohort named ELSI‐Brazil was used to estimate the prevalence of 10 modifiable risk factors for dementia among 2 races ‐ White and Indigenous. he ELSI‐Brazil cohort consists of 9412 individuals (63.55+‐10.14 years of age). This cohort comprises individuals at/ or above 50 years of age from across the country. Complex sampling warrants nationwide representativity for diseases with low prevalence. Races were self‐reported according to the Brazilian Census. Sample weighting was used to estimate the prevalence and PAF of each risk factor in each race.ResultsAmong 3810 individuals included, 220 were Indigenous individuals. The Indigenous were younger (mean age 62.6 [±9.6] years) and less educated (mean 4.3 [±4.0] years) than the White (mean age 64 years [±10.2], mean education years 6.2 [±4.4]). Both were composed by most females. The most important weighted PAF were hearing loss for both races (Indigenous 16.7%; White 15.2%). The most prevalent risk factor for both were less education, which were higher in Indigenous individuals (69.5%) than in White individuals (55.1%). By contrast, social isolation was less prevalent in Indigenous (1.5%) than White (5.1%). Overall adjusted PAF was lower in Indigneous (38.9%), compared to White (49,2%).ConclusionWhite and Indigenous presented different prevalence of risk factors, though they had hearing loss as the most impacting risk factor for dementia. However, it seemed that Ocidental risk factors didn’t produce the same effect in indigenous individuals as in white individuals. Thus, indigenous individuals presented a distinct profile of risk factors of dementia than individuals from other self‐reported races.
Impact of the pandemic time on the mental health of Chilean caregivers: 1‐year follow‐up preliminary results
Authors: Olavarria Loreto , Loyola Walter Sepúlveda , Caramelli Paulo , Barbosa Maira Tonidandel , Andrade Caíssa , Lema Jose , Slachevsky Andrea 
Published: December 2023

AbstractBackgroundThe worldwide COVID‐19 pandemic has been a major challenge for the health system in the past years. From March 2020 until 2022 there were extensive lockdowns in Latin America to ensure physical distance and reduce virus transmission. Previous studies reported the negative impact of social isolation on people living with dementia, however, the impact on caregivers has been little studied so far. This study analyses the mental impact of the pandemic time on caregivers of people with dementia.MethodIn order to evaluate clinical and behavioral changes from the prior assessment conducted in 2020 with people with dementia and their family caregivers, a 1‐year follow‐up phone study was conducted with the same sample from the previous research. Participants from Chile were assessed by two semi‐structured questionnaires.Results106 caregivers of patients with dementia were interviewed during the year 2020 (age: 73.3 ± 9.5 years; female: 57%). After one year of follow‐up, 61 caregivers were contacted. Compared to baseline, after one year of follow‐up, 75% % of the caregivers reported worse physical and mental health (p:0.028), 56% more sadness associated with patient care (p:0.001); 93% reduced sleeping time (p:0.07) and 51% received more help to care the patient with dementia (p:0.036). Results are reported in table 1.ConclusionAlthough the caregiver had more daily assistance in 2021 compared with 2020, the pandemic time had a negative impact on their physical and psychological health. Even if these results might be explained by the normal evolution of dementia, the follow‐up results did not show a significant behavioral change in the person with dementia, and so the changes in the caregiver might be more a consequence of the pandemic rather than exclusively the disease.
Arterial spin‐labeling spatial coefficient of variation is associated with cerebral small vessel disease
Authors: Robb W Hudson , Kim Darcie S , Houston Michelle L , Pechman Kimberly R. , Verde Audrey R. , Davis L. Taylor , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2023

AbstractBackgroundCerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer’s disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status.ResultsGrey matter CBF was unrelated to all SVD outcomes (p‐values>0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06).ConclusionsOur findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances.
Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082
Plasma p‐tau181 levels in Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB)
Authors: Hsiung Ging‐Yuek Robin , Kumar Pankaj , Mousavi Ali , Encarnacion Mary , Frykman Hans 
Published: December 2023

AbstractBackgroundThe fundamental pathological process in AD involves amyloid(Aβ) deposition and Tau hyperphosphorylation (ptau). Plasma ptau has been proven as more accessible and less invasive biomarker than CSF for the assessment of AD pathological features. DLB is another common cause of dementia in the elderly and has overlapping features with AD. Thus, the detection of Alzheimer’s biomarkers might be useful for distinguishing the underlying pathology of AD from other concurrent pathologic processes. In this study, we compared the plasma levels of p‐tau181 in patients with clinically diagnosed DLB and AD.MethodWe examined EDTA plasma samples of patients assessed at the UBC Hospital Clinic for AD. The cohort was clinically characterized as control (n = 89) if no significant cognitive impairment was found, AD (n = 195) if they fulfill the NIA‐AA criteria (McKhann 2011), and DLB (n = 39) if they fulfill the consensus criteria for DLB (McKeith 2005; McKeith 2017). The samples were analyzed by a p‐tau181‐specific Simoa assay.ResultThe mean age of the cohort is 69.2 ± 10.3 with the control 63.4 ± 8.7, AD 70.1 ±9.9 and DLB 77.8 ± 8. There are 74.2% females in the controls, 52.8% in AD, and 35.9% in DLB.).The patients with DLB were older than the cases of AD and controls (p<0.001) and there was no significant effect of age on plasma ptau‐181 concentrations (p = 0.65). There were more females in the controls and AD groups compared to DLB (p<0.001), however, there was no significant correlation between sex and plasma ptau‐181 (p = 0.24). While the plasma p‐tau181 concentrations of cases with AD (74.1 ± 35.6 pg/ml) were slightly higher than DLB (73.2 ± 44.4 pg/ml), they were not significantly different. However, they were significantly higher than the control group (26.5 ± 23 pg/ml) (p < 0.001).ConclusionIn current study, plasma p‐tau181 levels did not differentiate the DLB group from the AD, but both groups were significantly higher than controls. This suggests that DLB often have co‐existing AD pathology, making their p‐tau measurements like the AD group. Further studies with autopsy‐defined samples will be needed to clarify the role of plasma p‐tau181 in DLB.
PK/PD analyses of ARIA‐E and isolated ARIA‐H in Lecanemab Clarity AD study
Authors: Cao Youfang , Majid Oneeb , Hussein Ziad , Willis Brian A. , Takenaka Osamu , Penner Natasha , Yasuda Sanae , Reyderman Larisa 
Published: December 2023

AbstractBackgroundClinical efficacy of lecanemab was confirmed in a Phase 3 trial (Clarity AD, NCT03887455), reducing markers of amyloid in early Alzheimer’s disease and slowing cognitive and functional decline as compared to placebo. However, some subjects experienced amyloid‐related imaging abnormalities (ARIA) associated with edema/effusion (ARIA‐E) or hemorrhage (ARIA‐H). PK/PD analyses were performed to explore the potential relationship between ARIA‐E and isolated ARIA‐H incidences with lecanemab exposure and key covariates.MethodThe Clarity AD trial randomized 1795 participants to receive lecanemab (N = 898, 10 mg/kg bi‐weekly) or placebo (N = 897). A total of 177 ARIA‐E incidences were observed from pooled Phase 2 (NCT01767311) and Phase 3 (Clarity AD) data. Additionally, a total of 150 participants from Clarity AD trial experienced treatment‐emergent isolated ARIA‐H (an ARIA‐H event without concurrent ARIA‐E). The ARIA‐E incidence rate was modeled as a function of lecanemab steady state exposures, and effects of potential covariates were explored. Graphical PK/PD analysis was performed to examine the relationship between isolated ARIA‐H and lecanemab steady‐state exposures.ResultThe observed ARIA‐E incidence was best modeled using lecanemab maximum concentration at steady‐state (Css,max) with ApoE4 genotype identified as a significant covariate. The model indicates a higher ARIA‐E incidence in homozygous carriers compared to non‐homozygous carriers or noncarriers (p<0.0001). At mean lecanemab Css,max = 305 µg/ml in subjects receiving 10 mg/kg bi‐weekly in Clarity AD, the model predicted a 5.45% (95% CI: 3.75% ‐ 7.84%) incidence of ARIA‐E in noncarriers, 9.85% (95% CI: 7.96% ‐ 12.1%) in heterozygous, and 28.0% (95% CI: 22.6% ‐ 34.1%) in homozygous carriers. No other covariate explored (age, sex, race, baseline MMSE, or occurrence of anti‐drug antibodies) had a statistically significant effect on ARIA‐E incidence. For isolated ARIA‐H, the graphical analysis identified no apparent relationship between isolated ARIA‐H incidence with lecanemab exposure. Isolated ARIA‐H incidence was associated with ApoE4 genotype, with homozygous having the highest isolated ARIA‐H incidence.ConclusionThe incidence of ARIA‐E increased with lecanemab Css,max. The incidence rate of isolated ARIA‐H was demonstrated independent of lecanemab exposure. The ApoE4 genotype impacts both ARIA‐E and isolated ARIA‐H, with increased incidences in homozygous carriers compared to heterozygous carriers or non‐carriers.