bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual‐task gait and mild behavioral impairment: Findings on the interface between non‐cognitive dementia markers in the COMPASS‐ND study
Authors: Guan Dylan X. , Chen Hung‐Yu , Camicioli Richard , Montero‐Odasso Manuel , Smith Eric E. , Ismail Zahinoor 
Published: December 2021

AbstractBackgroundMild behavioral impairment (MBI) and poor dual‐task gait performance are non‐cognitive markers for dementia. Both MBI and dual‐task gait performance have been associated with an increased risk of cognitive decline, but to our knowledge the relationship between them has yet to be investigated.MethodCross‐sectional data from 193 non‐demented participants (10 cognitively normal, 48 subjective cognitive decline, 135 mild cognitive impairment; MCI) in the COMPASS‐ND study (February 2020 release) were analyzed. MBI was approximated using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) using a published algorithm. Dual‐task gait cost (DTGC), operationalized as the percentage difference between dual‐task and preferred walking speeds, was assessed under three cognitive tasks: animal naming, counting backwards by one, and serial seven subtractions. Multivariable linear regression was used to determine the association between global MBI burden and DTGC, adjusting for age, sex, years of education, and Montreal Cognitive Assessment (MoCA) score, or diagnosis. Models were additionally fitted for the subgroup of participants with MCI alone. Mediation analyses were conducted using bootstrapping to determine if the association between MBI and DTGC was mediated by global cognition (MoCA), executive function (Trail Making B), verbal (Rey Auditory Verbal Learning Test) or working (Digit Span) memory.ResultParticipants on average were 72.4 years old (52.8% female) and had completed 15.8 years of education. MBI symptoms were observed in 46.6% of participants. Greater overall MBI burden was associated with reduced gait speed and higher DTGC for all three gait conditions in MCI, and in all participants without dementia when controlling for diagnosis or MoCA (Table 1), except for DTGC under animal naming conditions when controlling for MoCA. The associations between MBI and DTGC were mediated by executive function but not global cognition, verbal or working memory (Table 2).ConclusionIn this group of older adults at risk but without dementia (SCD and MCI spectrum), MBI is associated with DTGC, which in itself is a dementia risk marker. Our findings support the role of these non‐cognitive dementia markers in the detection of at‐risk individuals. Identification of older adults at risk of incident dementia may be enhanced by considering MBI and DTGC in conjunction.
Ketones and improved cognition in MCI: Links to ApoE and white matter energetics
Authors: Cunnane Stephen , Roy Maggie , Rheault François , Fortier Melanie , Descoteaux Maxime , Castellano Christian‐Alexandre , St. Pierre Valerie , Bocti Christian , Fulop Tamas 
Published: December 2021

AbstractBackgroundThe capacity of ketones to improve cognition in mild cognitive impairment (MCI) may depend on ApoE4 status. In the BENEFIC RCT (NCT02551419), improvement in three cognitive domains was directly related to ketones from medium chain triglyceride (kMCT) improving global brain energy status. Post‐kMCT, ketone uptake increased 2.9‐fold in total white matter (WM) and was significantly positively correlated to improved processing speed composite score in 8/9 WM fascicles, especially the fornix (r = 0.47‐0.61; p = 0.014‐0.072; n=16‐17/group). Here we report from the same trial the relationship to both ApoE4(‐) and to WM structural properties post‐intervention.MethodsIn MCI, cognitive outcomes were assessed before and after a 6‐month intervention involving an active arm (15 g kMCT twice/day; n=39) and placebo arm (non‐ketogenic vegetable oil; n=43), both emulsified into a lactose‐free skim milk drink. Brain imaging (18F‐fluorodeoxyglucose [FDG] and 11C‐acetoacetate PET, diffusion MRI at 3 Tesla) was done on a subset of the main cohort.ResultsParticipant demographics and imaging methods were previously reported (Fortier et al. Alz Dementia 2019). In ApoE4(‐) participants, two measures of executive function (verbal fluency [p≤0.016] and Stroop total errors [0.008]) improved more post‐kMCT (n=28) compared to placebo (n=32). Faster completion of the Trail‐making test (motor speed and visual scanning conditions that measure attention and processing speed), was also directly correlated to higher ketone uptake in most of these nine fascicles. Six months on kMCT did not significantly affect WM fascicle structural properties measured by diffusion imaging (apparent fiber density, free water). Diffusion‐tensor imaging metrics and FDG uptake were also unaffected in total WM and in most individual fascicles.ConclusionsIn MCI, the beneficial effect of kMCT on executive function was greater in ApoE4(‐). Better processing speed and attention was directly linked to improved WM energetics, specifically higher ketone uptake in fascicles affected in AD, but did not alter WM structural properties measurable by diffusion imaging. Ketones improved outcomes in all five main cognitive domains in MCI so a ketone‐based prevention‐type trial to delay the onset of AD is warranted. Acknowledgements: Supported by the Alzheimer Association, Nestlé Health Science, MITACS, FRQS and USherbrooke.
Entorhinal thickness: A marker of DHA supplementation efficacy?
Authors: Yassine Hussein N , Solomon Victoria A , He Xulei , Cordova Isabella , Kono Naoko , Mack Wendy J , Chui Helena C , Schneider Lon S , Harrington Michael G , Braskie Meredith N , Fonteh Alfred N 
Published: December 2021

AbstractBackgroundThe entorhinal cortex (ERC) area in the brain is affected early in AD, particularly among APOE4 carriers. We previously reported a positive association between plasma phospholipid docosahexaenoic acid (DHA) levels and the ERC thickness in the Aging Brain Program. We hypothesize that increases in plasma DHA after high‐dose DHA supplementation protects against thinning of the ERC when started before cognitive impairment including in APOE4 carriers, and that ERC thickness can be a useful marker for DHA supplementation efficacy.MethodWe examined the effect of DHA treatment and association of plasma DHA species on the changes in the ERC area in the DHA Brain Delivery Pilot Trial (NCT02541929). T1‐weighted MRI scans were collected at 3T and FreeSurfer software was used to segment the ERC thickness. Total DHA, DHA in phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and phosphatidylethanolamine (PE) were measured in plasma together with Red blood cell (RBC) DHA levels before and after randomization to 2 grams of triglyceride DHA per day vs placebo over 6 months (n=28). Participants were all cognitively normal, consumed less than 200 mg of DHA per day, and were stratified by APOE4 genotype before randomization.ResultDHA treatment, adjusted for APOE4, was associated with a significant increase in ERC area thickness compared with placebo (mean group difference in ERC change (95% CI) 0.161 (0.003, 0.319), p=0.046). Among DHA subspecies measured, greater increase in plasma PC DHA levels after supplementation was significantly correlated with greater ERC area (mean ERC change per SD of PC DHA=0.103, p=0.011). The association persisted after adjusting for APOE4 status (mean ERC change per SD of PC DHA=0.109, p=0.007), indicating that the effect was independent of APOE4 status.ConclusionThese preliminary findings support a protective effect of high dose DHA in preserving the ERC thickness, including among APOE4 carriers. This finding supports early intervention, before the onset of cognitive impairment, with high dose DHA supplementation in individuals at risk of cognitive decline. PREVENTE4 trial (NCT03613844) is ongoing to help understand whether high dose DHA can prevent cognitive decline in individuals at increased risk of AD.HNY is supported by AA NIRG‐15‐361854, R01AG054434, R21AG056518, ADDF GC‐201711‐2014197.
One in five community‐dwelling older adults will develop Alzheimer's dementia in five years
Authors: Ford Christopher N , Rajan Kumar B , Bennett David A 
Published: December 2021

AbstractBackgroundAlzheimer's dementia (AD) is the most common form of dementia and a growing public health problem. By 2050, one in 85 adults globally will have the disease, for which there are few effective treatments. The objective of this study was to estimate the five‐year incidence rate of AD among predominantly White, community‐dwelling older adults.MethodData were included from 837 community‐dwelling older adults in the Rush Memory and Aging Project (MAP) with ≥2 cognitive assessments and clinical neurological exams, which were collected annually for up to 15 years (mean: 5.06; SE: 0.01). Enrollment for the current study began in 2004. Participants in MAP were community‐dwelling older adults recruited from >40 retirement communities in Chicago beginning in 1997 and followed until death, first diagnosis of probable AD, or until lost to follow‐up. A life table was used to estimate follow‐up time. Estimates of the incidence rate in this and prior MAP studies reporting incidence of AD based on cognitive testing (not autopsy) were pooled. Fixed and random effects models were used to estimate the pooled incidence rate using Episheet.ResultIn the current study, the mean age was 82.1 years (SE: 1.5 years) and respondents were predominantly non‐Hispanic White (n=776; 92.7%), 5.7% non‐Hispanic Black (n=48) and predominantly female (n=633, 75.6%). There were 200 cases of probable AD over 5,098 person‐years of follow‐up (incidence rate: 0.039; 95% CI: 0.034; 0.045 cases per year of follow‐up). Six studies, including an estimated total of 27,816 person‐years of follow‐up and 1,045 cases of probable AD, were included in the pooled analysis. The pooled incidence rate from fixed effects models was 0.038 cases/year (95% CI: 0.036; 0.040). The pooled incidence rate from random effects models was 0.037 cases/year (95% CI: 0.035, 0.041). The test of heterogeneity was p=0.128.ConclusionThese findings suggest that one in five (19%) predominantly White, community‐dwelling older adults will develop AD over five years. The burden of AD is already high but expected to increase significantly as the average age of the US population increases. This points to an urgent and growing need to find an effective treatment for Alzheimer’s dementia.
Plasma p217+tau concordance with 18F‐NAV4694 beta‐amyloid and 18F‐MK6240 tau PET in mild Alzheimer’s disease and cognitively unimpaired participants in the AIBL/ADNeT cohort
Authors: Rowe Christopher C. , Doecke James D. , Saad Ziad S. , Triana‐Baltzer Gallen , Slemmon J. Randall , Krishnadas Natasha , Fowler Christopher J. , Rainey‐Smith Stephanie R. , Ward Larry , Robertson Joanne , Martins Ralph N. , Fripp Jurgen , Masters Colin L. , Villemagne Victor L. , Kolb Hartmuth C. , Dore Vincent 
Published: December 2021

AbstractBackgroundBeta‐amyloid (Aß) PET assists diagnosis of Alzheimer’s disease (AD) and has an important role in selection for trials. Aß PET is costly. Reports suggest that plasma measures of phospho‐tau have high concordance with both Aß and tau PET. We compared a new assay, plasma p217+tau to Aß and tau PET.Method181 MCI/mild AD and 222 cognitively unimpaired (CU) participants in AIBL and the Australian Dementia Network (ADNeT) trial screening program were studied. Aß PET threshold was set at 25 centiloids (CL) as the standard for defining a positive scan and also at 50 CL which best correlates with NIA/AA AD neuropathologic change criteria. In CU we also evaluated a 20 CL PET threshold as this may be used in preclinical trial selection. Tau PET threshold was set at the SUVR (normalised to cerebellar cortex) for a meta‐temporal ROI (entorhinal cortex, amygdala, parahippocampus, and fusiform, inferior and middle temporal gyri) at the 95th percentile of Aß PET negative CU. Plasma p217+tau was measured with SIMOA using a Janssen in‐house assay. ROC area under the curve (AUC) was generated with Youden Index defined sensitivity (sens) and specificity (spec).ResultRank‐order correlation between p217+tau and Aß CL was significant in MCI/AD: ρ=0.65, p<10‐22 and CU: ρ=0.45, p<10‐12 and with tau SUVR for MCI/AD:ρ=0.68, p<10‐25 and CU:ρ=0.32, p<10‐7. In MCI/AD the AUC for p217+tau to predict Aß >25CL was 0.91 (sens 83%, spec 85%) and at >50CL was 0.90 (sens 73%, spec 93%). For tau+ PET the AUC was 0.86 (sens 73%, spec 90%). In the CU, the AUC vs Aß >25CL was 0.84 (sens 81%, spec 81%) dropping to 0.79 (sens 72%, spec 82%) for the 20CL PET threshold. The AUC vs tau+ PET in CU was 0.87 (sens 90%, spec 76%).ConclusionPlasma p217+tau showed good concordance with PET defined Aß and tau positivity in both MCI/AD and CU indicating potential to support the diagnosis of AD and to screen for preclinical AD trials. Early triage with p217+tau may reduce the number of screening Aß PET needed to identify Aß+ PET CU for preclinical trials by 50%.
Evaluating robustness of the Centiloid scale against variations in amyloid PET image resolution
Authors: Shekari Mahnaz , Salvadó Gemma , Battle Mark R , Collij Lyduine E. , Heeman Fiona , Alves Isadora Lopes , Palombit Alessandro , Buckley Chris J , Farrar Gill , Bullich Santiago , Visser Pieter Jelle , Scheltens Philip , Barkhof Frederik , Gispert Juan Domingo ,   AMYPAD consortium
Published: December 2021

AbstractBackgroundThe Centiloid method enables direct quantitative comparison of amyloid‐PET scans acquired with different amyloid tracers. However, it does not explicitly model differences in image resolution which may have an impact on quantification, particularly in multicenter studies. This study evaluated the stability of the Centiloid scale with or without post‐processing smoothing to simulate distinct reconstruction settings. In addition, the effect of reference region selection was assessed.MethodsA total of 318 [18F]flutemetamol PET scans from the ADC and EMIF‐AD Twin 60++ cohorts are included in this study (Table 1). Scans were reconstructed with LOR‐Ramla algorithm. Additionally, images were smoothed to get an effective resolution of 8mm. All images were quantified with a validated Centiloid (CL) pipeline using the GAAIN cortical composite and five different reference regions (whole cerebellum, cerebellum gray, pons, whole cerebellum+brainstem and eroded white‐matter). To assess the impact of reconstruction settings on CL values, we calculated the mean absolute difference between CL values of the original reconstructions vs the smoothed images. Differences above 5CL were considered as relevant. Finally, Bland‐Altman plots were used to assess whether any proportional bias was present between these outcome measures.ResultsFigure 1 displays image quality differences between local reconstruction settings and post‐smoothed images. CL values were not significantly affected by reconstruction methods using either whole cerebellum, whole cerebellum+brainstem, or white‐matter as reference region (Table 2). However, for the images with a higher level of amyloid, ΔCL was higher than 5 using whole cerebellum. On the contrary, the CL was highly affected by image resolution when using the pons as reference region, introducing constant bias for all ranges of amyloid burden. Using cerebellum gray, ΔCL has an inverse linear relationship with amyloid burden, though it was below 5CL for subjects with low to moderate amyloid burden, and differences above 5 were observed for images with CL above 80 (Figure 2).ConclusionWhole cerebellum and whole cerebellum+brainstem, the standard reference regions in CL quantification, are capable of providing stable CL values irrespective of image resolution for a wide range of amyloid burden. Other reference regions were less stable.
Evaluation of sensory gating efficiency in adults with Down syndrome
Authors: Le April 
Published: December 2021

AbstractBackgroundIn Down syndrome (DS), the amyloid precursor protein (APP) gene‐dosing effect drives a lifelong over‐production of amyloid‐beta (Aβ). The accumulation of Aβ begins to manifest as amyloid plaques as early as the teens and virtually in all by 40 years. The progression of Alzheimer’s Disease(AD)‐related neuropathology may underlie inhibitory disruption leading to over‐ or under‐sensitivity to auditory processing and cognitive deficits in DS. In positron electromagnetic tomography (PET) studies in DS, amyloid deposition has a defined temporal‐spatial profile that begins in the striatum and predictably progresses to the dorsolateral pre‐frontal cortex (DLPFC) and ventral pre‐frontal cortex (VPFC). Typically developing (TD) individuals with AD exhibit deficits of sensory gating, which can lead to sensory overload and disruption of higher cognitive processes. The auditory paired‐click paradigm has been used to evaluate sensory gating deficits in AD. We extend this inquiry to a cohort with DS to assess sensory gating in adults with DS by measuring the P50 and the N100 event‐related potential (ERP) components. The P50 component is elicited 50 ms post‐stimulus, involves the DLPFC and is sensitive to striatum‐dependent sensory gating. The N100 is elicited 100 ms post‐stimulus by auditory stimuli in absence of task demands.MethodIn this cross‐sectional study, data were collected using high‐density QEEG in 39 DS adults and 39 age‐matched TD controls. In this paradigm, two identical auditory stimuli (S1 and S2) were presented. For each stimuli, the response latency and amplitudes of the P50, and more salient N100 component were measured at the Cz and Fz electrode sites. General linear models examined the modulation of the ERP responses to S1 and S2 between the two groups.ResultWith P50 and N100 response amplitudes, an effect of stimulus was found. In the DS group, longer response latencies for the P50 and N100 corresponding to both S1 and S2 were observed.ConclusionIn DS, the ability to gate‐out irrelevant sensory information is intact when compared to TD; however, there is an overall slower processing of auditory stimuli, which may be attributed to amyloidopathy. The EEG‐based paired‐click paradigm offers functional insight into potential biomarkers for pre‐clinical AD in DS.
Neighborhood racial/ethnic segregation and cognition in older adults
Authors: Meyer Oanh L , Besser Lilah M , Booker Michaela , Luu Elaine , Mitsova Diana , Tobias Michele , Whitmer Rachel A , Farias Sarah Tomaszewski , DeCarli Charles S , Mungas Dan M 
Published: December 2021

AbstractBackgroundSocial determinants of health, including neighborhood factors, play a key role in the health of diverse older adults. Yet few longitudinal studies have examined the role of neighborhood racial/ethnic segregation on cognitive function and cognitive decline in both Latinos and Blacks, two populations at greater risk for Alzheimer’s disease and related dementias. We examined how one measure of residential segregation is associated with cognitive outcomes in a diverse cohort.MethodsWe evaluated older non‐Hispanic White (NHW), Black, and Latino participants evaluated at the UC Davis Alzheimer’s Disease Research Center. Individual level addresses were geocoded at the initial visit and appended to U.S. Census 2010 data. Residential segregation was measured using the Getis‐Ord Gi* statistic; this spatial measure of clustering was created for Latino and Black clustering separately. Cognitive outcomes included validated measures of episodic memory, semantic memory, and executive function. We used mixed effects multivariate regression models to evaluate associations between segregation and cognitive function and decline, controlling for age, sex, education, cognitive status at initial visit, clinic versus community recruited, site, vascular risk score, number of visits, neighborhood SES, and population density.ResultsThe sample included 452 participants (mean age=75, SD = 7), 64% female, and 46% NHW, 26% Black, and 21% Latino, in 309 census tracts/neighborhoods. In race‐stratified adjusted analyses, Blacks demonstrated worse episodic memory at baseline among those living in neighborhoods with a higher clustering of Blacks (ß = ‐0.046; 95% CI: ‐0.075, ‐0.016) and worse executive function at baseline among those living in neighborhoods with a higher clustering of Latinos (ß = ‐0.025; 95% CI: ‐0.042, ‐0.008). Latinos demonstrated slower annual declines on episodic memory when living in neighborhoods with a greater clustering of Blacks (ß = 0.008; 95% CI: 0.004, 0.011) and/or Latinos (ß = 0.003; 95% CI: 0.001, 0.005). NHWs had slower annual declines on semantic memory when living in neighborhoods with a greater clustering of Latinos (ß = 0.005; 95% CI: 0.001, 0.008).ConclusionsThere may be some benefit for Latinos and NHWs living in ethnically clustered neighborhoods. Future research is needed to further investigate these findings.
Sex and APOE genotype‐specific white matter changes in Alzheimer’s disease
Authors: Horgusluoglu‐Moloch Emrin , Wang Minghui , Zhou Xianxiao , Zeng Qi , Zhang Bin 
Published: December 2021

AbstractBackgroundAPOE ε4 genotype and sex difference represent strong risk factors for Alzheimer’s Disease (AD) that also lead to white matter (WM) microstructural changes. However, it is still not clear which brain regions have the strongest changes with APOE ε3 and ε4 allele carrier status and sex difference, and what are the key drivers and biological pathways underlying WM abnormality during disease progression. In this study, we present a new comprehensive framework to identify sex‐ and APOE genotype‐specific WM changes in specific brain regions with AD severity using the data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐GO/2).MethodDTI‐derived features including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1), radial diffusivity (RD) were calculated from ADNIGO/2 (N = 232). ADNI participants were classified depending on their sex and APOE genotype status as female APOE ε3/3, male APOE ε3/3, female APOE ε4 positive, and male APOE ε4 positive. Through correlating DTI features with the clinical/cognitive traits, we systematically rank‐ordered 176 brain regions in relation to disease severity for each group. Multiscale Embedded Gene co‐Expression Network Analysis (MEGENA) was performed using processed expression data to identify clusters of highly correlated genes and DTI‐features as modules. Gene Set Enrichment Analysis (GSEA) was carried out to annotate each module with enriched pathways for each group.ResultThe parahippocampal gyrus (PHG)‐right, posterior thalamic radiation (PTR)‐left, hippocampus (HIPPO)‐left, and the superior temporal gyrus (STG)‐right were top‐ranked regions with sex and APOE ε3 and ε4 alleles carrier status (Figure 1A‐D). WM changes in PTR‐right are the only specific for the male APOE ε4+ group compared to the other groups. PHG‐right is highly associated with worse AD clinical outcomes in APOE ε4 allele carriers regardless of sex difference. DTI features in MTWM‐left is significantly correlated with only female APOE ε3 group. Besides, the immune system, mitochondrial regulation, and myeloid cell differentiation are among the pathways enriched with modules in different sex and APOE genotype groups in top brain regions (Table 1).ConclusionEnhanced understanding of the biological processes and key drivers related to sex‐ and APOE genotype‐specific WM microstructural changes could lead to novel therapeutic strategies for AD.