bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial and Ethnic Differences in Occupational Complexity and Late‐Life Cognition
Authors: Soh Yenee , Eng Chloe W. , Hodis Jeffrey D. , Mayeda Elizabeth Rose , Lee Catherine , Peterson Rachel L. , Whitmer Rachel A. , Glymour M. Maria , Gilsanz Paola 
Published: December 2022

AbstractBackgroundStructural racism affects employment opportunities, resulting in occupational segregation and potential racial and ethnic health disparities. Research examining the association between occupational complexity and late‐life cognition within and across racial and ethnic groups is limited. We aim to address this research gap using the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort of Asian, Black, Latino and White community‐dwelling participants aged 65+ years.MethodsWe linked occupational complexity scores (from the Dictionary of Occupational Titles) for data (range: 0‐6), people (0‐8), and things (0‐7) to self‐reported main lifetime occupation. We assessed baseline domain‐specific cognition (executive functioning, verbal episodic memory, and semantic memory) using the Spanish and English Neuropsychological Assessment Scales. Using linear regression models, we estimated associations between each occupational complexity measure and domain‐specific z‐scores, adjusting for age, sex, race and ethnicity, and education. We also assessed effect modification by race and ethnicity.ResultsAmong 1,548 participants (mean age = 76 years), 24% identified as Asian, 27% as Black, 19% as Latino, 29% as White, and 50% had a college degree or higher (Table 1). Occupational complexity with data and people varied across race and ethnicity (p‐value: >0.001 and 0.016, respectively), but not for complexity with things. Greater occupational complexity with data was associated with higher executive function (β = 0.05 SD units; 95% CI:0.02‐0.09), semantic memory (0.07 SD units; 95% CI:0.04‐0.11) and verbal episodic memory (0.06 SD units; 95% CI:0.02‐0.10) (Figure 1). Complexity with people was associated with higher executive function and semantic memory only. Complexity with things was not associated with any cognitive domain. Effect modification by race and ethnicity was significant, such that the association between greater occupational complexity with data and higher semantic memory was stronger among Latinos, compared to other racial groups.ConclusionWithin a diverse cohort, greater occupational complexity with data and people were associated with higher late‐life cognition. Occupational complexity scores varied by race and ethnicity, as well as its associations with cognitive domains. These findings suggest that racial and ethnic differences in occupational complexity may contribute to cognitive health disparities.
Alzheimer brains: increased soluble amyloid peptides, but decreased lipid rafts
Authors: Thorwald Max A , Finch Caleb E 
Published: December 2022

AbstractBackgroundPET imaging studies of AD patients show progressive increases of fibrillar Aβ‐ amyloid. Because current PET ligands underestimate non‐fibrillar forms, we assayed soluble Aβ in AD and controls. To identify mechanisms responsible for soluble Aβ in AD brains, we examined lipid rafts (LR), where APP is enzymatically processed. Frontal cortex was compared with cerebellum, which has minimal AD pathology.MethodPostmortem samples (N=48) were age‐and sex matched for Braak scores. Soluble Aβ was extracted from homogenates of full thickness frontal cortex by isotonic buffer and mild detergent (RIPA; 1% NP40) and centrifuged (10,000g/1h). Supernates were assayed by dot blots with antibodies for Aβ40 and Aβ42 (Biolegend, San Diego, CA). Aβ was assayed as relative fluorescent units per gm brain. LR fractions were isolated from these same brains by kit (Invent Biotechnologies; LR‐039), validated by ultracentrifugal fractionation.ResultCompared with cognitively normal controls (Braak 0‐1), elevations of soluble Aβ40 and Aβ42 were similar for intermediate and later stage AD (Braak 2‐3 and 4‐6). Clinical grade AD had greater increase of soluble Aβ40 (+400%) than Aβ42 (+50%) (p<0.05). LR raft yield per gram AD frontal cortex was 20% below controls (p<0.05), while cerebellar LR did not differ by Braak score. The composition of LR had a similar pattern, with 35% AD decreases of total protein and cholesterol (p<0.05); cerebellar LR again did not differ by Braak score. However, LR 4‐HNE, a marker of oxidative damage, was similarly increased in AD cortex and AD cerebellum.ConclusionThe extensive overlap of soluble Aβ levels in controls with AD contrasts with the PET findings on fibrillar Aβ. These findings further support fibrillar Aβ as a biomarker for AD treatments and show the need for more detailed postmortem analysis of diverse soluble and insoluble Aβ aggregates in relation to PET. The decreased LR in AD frontal cortex is consistent with its extensive neuronal loss, in contrast to the cerebellum. Further studies will examine LR enzymes of APP processing as a source of the increased soluble Aβ in AD, and subcellular clearance processes, which may be impaired in association with the oxidative damage indicated by increased 4‐HNE.
Comparing ARIA‐E severity scales and effects of treatment management thresholds
Authors: Klein Gregory , Bracoud Luc , Purcell Derk , Barakos Jerome , Fiebach Jochen B. , Scelsi Marzia A. , Delmar Paul , Lyons Marco , Wojtowicz Jakub , Bullain Szofia , Barkhof Frederik , Fontoura Paulo , Baudler Monika , Doody Rachelle S. 
Published: December 2022

AbstractBackgroundVasogenic edema and sulcal effusions detected with Magnetic Resonance Imaging (MRI), known as Amyloid‐Related Imaging Abnormalities‐Edema (ARIA‐E), are manageable side effects of anti‐amyloid immunotherapies. Periodic MRI scans with severity assessment of ARIA‐E are used in clinical trials or to guide practice with these therapies.Several scales with varying complexity measure radiological ARIA‐E severity to guide dosing. The ongoing GRADUATE studies use the 60‐point Barkhof Grand Total Scale (BGTS)1, continuing treatment for asymptomatic ARIA‐E ≤ 3, and temporarily suspending dosing for BGTS > 3. Other studies have used Simple ARIA‐E Severity Scales2 (SAESS‐3, SAESS‐5), continuing treatment for asymptomatic SAESS‐3 ≤ 1, but temporarily suspending dose for SAESS‐3 > 13. We previously reported good correlation between BGTS, SAESS‐3, and SAESS‐5 by a single reader. Here we report correlations among these scales scored by multiple readers and assess the impact of these various scores on ARIA management.MethodsT2‐FLAIR MRI scans were selected from a representative set of incident ARIA‐E cases (70 with previously detected ARIA‐E, 5 without ARIA‐E from original BGTS assessment) in the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) Phase III studies. Three experienced neuroradiologists scored ARIA‐E severity using the 3 scales from pairs of baseline/follow‐up scans, blinded to prior read results. Median results of the 3 readers were computed for further analysis.ResultInter‐reader agreement for all 3 scales was high (ICC=0.866 [0.811, 0.908], 0.888 [0.841, 0.924], and 0.858 [0.776, 0.910] for the SAESS‐3, SAESS‐5, and BGTS scales respectively). Spearman’s rank correlation with BGTS scale was 0.88 for the SAESS‐3 scale and 0.90 for SAESS‐5. Median interquartile range (IQR) BGTS scores for the two simplified scales are shown in Figure 1. Best agreement for the SAESS‐3 > 1 treatment management threshold was achieved with BGTS > 3, with an accuracy of 93.3% (Figure 2).ConclusionsSAESS‐3 and SAESS‐5, which may be more suitable for routine clinical practice, are well correlated to the BGTS scale. Treatment management based on the SAESS‐3 > 1 threshold shows high agreement with the BGTS > 3 threshold.1. Barkhof et al., 2013; AJNR 34:8.2. Bracoud et al., 2017; AAIC. P1‐047.3. ADUHELM (aducanumab‐avwa) FDA PI.
Meta‐analysis employing the African Genome Resources panel identifies novel Alzheimer disease risk loci in African Americans
Authors: Kurup Jiji Thulaseedhara , Kunkle Brian W. , Hamilton‐Nelson Kara L. , Jean‐Francois Melissa , Schmidt Michael A. , Martin Eden R , Wang Li‐San , Beecham Gary W. , Farrer Lindsay A. , Haines Jonathan L. , Byrd Goldie S. , Schellenberg Gerard D. , Mayeux Richard , Pericak‐Vance Margaret A. , Reitz Christiane ,   Alzheimer’s Disease Genetics Consortium
Published: December 2022

AbstractBackgroundIn the largest Alzheimer disease (AD) genome‐wide association studies to date for African‐Americans (AA; Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified in addition to APOE several novel susceptibility loci, including ABCA7, API5, RBFOX1 and IGF1R. We followed up these analyses with an increased sample size (2,913 cases, 5,802 controls) employing the African Genome Resource (AGR) panel.MethodSingle‐variant association analysis was conducted adjusting for age, sex, principal components and subsequently APOE, applying logistic regression for case‐control and general estimating equations for family‐based datasets. Within‐study results were meta‐analyzed using METAL. Gene‐based and pathway analyses were conducted via MAGMA.ResultIn addition to the previously reported AA risk loci, we identified three novel signals reaching genome‐wide significance at chromosomes 3p24 (TOP2B; P = 4.7×10−8), 3q26 (NCEH1; P = 3.7×10−8) and 9p23 (MPDZ; P = 1.7×10−8), and seventeen novel loci reaching suggestive significance at p ≤ 9×10−7. NCEH1 modulates cholesterol metabolism and is neuroprotective against α‐synuclein toxicity; MPDZ encodes a scaffolding protein involved in cytoskeleton remodeling. Top2B encodes a DNA topoisomerase involved in DNA transcription. Gene‐based analyses identified SLC39A3 (P = 2.9×10−6), involved in zinc transport, as a novel candidate gene. Pathway analyses support the notion that besides immunity, synaptic function, transcription/DNA repair, lipid processing, and intracellular trafficking, which overlap with the major AD‐associated pathways in non‐Hispanic Whites, also renal function is involved in AD etiology in African Americans.ConclusionWe identified several novel candidate loci for AD in AA. While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non‐Hispanic White individuals, the disease‐associated loci within these pathways differ. Identification of a significant number of loci at suggestive significance indicates that future studies with further increased sample size will be valuable to identify additional disease‐associated loci in this ethnic group.
Intragenic loci within TOMM40 enhances APOE expression in human microglia
Authors: Oron Oded , Ramirez Aura Maria , Wang Liyong , Vasquez Marina Lipkin , DeRosa Brooke A , Celis Katrina , Chesi Alessandra , Grant Struan F.A. , Young Juan J , Nuytemans Karen , Vance Jeffery M. , Dykxhoorn Derek M. 
Published: December 2022

AbstractBackgroundPreviously, we demonstrated that the ancestry‐related risk for Late Onset Alzheimer’s Disease (LOAD) is driven by a local genomic region (termed Local Ancestry; LA) around APOEε4. Furthermore, we showed that in the brain of individuals bearing European LA there is higher expression of APOEε4 compared to those with African LA. In a follow‐up study, utilizing reporter assays and Capture‐C data we located two intronic regions within the European LA, both in the TOMM40 gene (named B10 and B13), that increased APOE expression in microglia and astrocytes. In this study, we sought to validate their regulatory role in APOE expression using CRISPR interference/activation (CRISPRi/a).MethodHuman Microglial Clone 3 (HMC3) CRISPRi/a lines were produced by transducing inducible dCas9‐VP64 (Activation), dCas9‐KRAB (Interference) or dCas9 (control) using lentiviral vectors. To direct the dCas9 constructs to our regions of interest, we generated multiplex vectors that encode 4 short‐guide RNAs (sgRNAs) targeting either B10 or B13. We used 4 different sgRNAs in each case to ensure full‐length coverage of the tested regions (∼850bp size). An empty multiplex vector was used as a control. We then transduced either of the multiplex vectors into the HMC3 CRISPRi/a lines. We induced expression of the dCas9 constructs for 2 or 6 days with Doxycycline (2ug/ml). RNA was extracted and the expression of APOE and TOMM40 was measured by qRT‐PCR.Result
APOE expression significantly increased when targeting B10 or B13 (p=0.001; p=0.003 respectively) with dCas9‐VP64 after 2 days of Doxycycline treatment. Six days after treatment the significance persisted only when targeting B10 (p=0.01). No significant changes in APOE expression were observed in the cells bearing the dCas9‐KRAB presumably due to low endogenous APOE levels. Expression of TOMM40 did not vary under any treatment.ConclusionThese preliminary results support our previous findings that regions B10 and B13 may act as regulators for APOE expression as demonstrated by the elevation of ApoE expression when targeting an activator to these regions. The expression of TOMM40 did not vary across cell lines in the evaluated time points supporting that the effect observed is specific for APOE.
Macropinocytosis of APP is controlled by a cascade of regulatory proteins
Authors: Krupa Jordan M , Tsang Adrianna R , Seah Claudia , Pasternak Stephen H 
Published: December 2022

AbstractBackgroundThe internalization of the Amyloid Precursor Protein (APP) is recognized as an important step in beta‐amyloid (Aβ) production. We have discovered that macropinocytosis of cell surface APP leads to rapid transport directly to lysosomes, bypassing early and late endosomes. This process leads to APP cleavage to Aβ and is regulated in part by Arf6.Here, we hypothesize that the binding/cross‐linking of APP at the cell surface recruits Fe65 and results in the recruitment and activation of Arf6. Arf6 then activates downstream small GTPases that are known to regulate macropinocytosis in non‐neuronal cells (including Rac1, Cdc42 and RhoA) leading to APP internalization by macropinocytosis.MethodNeuro2a neuronal cells are transfected with fluorescent‐tagged proteins including Fe65, Rac1, Cdc42 and RhoA. Membrane PI(4,5)P2, a marker for membrane ruffling and the initiation of macropinocytosis, is visualized using fluorescent‐tagged marker known as PLCdelta‐PH. Cells are cultured in 37°C confocal dishes on the stage of a Leica SP8 confocal microscope. Fluorescent‐labelled anti‐APP antibodies are added to bind/cross‐link APP at the plasma membrane. We then use confocal microscopy/live cell imaging to visualize the recruitment of the regulatory proteins in real time.ResultUpon anti‐APP antibody binding, we can see APP recruited to sites on the plasma membrane enriched with PI(4,5)P2 and the plasma membrane begins to ruffle. We see Fe65 rapidly recruited to the membrane, along with active Arf6 at these sites of membrane ruffling. We also observe Rac1, Cdc42 and RhoA recruited to these regions. APP at these sites is then observed to rapidly internalize to lysosomes, demonstrated by its colocalization with the lysosomal marker LAMP1.ConclusionThese results demonstrate the active recruitment of GTPase proteins known to regulate macropinocytosis to the membrane at sites of APP binding/cross‐linking. These regulators could be targeted to modulate APP trafficking and reduce the production of Aβ.
Perceptions of staff and leadership teams on implementation of telepresence robots in long‐term care: a qualitative descriptive study
Authors: Wong Joey , Young Erika , Hung Lillian , Mann Jim , Jackson Lynn 
Published: December 2022

AbstractBackgroundCOVID‐19’s physical distancing mandates have increased the likelihood of experiencing social isolation and loneliness for residents in long‐term care (LTC), especially those living with dementia. Social isolation correlates with health risks, including depression and cognitive decline. Telepresence robots can be remotely driven and facilitate social interactions through videoconferencing. Researchers have begun to explore opportunities of using these robots in the healthcare field; however, there is a research gap on examining factors influencing their implementation in LTC from the perspectives of key stakeholders. This qualitative descriptive study focuses on exploring LTC staff and leadership teams’ perspectives on facilitators and barriers to implementing telepresence robots.MethodWe employed purposive and snowballing methods to recruit 22 participants from two LTC homes in British Columbia, Canada: operational and unit leaders, and interdisciplinary staff including nursing staff, care aides and allied health practitioners. Consolidated Framework for Implementation Research (CFIR) guided our data collection and analysis. Semi‐structured interviews were conducted by virtual meetings. Thematic analysis was performed to identify themes.ResultAnalysis of the data produced three themes: (a) perceived needs and values for family‐resident connections, (b) engagement through conversation and partnership, and (c) confidence with training and timely support. Based on the findings and CFIR guidance, we offer a preliminary conceptual tool “START”: Share benefits and successes; Tailor policies and plans with staff partners; Acknowledge and address staff concerns; Repeated training and demonstrations; and Timely technical support.ConclusionThis study offers pragmatic insights into staff and leadership teams’ perceptions of facilitators and barriers of implementing telepresence robots in LTC. The complexity of technology implementation will require executive and leadership teams to consider additional factors beyond the Plan‐Do‐Study‐Act (PDSA) cycle.
Effects of an Alzheimer’s and Dementia Care Co‐management Program on Quality, Clinical Outcomes, and Utilization
Authors: Reuben David , Panlilio Michelle ,   UCLA Alzheimer’s and Dementia Care Program
Published: December 2022

AbstractBackground: The quality of care provided to persons living with dementia (PLWD) and their care partners (CPs) is low, clinical outcomes are poor, and costs are high. Co‐management of dementia care by Advance Practice Providers (APPs) has the potential to improve all of these metrics.Method: The UCLA Alzheimer’s and Dementia Care (ADC) Program is a health system‐based co‐management model of APP Specialists (DCSs) working with primary care and specialty physicians that is designed to meet dementia care needs. DCSs approach the PLWD and CP as a dyad, providing support, including community‐based resources, to both; behavioral and medication management; and care coordination. The program has provided dementia care for over 3400 PLWD and has a current census of over 750 PLWD who are cared for by 4 nurse practitioner DCSs.ResultQuality of care based on established dementia quality indicators assessed by medical record review was 92%. Based on an analysis of the first 1091 PLWD and their CPs, prior to entering our program, many caregivers were poorly informed about dementia caregiving and felt they were fighting this battle alone. One‐third had high stress and more than 10 percent were depressed. By the end of a year in the program, confidence in handling problems and complications of Alzheimer’s disease and dementia improved by 72 percent. CP strain (Modified Caregiver Strain Index), distress (Neuropsychological Inventory‐Distress), and depression (PHQ‐9) were reduced (all P<0.001). Moreover, the program reduced emergency department visits by 20%, days spent in the hospital by 26%, admissions to nursing homes for long‐term care by 40%, (all P<0.05) and overall Medicare costs by $2404 per person/year. The ADC Program has been disseminated to 18 sites nationwide and more than 5000 PLWD and their CPs have received ADC care.ConclusionDementia co‐management with APPs can improve quality and clinical outcomes and reduce health care utilization and costs. The ADC Program can be implemented in diverse health systems indicating the potential for widespread dissemination.
The influence of cognitive status on perivascular space enlargement trajectories in a longitudinal aging cohort
Authors: Lynch Kirsten M , Toga Arthur W. , Choupan Jeiran 
Published: December 2022

AbstractBackgroundPerivascular space (PVS) enlargement is associated with dysfunctional waste clearance and can hinder the removal of toxic metabolic substrates, such as amyloid beta (Aβ). Increased PVS visibility in white matter has been observed in cross‐sectional studies of patients with Alzheimer’s disease (AD) and mild cognitive impairment (AD). However, the utility of PVS morphology as a diagnostic biomarker for AD pathology is hindered by the lack of knowledge regarding the time course of PVS alterations across diagnostic groups. In the present study, we characterize the relationship between cognitive status and PVS morphological trajectories with age in a longitudinal cohort. Findings from this study will provide insight into the role of waste clearance processes in AD disease pathogenesis.MethodLongitudinal neuroimaging data from 500 cognitively normal (CN) subjects, patients with stable MCI (sMCI), and patients with MCI that later convert to AD (cMCI) were obtained from ADNI3. White matter PVS morphological features were automatically defined according to the methods described in (4) using optimally thresholded vesselness maps on high resolution T1w scans. The influence of class membership on the rate of PVS alterations over time were assessed with a linear mixed effects models with REML after controlling for baseline age, gender, years of education and total white matter volume.ResultWe found a significant interaction between cognitive status and time on mean PVS cross‐sectional diameter in the white matter, where the rate of change of PVS enlargement in patients with cMCI was greater compared to CN controls (B=‐.22, t(491)=‐2.06, p=.039) and patients with sMCI (B=‐.21, t(491)=‐2.03, p=.043). No significant differences in the age‐related change to PVS count or volume were observed between groups.ConclusionOur findings show patients with MCI that later progress to AD show accelerated PVS enlargement compared to patients that remain in the preclinical stages of cognitive decline. Our results support the growing body of research that demonstrates a relationship between pathological PVS enlargement and neurodegenerative disorders characterized by dysfunctional waste clearance. Parenchymal PVS caliber may therefore provide an informative biomarker to aid in the early diagnosis of AD and other amyloidopathies prior to the formal onset of deleterious symptoms.