bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurocognitive effects of immune checkpoint inhibitors: A literature review
Authors: Mostafa Neveen , Raji Mukaila 
Published: December 2021

AbstractBackgroundImmune checkpoint inhibitors (ICI) are novel but rapidly growing class of cancer treatments. They have pleotropic effects on several cancer‐specific targets that underlie their therapeutic properties. These targets include programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte antigen 4 pathways. ICI have been approved in treatment guidelines of several cancers like melanoma and lung cancers and are being routinely used in clinical practice due to its proven efficacy.The mechanism of ICI primarily targets the immune system, which also serves important roles in the structure and function of the central and peripheral nervous system. The reported associated adverse effects are essentially immune mediated due to T‐cell activity upregulation that causes disrupted immune tolerance. The same mechanism leading to cancer death might be driving the neurocognitive sequalae. Several specific neurological adverse events were described due to the role of inflammatory pathways in mediating behavioral and cognitive functions.ICI have clear proven responses, leading to increase in the overall survival such that patients are now living longer with its side effects. Thus, it is essential to understand and assess the long‐term side effects and quality of life outcome among the growing population of cancer survivors previously treated with ICI.MethodThis review discusses the reported cognitive changes associated with immune checkpoint inhibitors. We employed a systematic search of literature in PubMed database, up to November 2020, mentioning neurological and cognitive side effects in patients treated with ICIs. Eligible studies included clinical trials, observational studies and case reportsResultThe clinical spectrum of neurological disorders is highly heterogeneous. Most of the reported neurological adverse events consist of non‐specific symptoms such as headache and fatigue, with the more functionally devastating ones being myasthenia gravis, demyelinating polyradiculopathy, meningitis and limbic encephalitis. Cognitive decline and memory problems were infrequently reported in the reviewed studies.ConclusionAlthough few clinical studies have targeted ICI immunotherapy for associated neurological sequelae, it appears that cognitive decline is not a common adverse effect for ICI. However, over time and with longer use of ICI, there will be a need for more rigorous studies to explore possible long‐term neurological complications.
Sleep efficiency is associated with amyloid burden, cerebral blood flow, and cognition in healthy older adults
Authors: Fenton Laura E , Albrecht Daniel S , Isenberg Lisette , Aslanyan Vahan , Stradford Joy , Monreal Teresa , Pa Judy 
Published: December 2021

AbstractBackgroundPrior work has identified associations between sleep quality and amyloid‐beta (Aβ). However, how sleep efficiency relates to Aβ, cerebral blood flow (CBF), and cognition are not well understood. The objective of this study was to evaluate these relationships and the modifying role of APOE4 status.MethodObjective sleep efficiency, Aβ, CBF, and cognitive performance on neuropsychological assessments (MoCA, Flanker, CVLT, and Complex Figure) were examined in a sample of 52 non‐demented, older adults (age=66.5+6.82, 67% female, 27% APOE4 carriers). Sleep efficiency, defined as the percentage of time asleep within a given sleep period, was objectively measured using the GENEActiv tri‐axis accelerometer for an average of 30.25 days. Aβ was measured in vivo using positron emission tomography and the F‐18 florbetaben tracer to calculate composite SUVR scores. Global gray matter CBF was quantified using a pseudo‐continuous arterial spin labeling MRI scan. All analyses were adjusted for age, sex, and education (for cognitive measures).ResultOverall, higher sleep efficiency was associated with lower Aβ burden (p=.04), higher CBF (p=.03), higher MoCA scores (p=.05) and a trend for better Complex Figure Test recall (p=.07). There was a significant moderating effect of APOE4 status on the association between sleep and Aβ, such that poorer sleep efficiency was associated with higher Aβ burden in APOE4 carriers only (p=.01). APOE4 moderation was not observed for CBF. When stratified by high and low sleep efficiency levels (median split), APOE4 carrier status predicted Aβ burden only in individuals with low sleep efficiency (p =.02). Additionally, sleep efficiency predicted performance on long delay free recall of the CVLT and Complex Figure Test (p=.01) in the low sleep efficiency group only. No association between sleep efficiency and Flanker were observed.ConclusionThese results provide evidence that sleep efficiency is associated with brain health and cognition, and suggest a modifying effect of APOE4 on the relationship between sleep and amyloid. Mechanistic evidence from animal models and human studies suggests that impaired slow wave activity during NREM sleep may disrupt dynamic fluid oscillations important for amyloid clearance and brain blood flow. Future work is needed to understand the causal and temporal relationships between these processes.
The impact of COVID‐19 on the well‐being and cognition of older adults living in the United States and Latin America
Authors: Babulal Ganesh M , Torres Valeria L , Acosta Daisy M , Aguero Cinthya , Aguilar‐Navarro Sara Gloria , Amariglio Rebecca E , Ussui Juliana Aya , Baena Ana Y , Bocanegra Yamile , Brucki Sonia MD , Bustin Julian , Cabrera Diego , Custodio Nilton , Diaz Monica M , Duque Lissette , Franco Idalid , Gatchel Jennifer R , Garza‐Naveda Ana Paola , Gonzalez‐Lara Mariana , Gutiérrez Lidia Antonia , Guzman‐Velez Edmarie , Hanseeuw Bernard J , Jiménez‐Velazquez Ivonne Z , Leon Tomas , Llibre‐Guerra Jorge J , Marquine Maria J , Martinez Jairo E , Medina Luis D , Miranda‐Castillo Claudia , Morlett Alejandra , Munera Diana , Nuñez‐Herrera Alberto , de Oliveira Maira Okada , Cancel Santiago Palmer , Pardilla‐Delgado Enmanuelle , Perales Jaime , Pluim Celina F , Ramirez‐Gomez Liliana A , Rentz Dorene , Rivera‐Fernandez Claudia , Rosselli Monica , Serrano Cecilia , Suing María Jose , Slachevsky Andrea , Soto Marcio , Sperling Reisa A , Torrente Fernando , Thumala Daniela , Vannini Patrizia , Vila‐Castelar Clara , Escalante Tatiana Mirella Yanez , Quiroz Yakeel T 
Published: December 2021

AbstractBackgroundIn the COVID‐19 pandemic, older adults from vulnerable ethnoracial groups are at high risk of infection, hospitalization, and death. We aimed to explore the pandemic’s impact on the well‐being and cognition of older adults within and outside of the United States (US).Method1,747 (646 White, 991 Latino, 77 Black, 33 Asian; 72% female) individuals from the US and 14 Latin American countries completed an online survey regarding well‐being and cognition during the pandemic. Outcome variables (pandemic impact, discrimination, loneliness, purpose of life, subjective cognitive concerns) were compared across four US ethnoracial groups, and Latinos living in the US and Latin America.ResultMean age was 66·5 (SD = 7·70) years and mean education was 15·4 (SD = 2·76) years. We found no differences in the pandemic’s overall impact across US ethnoracial groups. Compared to Whites, Latinos reported greater economic impact (p < ·001, ηp2 = .031); while Blacks reported experiencing discrimination more often (p < ·001, ηp2 = .050). Blacks and Latinos reported more positive coping (p < ·001, ηp2 = 040). Latin American Latinos reported greater pandemic impact (p < ·001, ηp2 =.013 ), more positive coping (p =·006, ηp2 =.008 ), and less discrimination than US Latinos (p < ·001, ηp2 = .013 ).ConclusionThe COVID‐19 pandemic has differentially impacted the well‐being of older ethnically diverse individuals in the US and Latin America. Future studies should examine how mediators like income and coping skills modify the pandemic’s impact.
Reduced amyloid and greater neuropsychological testing exclusion in the A4 study in individuals that self‐identify as non‐Hispanic Asian
Authors: Jin Meghan , Kennedy Gabriel , Deters Kacie D , Trelle Alexandra N , Donohue Michael C , Sperling Reisa A , Mormino Elizabeth C 
Published: December 2021

AbstractBackgroundThe prevalence of amyloid positivity among diverse groups of clinically asymptomatic older individuals is underexplored, especially in the context of prevention trials of Alzheimer’s disease (AD). We sought to determine whether rates of amyloid‐positivity differ in non‐Hispanic Asian individuals from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) study as compared to non‐Hispanic White individuals.MethodsWe compared cross‐sectional amyloid PET data for 169 self‐identified non‐Hispanic Asian (NHA) and 3843 non‐Hispanic White (NHW) from the A4 Study, controlling for age, sex, education, and APOE genotype (number of E4 and E2 alleles). We additionally examined neuropsychologic eligibility data for the 111 NHA and 1910 NHW that did not meet study criteria to advance to the PET visit ("PET‐screenfail"). Finally, Japanese language was used as a proxy variable to account for potential site differences (Tokyo versus North American recruitment sites; 99/169 NHA with PET and 57/111 NHA in the PET screenfail group indicated Japanese as their primary language).ResultsIndividuals that self‐identify as NHA show lower levels of amyloid compared to NHW, both when treating amyloid dichotomously or continuously (see Figure, and Table). Overall, NHA are more likely to screenfail before the PET visit compared to NHW (40% versus 31%; X2=7.8, df = 1, p‐value = 0.0052). NHA that screenfail before the PET visit have lower MMSE (p<0.0001) and Logical Memory delayed recall (p<0.0001) scores than the NHW screenfail group. All results remained similar when additionally controlling for language as a proxy for site.ConclusionsSelf‐identified NHA individuals show reduced amyloid‐positivity in a large‐scale prevention trial of AD, similar to our previous report in non‐Hispanic Blacks. Recruitment strategies and eligibility requirements deserve more attention, as increased exclusion due to scores on the MMSE and Logical Memory likely reflect inadequacy in these measurements across diverse populations. These findings highlight bias within PET datasets and gaps in knowledge related to key AD biomarkers in diverse individuals.
Pre‐pivotal clinical study of β‐amyloid in the ocular lens by Sapphire II‐aftobetin eye scan: Correlation with amyloid PET imaging in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD)
Authors: Goldstein Lee E. , Wilke Susanne , Goodman Ira J. , Nilan Dennis , Sadowsky Carl H. 
Published: December 2021

AbstractBackgroundWe identified AD‐associated Aβ pathology in ocular lenses from patients with neuropathologically‐confirmed AD but not non‐AD neurodegenerative diseases or normal aging (Goldstein et al., Lancet, 2003). We reported identical early‐onset Aβ lens pathology in Down syndrome (Moncaster et al., 2010). In Framingham Eye Study participants, we found that AD phenotypes are expressed years‐to‐decade+ earlier in lens than brain and identified a new GWAS‐significant AD risk gene (CTNND2, δ‐catenin) that modulates Aβ expression in lens and brain (Jun et al., 2012). This research spurred development of a novel drug‐device eye scanner (Sapphire II‐Aftobetin system) that combines a topically‐applied Aβ‐binding fluorescent ligand (Aftobetin) with a purpose‐designed fluorescence laser eye scanner (FLES). Sapphire II detects lens Aβ with high reliability, sensitivity, specificity, and SNR. Clinical testing showed that Sapphire II distinguishes subjects with probable AD from normal controls (Kerbage et al., Front Neurol, 2013; Am J Alz Dis Dement, 2015). This study evaluated Sapphire II compared to amyloid PET scans in subjects with MCI or early AD.Method48 participants: 28 MCI, 16 mild AD, 4 normal controls (NC); age range: 60‐85 years. MCI and AD subjects underwent cognitive testing and amyloid PET scans (Florbetapir, Amyvid). The Sapphire II system detects a highly‐specific fluorescent lifetime decay spectroscopic signature associated with bound Aftobetin‐Aβ complexes in the lens. Each scan requires <1 sec. Multiple scans can be acquired in a single sitting.Result43 subjects have been evaluated to date. No serious adverse events have been reported. Subject correlation with amyloid PET yielded 75% specificity, 100% sensitivity, 95% accuracy, 94% PPV, and 100% NPV. To date, there has been no subject in which Sapphire II was negative and amyloid‐PET was positive. Of the 39 Sapphire II‐positive subjects, 26 were amyloid‐PET positive. Evaluation of individual PET scans and cognitive testing suggest that lens amyloid burden assessed by Sapphire II eye scan is more sensitive than amyloid PET compared to clinical criteria.ConclusionThe Sapphire II‐Aftobetin drug‐device combination platform provides a safe, sensitive, and convenient screening tool for rapid non‐invasive evaluation of AD‐associated β‐amyloid (Aβ) burden in subjects with MCI and mild AD.
Self‐reported and informant‐reported depressive symptoms are independent and divergent predictors of new onset dementia in older adults
Authors: Rehman Tanaeem , McGirr Alexander , Ismail Zahinoor 
Published: December 2021

AbstractBackgroundDepressive symptoms in older adults are important predictors of incident dementia. Symptoms can be assessed in several ways, including self‐reported or informant‐reported measures. It is unclear whether one is superior in predicting dementia onset or how to interpret discordant reports. Here, in a large sample of non‐dementia older adults for whom depressive symptoms were assessed via both self‐report and informant‐report, we test independent and divergent prognostic utility for dementia.MethodData from 10,684 non‐dementia subjects from the National Alzheimer’s Coordinating Centre were analysed. This included individuals with normal cognition (NC; CDR=0) and Mild Cognitive Impairment (MCI; CDR=0.5). Geriatric Depression Scale‐15 (GDS) was used for self‐report and the Neuropsychiatric Inventory Questionnaire depression item (NPI‐Q‐D) was used for informant‐report. Cox regression and Kaplan Meier (KM) survival analyses were used to explore the measures as independent predictors of dementia, and the putative interaction between them. Outcome was defined as change to CDR≥1 at follow‐up. The cox model was adjusted for age, sex, and education. CDR category was included to determine applicability of findings across cognitive categories. GDS‐15 and NPI‐Q‐D scores were added as continuous predictors. For the KM analysis, depressive symptoms were dichotomized as GDS+/GDS‐ and NPI‐Q‐D+/NPI‐Q‐D‐ using cut‐off scores of ≥5 for GDS‐15 and ≥2 for NPI‐Q‐Depression.ResultGDS (HR: 1.096; CI: 1.070–1.122) and NPI‐Q‐D (HR: 1.428; CI: 1.291–1.580) independently predicted dementia, with a significant interaction between them (p<0.000) even after controlling for CDR. KM analyses showed that in the self‐reported non‐depressed group (GDS‐), there was a significant difference in the hazard of incident dementia based on the informant report. The discordant group i.e., GDS‐/NPI‐Q‐D+ progressed to dementia significantly faster (9.6yrs; SD=0.292) compared to the GDS‐/NPIQ‐D‐ group (12.0yrs; SD=0.055) (p<0.000; Log‐rank test). No significant difference was found based on informant reports in the GDS+ group (p=0.114).ConclusionSelf‐reported and informant‐reported depressive symptoms are not duplicative, and independently predict dementia risk across cognitive categories. Informant report is particularly important when self‐report is negative, to detect individuals with compromised insight at higher risk for progression. Discordance of self‐informant reports require greater clinical and research consideration in NC and MCI populations.
Clinical profile of an Alzheimer´s disease cohort in the Peruvian population
Authors: Cornejo‐Olivas Mario R , Mena Pedro Ramon , Illanes‐Manrique Maryenela , Adams Larry D. , Marca Victoria , Isasi Rosario , Castro‐Suarez Sheila , Beecham Gary W. , Mejía Koni Katerin , Vance Jeffery M. , Manrique‐Enciso Carla , Cuccaro Michael L. , Meza‐Vega Maria , Pericak‐Vance Margaret A. 
Published: December 2021

AbstractBackgroundAmong older Peruvians (over 65‐years) the prevalence of dementia is 7%, with 56% meeting clinical criteria for Alzheimer Disease (AD). Peruvians, are an admixed population with approximately 80% Amerindian ancestral background. We have ascertained a cohort of Alzheimer Disease (AD) cases and cognitively intact controls for genetic studies.MethodAll participants have been recruited since 2019 using community outreach ascertainment strategies and hospital‐based recruitment from Lima, Peru. Cases were assessed by neurologist following NINDS/ADRDA criteria; and completed a comprehensive neurocognitive, neuropsychiatric and functional assessments. Controls were screened using MMSE, Clock drawing test and Pfeffer functional activities questionnaire. IRBs approvals from the participating Peruvian institutions and University of Miami were obtained for this study.ResultA total of 102 AD cases (4 familial cases) and 152 controls were recruited since 2019 to December 2020. For AD cases: age at examination were 76.5±9.09, age at onset were 72.15±8.82, and 63.7% were female, average of 9.9±4.9 year of education. For controls: age at examination were 73.13±6.54, 62.5% were female, average of 11.62±4.41 year of education. Among cases diagnosis was classified as: 62.8% possible AD (two cases screened for Cerebrospinal fluid Abeta42 and tau protein levels) and 37.2% probable AD. Clinical and cognitive assessment profile for cases: MMSE average score was 17.2± 4.9 and Addenbrook’s Cognitive Examination average score was 38.5± 21.7 with memory loss predominance. Based on NPI the most frequent neuropsychiatric symptoms were irritability (51%), delusions (46%) and apathy (45%). Severity of dementia were assessed by CDR (CDR=3 for 33.9%, CDR=2 for 32.3%, CDR=1 for 24.2% and CDR=0.5 for 9.7%). Depressive symptoms were assessed with Geriatric Depression Scale with an average of 4.4±3.5 .ConclusionThe clinical features of the AD cohort in the Peruvian population are consistent with previous reports. There is a tendency of a higher level of education in the control . Among the Peruvian AD cohort, the main neuropsychiatric symptoms are irritability, delusions and apathy consistent with the predominance of moderate to severe dementia. Reference: Marca V. et al. Dissecting the role of Amerindian genetic ancestry and ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population, Neurobiology of Aging, 2020.
Plasma transcript profiling identifies significant differentially expressed genes and expression of quantitative trait loci in African Americans
Authors: Carrasquillo Minerva M. , Jin Jianli , Reddy Joseph S. , Crook Julia E. , Lincoln Sarah J. , Ho Charlotte C.G. , Malphrus Kimberly G. , Nguyen Thuy , Greig‐Custo Maria T. , Lucas John A. , Graff‐Radford Neill R. , Ertekin‐Taner Nilufer 
Published: December 2021

AbstractBackgroundAfrican Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being ∼2X higher in this population compared to non‐Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing primarily on the identification of genetic risk factors and novel plasma biomarkers.MethodUtilizing plasma samples from FCA3DS AD cases (n=158) and cognitively unimpaired elderly controls (n=272), we have performed differential gene expression (DEG) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom NanoString® panel that we have designed to measure transcript levels in plasma of genes relevant to AD. Transcript counts were determined using the NanoString® nCounter system, following manufacturer’s protocols. Transcript counts from 43 of the 50 customs assays passed pre‐established quality control thresholds and were utilized for the DEG and eQTL analyses. Our published FCA3DS whole exome sequence (WES) data was utilized for the eQTL analyses. Linear mixed models adjusted for relevant biological and technical covariates were implemented with the lme4 package in R software (v3.6.2) for the DEG and eQTL analyses.ResultAn association with higher plasma CLU in controls compared to AD remained significant after Bonferroni correction for the 43 transcripts tested. The eQTL analysis revealed significant association (FDR q‐value<0.05) with 105 WES variants in cis with 22 of 43 genes tested, including variants in genes previously associated with AD risk in AA.
ConclusionThe results from this AA plasma eQTL analysis revealed ABCA7 variants that are significantly associated with lower plasma ABCA7 transcript levels. One of the significant plasma ABCA7 eQTLs was previously shown by our group to be associated with increased AD risk in AA, suggesting that this may be a functional eQTL underlying the risk of AD in AA. The association of higher levels of CLU transcript in plasma from controls compared to AD is in line with results published by others which showed that higher baseline concentration of clusterin protein in plasma was associated with slower rates of brain atrophy. These results support plasma transcripts as novel endophenotypes in AD biomarker studies.
Reduced longitudinal change in 18F‐flortaucipir PET is associated with clinical phenotype in atypical Alzheimer’s disease
Authors: Phillips Jeffrey S , Nitchie Frederick J. , Da Re Fulvio , Olm Christopher A , Cook Philip , McMillan Corey T , Irwin David J. , Gee James C. , Dubroff Jacob G. , Grossman Murray , Nasrallah Ilya M. 
Published: December 2021

AbstractBackgroundLongitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer’s disease (AD) have noted reduced increases or frank decreases in tau signal. It is unclear whether these reductions reflect measurement/processing error or biological changes in advanced neurodegeneration.MethodWe assessed regional and interindividual variation in rates of longitudinal change on 18F‐flortaucipir PET imaging in 24 amyloid‐β+ patients with atypical, early‐onset amnestic or non‐amnestic AD and 117 amyloid‐β+ participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.ResultIn atypical AD, 18F‐flortaucipir uptake appeared to slow or decline over time in areas with high baseline signal and older individuals with greater cognitive impairment. In secondary analyses, these effects were not explained by regression to the mean or atrophy. Among ADNI participants, longitudinal change was reduced in early Braak stage regions relative to late‐stage neocortical areas, demonstrating partial generalization of findings from atypical AD.ConclusionResults suggested that radioligand uptake may plateau or decline in advanced neurodegeneration. Further research is warranted to investigate whether results generalize to other tau‐binding radioligands and to typical, later‐onset AD.