bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal‐retrosplenial connectivity is associated with tau pathology and memory in cognitively normal older adults
Authors: Ziontz Jacob , Adams Jenna N. , Baker Suzanne L. , Jagust William J. 
Published: December 2020

AbstractBackgroundTau pathology is thought to spread transneuronally from medial temporal lobe (MTL) to medial parietal lobe (MPL) in cognitively normal older adults, but it is not known precisely which structures and processes are involved. We hypothesize that functional connectivity influences tau spread from hippocampus to the MPL, with consequences for cognition.MethodNinety‐seven cognitively normal older adults from the Berkeley Aging Cohort Study (76.4±6.1 years) received tau‐PET with 18F‐Flortaucipir, Aβ‐PET with 11C‐PiB, and resting state fMRI. We assessed unilateral resting state functional connectivity (FC) between retrosplenial cortex (RsC), an area of known connectivity with the MTL, and hippocampus (HC), anterolateral entorhinal cortex (alEC), and posteromedial entorhinal cortex (pmEC). We then used linear models to examine the association of FC strength (β‐weight) between RsC and the proportion of suprathreshold voxels for tau accumulation (SUVR>1.4) in MPL. Finally, we examined interactions between FC strength and tau to predict downstream tau accumulation and memory.ResultSemipartial region‐region correlations revealed RsC FC with HC in both hemispheres [Left: β=0.33, p<0.001, Right: β=0.40, p<0.001], but not with alEC or pmEC in either hemisphere (Figure 1). Adjusting for age, sex, and amyloid status, proportion of suprathreshold voxels in MPL was associated with RsC‐HC connectivity strength bilaterally [Left: β=0.153, p=0.004; Right: β=0.186, p=0.002], but not RsC‐alEC or RsC‐pmEC connectivity strength (Figure 2). In addition, proportion of suprathreshold voxels in MPL was associated with the interaction between RsC‐HC connectivity strength and hippocampal tau (pvc‐SUVR) [Left: β=0.586, p=0.008; Right: β=0.613, p=0.022] (Figure 3a). Adjusting for age, years of education, and practice effects, the interaction between RsC‐HC connectivity strength and MPL tau (left hemisphere only) was associated with spatial memory performance [β=‐12.773, p=0.002] (Figure 3b).ConclusionIn cognitively normal older adults, RsC exhibits FC with hippocampus but not alEC or pmEC, and the strength of this RsC‐HC connectivity predicts tau accumulation in the MPL, suggesting that tau pathology spreads to MPL through the hippocampus. Further, RsC‐HC connectivity modulated the relationship between MTL and MPL tau as well as between MPL tau and spatial memory, indicating that MTL‐MPL FC may influence the spread of tau and cognitive function.
ApoE4 associated with higher tau accumulation independent of amyloid burden
Authors: Neitzel Julia , Franzmeier Nicolai , Rubinski Anna , Binette Alexa Pichet , Poirier Judes , Villeneuve Sylvia , Ewers Michael ,   PREVENT‐AD Research Group and the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2020

AbstractBackgroundApoE4 carriage is the strongest genetic risk factor for developing late‐onset AD. Previous studies suggest that ApoE is involved in the amyloid pathway, and that elevated AD risk in ApoE4‐carriers is conferred by higher beta‐amyloid levels. However, recent animal work suggests that ApoE4 is also associated with increased tau pathology (Shi et al, 2017, Nature). Yet, it is unclear whether this association between ApoE4 and tau pathology translates to humans. Thus, the main aim of the current study was to test whether ApoE4 has an amyloid‐independent effect on cross‐sectional and longitudinal tau‐PET in humans.MethodFor longitudinal analyses, we included baseline AV45 amyloid‐PET and longitudinal AV1451 tau‐PET (∼1.3 years follow‐up) from 111 ADNI participants (42ε4+,69ε4‐) including cognitively normal (CN), mild cognitive impairment (MCI) and AD dementia (ADD). For cross‐sectional analyses, we additionally included tau‐ and amyloid‐PET from 254 CN and MCI participants (83ε4+,171ε4) from ADNI (not overlapping with the longitudinal ADNI sample) plus 128 CN participants (53ε4+,75ε4‐) from the PREVENT‐AD cohort (Table 1). Average baseline PET‐SUVR and annual change rates were quantified within 68 Freesurfer‐defined cortical brain regions (Figure 1). Analysis of covariance (ANCOVA) was used to investigate differences in cross‐sectional tau‐PET or longitudinal tau‐PET changes between ApoE4 carriers versus non‐carriers, controlling continuous measures of global amyloid‐PET. Post‐hoc subgroup analyses tested potential ApoE4 effects with a more rigorous control of amyloid‐PET by including only participants with the same amyloid status.ResultFor cross‐sectional analyses, we found ApoE4 carriers to show higher tau‐PET compared to non‐carriers after controlling global amyloid‐PET (Figure 2). Across samples, medial temporal areas (entorhinal cortex,parahippocampus) showed the strongest ApoE effect. The amyloid‐independent effect of ApoE4 on medial temporal tau‐PET remained significant in post‐hoc analyses of only amyloid‐positive ADNI or amyloid‐negative PREVENT‐AD participants (data not shown). For longitudinal analyses, we found significantly higher tau‐PET changes in ApoE4 carriers controlled for baseline amyloid‐PET (Figure 3). Strongest effects were found in posterior brain areas (lateral occipital, superior parietal) which remained significant in post‐hoc subgroup analyses.ConclusionThe current results suggest that there is an amyloid‐independent association between ApoE4 and elevated tau‐PET specifically in medial temporal regions.
Sensory impairments and cognition in a diverse cohort: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: George Kristen M , Peterson Rachel , Gilsanz Paola , Mayeda Elizabeth Rose , Mungas Dan M , Glymour M Maria , Brenowitz Willa D , Whitmer Rachel A 
Published: December 2020

AbstractBackgroundSensory impairments have been associated with poor cognition in primarily non‐Latino White cohorts. We used the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study to examine racial/ethnic differences in the association between sensory impairments and cognition.MethodKHANDLE includes diverse, community‐dwelling adults ages 65+ living in North California and aims to evaluate how race/ethnicity influence brain health. Analysis included 1,623 Asian (24%), Black (26%), Latino (18%), and White (32%) individuals. Participants rated their hearing and vision and were classified as impaired (self‐report of “Fair” or “Poor”) or not impaired (“Excellent,” “Very Good,” or “Good”) in hearing, vision, or both. Cognition was measured using the Spanish and English Neuropsychological Assessment Scales (SENAS). Cognitive test scores for executive function, semantic memory, and verbal episodic memory were z‐standardized and averaged for a global z‐score. Linear regression was used to estimate the associations between sensory impairments and cognition, adjusted for age, gender, race, education, income, waist circumference, physical activity, alcohol consumption, and ever smoking tobacco. Race/ethnicity interaction terms were tested.ResultParticipants had a mean age of 76 (SD=7). Whites (23.9%) were the most likely to report hearing impairment followed by Latinos (19.4%), Asians (18.0%), and Blacks (11.6%). Latinos (13.2%) were the most likely to report vision impairment followed by Blacks (12.5%), Asians (10.3%), and Whites (8.6%). Blacks (16.0%) were the most likely to report concurrent vision and hearing impairment followed by Latinos (11.8%), Asians (11.3%), and Whites (9.8%). Associations between sensory impairments and cognition did not differ by race/ethnicity. Associations remained consistent across the cognitive domains but were strongest for semantic memory. Hearing impairment was not associated with global cognition [β(95% CI):‐0.04(‐0.12, 0.05)]. Participants with visual impairments had worse global cognition than those without visual impairment [β:‐0.18(‐0.27, ‐0.09)]. Compared to those with no impairments, global cognition did not differ for participants with one impairment [β:‐0.03(‐0.12, 0.05)], but was significantly worse in those with dual sensory impairments [β:‐0.20(‐0.33, ‐0.08)].ConclusionWe found no racial/ethnic differences in the association between sensory impairments and cognition. Self‐reported vision impairment was associated with poor cognition, but self‐reported hearing impairment was not.
Neurocognitive testing in a diverse linguistic setting: Measurement invariance of ICMR‐Neuro Cognitive Tool Box across five languages
Authors: Alladi Suvarna , Varghese Feba Anna , Paplikar Avanthi , Sharma Meenakshi ,   ICMR Neurocognitive Tool Box Consortium
Published: December 2020

AbstractBackgroundRecently there have been ongoing efforts to harmonise research across dementia cohorts from different centres and countries. Establishing comparability of cognitive test performance across languages and educational levels therefore becomes crucial. Differences due to educational disparity or linguistic variability will need to be differentiated from more genuine differences due to disease. This is especially important in countries like India that are characterised by a socioculturally heterogeneous population. To address this, the Indian Council of Medical Research‐Neuro Cognitive Test Battery (ICMR‐NCTB) was developed and validated to diagnose dementia in five Indian languages. In this study, we aimed to investigate the cognitive construct and comparability of the ICMR‐NCTB across five Indian languages using confirmatory factor analysis and measurement invariance.Methods991 healthy literate controls with normal cognition (Telugu = 302; Hindi = 191, Malayalam = 195; Bengali = 135 and Kannada = 168) were assessed with the ICMR NCTB which includes tests of attention/executive function, verbal and visual episodic memory, language and visuospatial Functions. The dimensional structure of ICMR‐NCTB was studied with regard to its cognitive constructs, and measurement invariance across five different Indian languages was evaluated.ResultsConfirmatory factor analysis of the data demonstrated that a five factor model in which the tests were divided into the cognitive domains: attention/executive function, verbal memory, non‐verbal memory, language and visuospatial functions provided the best model fit both within and across all five languages. Analysis of factorial invariance across groups indicated that configural and metric invariance were achieved, thereby suggesting that the tests of the ICMR‐NCTB measure the same cognitive construct across different languages. On analyzing scalar invariance, non‐invariance of intercept was demonstrated, indicating a possible measurement bias between the different language groups.ConclusionsThe study results indicate that cognitive constructs measured by the tests in the ICMR‐NCTB across the five different Indian languages are the same. However, there are differences that influence the performance of subjects across languages groups. The study findings have significant implications for harmonising cognitive test data in dementia research that involves linguistically diverse cohorts.
Pharmacokinetics and safety profile of intramuscular administration of allopregnanolone in patients with Alzheimer’s disease
Authors: Hernandez Gerson D. , Lopez Claudia M. , Wang Yiwei , Rodgers Kathleen E. , Schneider Lon , Brinton Roberta Diaz 
Published: December 2020

AbstractBackgroundAllopregnanolone (Allo) is a novel regenerative therapeutic that also reduces the burden of Alzheimer’s disease (AD) pathology. We have previously established safety, tolerability and a pharmacokinetic profile of Allo administered intravenously in AD patients. In this phase 1b trial, we assess the safety, tolerability and pharmacokinetics of Allo administered via an intramuscular injection in patients with AD.MethodAn open label, multiple ascending dose, phase 1b clinical trial was conducted in patients ranging from mild cognitive impairment due to AD to moderate AD. Men and women age ≥ 55 years, with a MMSE score ≥10 were recruited to the study. Patients had previously participated in the phase 1 study of Allo administered IV. Participants received weekly intramuscular injections with a dose escalation regimen of 4, 8, 12 and 16mg of Allo. Blood was collected before the injection and after at the following timepoints: 5, 15, 30, 45 minutes; 1, 2, and 4 hours. Primary outcomes included safety and tolerability parameters. Secondary endpoints included PK parameters: tmax (time to reach maximum plasma concentration), Cmax (maximum plasma concentration), AUC0‐last (area under the plasma concentration‐time curve from time zero to time of the last measured concentration above the limit of quantification), AUC0‐inf (area under the plasma concentration‐time curve from zero to infinity), t½ (terminal elimination half‐life).This is part of an IV to IM bridging study to determine the IM formulation dose that is equivalent to the IV Allo dosing (Clinicaltrials.gov: NCT03748303).ResultA total of 6 participants have completed the pharmacokinetic assessment. Injection was well tolerated and did not elicit adverse events. Pharmacokinetic profile indicates direct rank order and near dose proportionality for both Tmax and AUCinf. Second group dosing and study procedures are currently underway.ConclusionIntramuscular administration of allopregnanolone was well tolerated, and did not elicit adverse effects in the initial cohort. Pharmacokinetic profile indicates direct rank order and near dose proportionality for both Tmax and AUCinf. Acknowledgments: Alzheimer’s Association Part The Cloud, Alzheimer’s Drug Discovery Foundation.
Sex differences in body composition in non‐demented individuals with autosomal dominant Alzheimer’s disease
Authors: Ramirez‐Gomez Liliana A , Fuller Joshua T , Rabin Jennifer S , Bocanegra Yamile , Guzman‐Velez Edmarie , Vila‐Castelar Clara , Pardilla‐Delgado Enmanuelle , Schoemaker Dorothee , Gatchel Jennifer R , Baena Ana , Giraldo‐Chica Margarita , Munoz Claudia , Tirado Victoria , Henao Eliana , Lopera Francisco , Quiroz Yakeel T. 
Published: December 2020

AbstractBackgroundBody mass index (BMI) is a known risk factor for Alzheimer’s disease (AD). Research with autosomal dominant Alzheimer’s disease (ADAD) has shown a relationship between lower BMI, greater amyloid burden and worse memory performance in presymptomatic mutation carriers. Women have a higher incidence of AD, and may be more susceptible to AD‐ related pathology. However, little is known about the effects of sex/gender on BMI in individuals at increased risk for AD. As carriers of ADAD mutations are destined to develop early‐onset dementia, they allow us to investigate sex differences without aging confounds known to vary by sex (i.e., life expectancy, menopause). We sought to examine sex differences in BMI in non‐demented mutation carriers and non‐carriers from a Colombian kindred with ADAD.Method191 carriers of the Presenilin‐1 E280A mutation (104 females; age range: 18‐55 years) and 261 age‐matched non‐carriers (165 females) were included. All participants completed clinical and cognitive assessments, including BMI (kg/m2) measures, MMSE and CERAD Word List tests. Mann‐Whitney‐U test was used to examine sex differences on BMI. General linear models were used to examine the associations between BMI, MMSE and memory, controlling for age and education.ResultCompared to non‐carriers, carriers had lower BMI (carriers: 23.05 +/‐ 3.65; non‐carriers: 24.26 +/‐ 3.92, p=0.002). In carriers, lower BMI was associated with worse performance on MMSE (r=0.49, p=0.001). Compared to male carriers, female carriers had greater BMI (males: 22.4 +/‐ 3.3, females: 23.5 +/‐ 3.7, p=0.04), and performed worse on the MMSE (males: 28.19 +/‐1.8, females: 27.91 +/‐1.91, p=0.04). There was a trend for female carriers to also have worse memory performance (p=0.06). Sex differences were not observed in non‐carriers. There were no associations between BMI and memory.ConclusionThere are sex differences in body composition in carriers of ADAD without dementia. These findings suggest that changes in BMI may reflect early signs of abnormal systemic responses to AD‐related pathology. Future studies should examine longitudinal changes in BMI, from preclinical to clinical stages, and other contributing factors (e.g. vascular risk factors and sex hormones) to determine the potential role of BMI as a risk factor for dementia.
Physical activity and vascular cognitive health: Who may benefit most?
Authors: Shaaban C Elizabeth , Chang Chung‐Chou H , Ganguli Mary 
Published: December 2020

AbstractBackgroundThe majority of people with dementia in the population have mixed neurodegenerative and cerebrovascular pathology. Stroke and dementia share many risk factors, and both have potential to impair function and quality of life. Therefore, a comprehensive understanding of vascular brain and cognitive health should integrate stroke and dementia. The association of physical activity (PA) with lower dementia risk suggests PA is a promising strategy to reduce stroke and dementia, and it is critical to understand who may benefit most.MethodsWithin a population‐based cohort study, with up to 10 years of follow‐up, we indexed PA by cumulative weekly minutes walked for exercise. We used survival analysis classification and regression trees (CART) to test which sub‐groups are at greatest risk for a composite outcome of stroke/dementia and to determine optimal PA cutoffs associated with no stroke/dementia in sub‐groups of interest.ResultsOf 1,982 participants recruited from voter rolls, 1,624 were free from stroke and dementia at baseline and had follow‐up visits. 62% were female, 5% Black, 42% had > high school education, 21% were APOE4+, and 65% were hypertensive at baseline. During 9,354 person‐years of follow‐up, N=133 developed stroke/dementia. The median cumulative walking time was 60.0 minutes. Among those with high PA, a group aged 82‐94 + APOE4+ had the highest risk (relative hazard ratio(RHR) of 6.4). In those with low PA, a group aged 82‐99+≥HS education+Black had the greatest risk of dementia/stroke (RHR=4.1). When examining thresholds in women, those APOE4‐, and those with hypertension (HTN), the optimal cutpoint was around 40‐50 minutes across a mean follow‐up time of nearly 6 years. Thresholds could not be determined for men, APOE4+, and those without HTN, likely due to smaller within strata sample sizes; however, the overall population cutpoint of 160 minutes suggests that thresholds in men, APOE4+, and those without HTN may be higher.ConclusionsOur results add evidence that PA can reduce risk of stroke and dementia. Women, those who are APOE4‐, and those with HTN may need fewer minutes of PA than the overall population in order to benefit. These findings are relevant from a personalized medicine perspective.
Plasma neurofilament light chain levels reflect caregiver burden and social cognition measures in familial frontotemporal lobar degeneration (FTLD)
Authors: Heuer Hilary W. , Rojas Julio C. , Toller Gianina , Rankin Katherine , Brushaber Danielle , Appleby Brian , Bordelon Yvette M. , Dickerson Brad C. , Kimiko Domoto‐Reilly , Faber Kelley , Foroud Tatiana M. , Forsberg Leah K , Ghoshal Nupur , Grant Ian , Graff‐Radford Neill R. , Grossman Murray , Hsiung Ging‐Yuek Robin , Huey Edward D. , Karydas Anna M. , Kaufer Daniel , Kerwin Diana R. , Lagone Emma , Litvan Irene , Ljubenkov Peter A. , Mackenzie Ian R. , Mendez Mario F. , Miller Bruce L. , Onyike Chiadi U. , Ramos Eliana Marisa , Rascovsky Katya , Roberson Erik D. , Tartaglia Carmela , Weintraub Sandra , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. ,   ARTFL/LEFFTDS Investigators
Published: December 2020

AbstractBackgroundPlasma NfL is a sensitive marker of axonal injury that is elevated in symptomatic FTLD and asymptomatic carriers of FTLD‐associated genetic mutations at short‐term risk of phenoconversion to mild behavioral or cognitive impairment or dementia. In carriers of FTLD‐associated genetic mutations, NfL is associated with clinical measures of disease severity.MethodPlasma NfL was measured using single molecule array technology in baseline blood samples from 290 participants in the ARTFL/LEFFTDS consortia. Participants included 181 asymptomatic mutation carriers (C9orf72, GRN, and MAPT); 45 with mild impairment (MBI/MCI), and 64 with dementia. 103 family members without FTLD‐associated mutations served as asymptomatic controls. Social cognition scales were obtained through clinical evaluation at baseline, year 1, and year 2. Stepwise linear regressions assessed NfL relationships with baseline social cognition measures. Linear mixed models were used to test the ability of baseline NfL to predict longitudinal changes. Analyses corrected for age, sex, and genotype.ResultAt baseline, plasma NfL correlated with all measures of social cognition, regardless of genotype. Associations were strongest for the Revised Self‐monitoring Scale (RSMS;β = ‐.50, p < .001), total score of the Social Norms questionnaire (β= .48, p < .001), and caregiver burden (Zarit burden;β = .55, p < .001). Regardless of disease severity, baseline NfL related to worse RSMS scores over time (‐3.7 points at year 2/ LogNfL unit increase, 95% CI ‐1.7 to ‐5.7, p < .001). In MBI/MCI, higher baseline NfL was associated with worse longitudinal scores on the Social Norms questionnaire (‐5.9 points at year 2/LogNfL unit increase, 95% CI ‐1.1 to ‐10.7, p = .016). No associations were seen in asymptomatic non‐carriers.ConclusionIn this familial FTLD cohort, plasma NfL is correlated with clinical measures of social cognition and caregiver burden. Higher baseline plasma NfL concentrations are associated with worsening self‐monitoring and social norms scores over time. These associations suggest that NfL is correlated with clinically meaningful measures that may be relevant to therapeutic development.