bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physical Activity Relates to Lower Astrocytic Activation and Axonal Breakdown in Clinically Normal Older Adults
Authors: VandeBunte Anna M , Lee Shannon Y. , Paolillo Emily W , Rojas Julio C. , Chan Brandon , Lago Argentina Lario , Kramer Joel H. , Casaletto Kaitlin B 
Published: December 2022

AbstractBackgroundPhysical activity is associated with >30% reduced risk of dementia. However, the biological mechanisms underlying exercise as a protective factor against cognitive decline remain unclear. Astrocytic activation and axonal breakdown, as measured by plasma glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), respectively, are pathways disrupted early in cognitive aging and neurodegenerative disease. We aimed to examine whether an objective measure of physical activity (FitbitTM) related to plasma levels of GFAP and NfL in clinically normal older adults.Method57 clinically normal older adults completed 30‐day FitbitTM Flex2 monitoring (average daily steps and calories burned estimated) and a blood draw with plasma analyzed via Quanterix SIMOA for GFAP and NfL. A subset (n = 48) completed an amyloid PET scan (18F‐AV45 or 11C‐PIB). Pairwise correlations and linear regression models adjusting for age and cerebral amyloid burden evaluated the associations among Fitbit metrics and plasma markers of interest.ResultHigher Fitbit calories burned and step count correlated with lower levels of GFAP (r = ‐0.33 to ‐0.54, p<0.01) and NfL (r = ‐0.36 to ‐0.45, p<0.01). After controlling for age, average calories burned remained significantly associated with GFAP (β = ‐0.40, p< 0.01) and NfL (β = ‐0.30, p<0.01), while the associations attenuated between total steps with GFAP (β = ‐0.14, p = 0.31) and NfL (β = ‐0.17, p = 0.18). Effect sizes for all models remained similar further adjusting for amyloid PET centiloid levels (calories burned: GFAP: β = ‐0.44, p< 0.01; NfL: β = ‐0.29, p = 0.06; and total steps: GFAP: β = ‐0.23, p = 0.14; NfL: β = ‐0.26, p = 0.10). Interactions between Fitbit metrics and amyloid PET centiloids were not statistically significant for GFAP or NFL (ps >0.5).ConclusionGreater step count and, particularly, calories burned was associated with markers of lower astrocytic inflammation and axonal degeneration in older adults. Our results demonstrate that calories burned may have a more direct (and positive) impact on axonal and astrocytic health in comparison to overall movement. Consequently, these findings suggest higher intensity calorie burning activities may be an important brain health recommendation for older adults. Careful understanding which aspects of physical activity map onto which biological pathways of brain health could inform more precise exercise recommendations and intervention.
Cross‐sectional and longitudinal comparison of 18F‐MK6240 and 18F‐Flortaucipir in populations matched for centiloid, age and MMSE
Authors: Bourgeat Pierrick , Krishnadas Natasha , Dore Vincent , Mulligan Rachel S , Tyrrell Regan , Bozinovski Svetlana , Huang Kun , Lamb Fiona , Fripp Jurgen , Villemagne Victor L , Rowe Christopher 
Published: December 2022

AbstractBackgroundLongitudinal tau quantification may provide a useful outcome measure in disease‐specific therapeutic trials. Different tau PET tracers may have different sensitivity to longitudinal changes, but without a head‐to‐head comparison, equating results from different cohorts using different tracers can be biased. In this study, we aim to minimise this bias by matching participants in two cohorts imaged using 18F‐MK6240 and 18F‐Flortaucipir (FTP).MethodA subset of 93 participants from AIBL and 93 from ADNI, imaged at baseline and 1 year later using 18F‐MK6240 and 18F‐FTP, respectively, were matched based on baseline clinical diagnosis, MMSE, age, and Centiloid value (CL). PET images were analysed with CapAIBL. Amyloid positivity (+/‐) was defined based on a threshold of 25CL. Subjects were grouped as 34 cognitively unimpaired amyloid negative (CU‐) and 24 positive (CU+), 18 mild cognitive impairment positive (MCI+) and 17 Alzheimer’s disease positive (AD+). Tracer retention was measured in the mesial temporal (Me), meta‐temporal (MT), temporoparietal (Te) and rest of the cortex (R). T‐tests were employed to assess group separation at baseline using SUVR and longitudinally using SUVR/Yr.ResultAs per selection criteria, there were no significant differences in age, MMSE or Centiloid between the cohorts using 18F‐MK6240 or 18F‐FTP in each subgroups. Baseline SUVR were significantly different between CU‐/CU+, CU+/MCI+ and CU+/AD+ in all regions for both tracers, except for CU‐/CU+ in R for 18F‐MK6240 (Figure 1). Using 18F‐MK6240, rate of change in CU+ was significantly higher than CU‐ in MT and Te, and both MCI+ and AD+ were higher than CU+ in R (Figure 2.Left). Using 18F‐FTP, rate of change in MCI+ was significantly higher than CU+ in Te, and AD+ higher than CU+ in MT, Te and R (Figure 2.Right).ConclusionIn our matched cohorts using 18F‐MK6240 or 18F‐FTP, we found that, at baseline, both tracers can detect significant differences between clinical groups. However, 18F‐MK6240 was able to detect higher rates of accumulation at preclinical stages (CU+). These results in well‐matched cohorts indicate that 18F‐MK6240 might be a more sensitive tracer to detect early accumulation. Longitudinal head‐to‐head comparison will be required to confirm these results.
Multi‐tracer comparison in Alzheimer’s disease, Corticobasal Degeneration and Progressive Supranuclear Palsy brains
Authors: Malarte Mona‐Lisa , Kumar Amit , Nordberg Agneta K 
Published: December 2022

AbstractBackgroundRecent CryoEM studies in tauopathies clearly bought forward one more time the complexity of these pathologies, and showed that it goes beyond the tau isoforms. Tau PET tracers play an important role in the understanding of this aspect. We have observed in post‐mortem brain tissue from Alzheimer’s disease (AD) patients that the second‐generation of tau PET tracers 3H‐PI2620, 3H‐MK6240, 3H‐RO948, all show similar regional distribution, but also comparable binding affinities to multiple binding sites in AD brain large hemispherical tissue section autoradiography and homogenates. In vitro autoradiography can mirror the in vivo binding pattern of PET tracers and be useful in pre‐clinical validations. The aim of this study was to perform a comparative multi‐tracer study in AD, PSP, CBD and control brains with several second generation tau‐tracers to obtain a deeper insight into tau spatial distribution and discriminative power of tau tracers in degenerative proteinopathies. We also want to study how the binding of the tracers correlate with other pathological hallmarks such as amyloid‐β and reactive astrogliosis.Methodswe performed radioligand binding assays in brain homogenates, in small tissue sections and large frozen hemispherical brain sections autoradiography using tau PET tracers (3H‐PI2620, 3H‐MK6240, 3H‐RO948, and 3H‐JNJ067) in comparison to reactive astrogliosis PET tracers (3H‐BU99008 and 3H‐Deprenyl) and amyloid tracer (3H‐PIB).ResultsIn ongoing studies, 3H‐PI2620, 3H‐MK6240 and 3H‐RO948 clearly followed a two binding sites model in AD brains. 3H‐PI2620 bound to two binding sites in the frontal cortex of both AD and CBD but to one site in PSP brains, but in similar high affinity range in the three pathologies. 3H‐RO948 and 3H‐MK6240 showed low binding in comparison to 3H‐PI2620 in CBD and PSP.ConclusionTau PET tracers showed similar affinities to multiple binding sites and similar regional distribution in AD brains. 3H‐MK6240 and 3H‐RO948 displayed selectivity for AD brains, while 3H‐PI2620 also showed similar binding affinity for CBD and PSP brains. Ongoing studies with several PET tracers targeting different pathological hallmarks will increase possible discriminative properties and provide new knowledge on the spatial distribution of tau and its correlation with other biomarkers in different tauopathies.
Herpes Viruses in the Baltimore Longitudinal Study of Aging:Associations with Brain Volumes, Cognitive Performance and Plasma Biomarkers
Authors: Duggan Michael R , Peng Zhongsheng , An Yang , Kitner‐Triolo Melissa , Shafer Andrea T , Davatzikos Christos , Erus Guray , Karikkineth Ajoy , Lewis Alexandria , Moghekar Abhay , Walker Keenan A 
Published: December 2022

AbstractBackgroundAlthough an infectious etiology of Alzheimer’s Disease (AD) has received renewed attention, the longitudinal effects of symptomatic herpes viruses (sHHV) infection on brain structure and cognition remain poorly understood, as does the effect of sHHV on AD/neurodegeneration biomarkers.MethodUsing data from the Baltimore Longitudinal Study of Aging (BLSA), we characterize the association of sHHV diagnoses – defined using ICD‐9 classification – with longitudinal changes in total and regional brain volumes obtained from 3T magnetic resonance imaging (MRI), and cognitive performance across five cognitive domains. Additionally, we relate sHHV to plasma biomarkers of AD (Ab42/40), astrogliosis (glial fibrillary acidic protein [GFAP]) and neurodegeneration (neurofilament light [NfL]). The study design is illustrated in Figure 1.ResultA total of 1,009 participants were included in the primary MRI analysis, 98% of whom were cognitively normal at baseline MRI. Having a sHHV diagnosis (N = 119) was associated with longitudinal reductions in white matter volume (annual additional rate of change ‐0.34 cm3; p = 0.035), particularly in the temporal cortex; however, there was no association between sHHV and change in total brain, total gray matter, or AD signature region volume (Table 1; Figure 2). Among the 119 participants with sHHV infection, exposure to antiviral treatment attenuated declines in occipital white matter (annual reduction in rate of change 0.10 cm3; p = 0.036). Although the sHHV group (N = 290) had higher cognitive scores on certain cognitive domains at baseline, sHHV diagnosis was associated with accelerated longitudinal declines in attention (annual additional rate of change ‐0.01 Z‐score; p = 0.008) (Figure 3). In cross‐sectional analyses, sHHV diagnosis (N = 83) was associated with elevated plasma GFAP (Figure 4). However, sHHV was unrelated to plasma Ab42/40 and NfL levels.ConclusionThese findings suggest an association of sHHV infection with white matter volume loss, attentional decline, and astrogliosis. Although the findings link sHHV to several neurocognitive features, the results do not support an association between sHHV and AD‐specific disease processes.
Novel remote episodic memory assessment: An Agile development pipeline methodology for task selection
Authors: Anwyl‐Irvine Alexander L , Kaula Alexander J , Cashdollar Nathan , Taptiklis Nick , Cormack Francesca K 
Published: December 2022

AbstractBackgroundThere is a growing need to remotely monitor episodic memory decline. Recent advances in available device technology offer an opportunity to deploy novel smart phone‐based cognitive assessments. However, candidate task design options are numerous and selecting the most clinically sensitive and usable by the target population is not a trivial task. Inspired by Agile software development, we present a case‐study of a rapid iterative process for developing and selecting candidates.MethodDesign requirements: 1) Potential for early sensitivity to episodic memory changes, defined by satisfactory performance distributions; 2) Optimized for high frequency Smart Phone deployment; 3) Acceptable user feedback.Three tasks were created: Exp 1 “Serial positioning task”, sequences of objects were memorized and recalled using a drag‐drop response (n=55). Exp 2 “Biographical association task”, AI generated faces were paired with information in a social media profile and later recalled either with questions or by clicking on probe faces (n=73). Exp 3 “Self‐generated pairing task”, where participants generated pairs of identities and later had to recall them (n=65). Each task implemented a minimum learning‐recall delay of 12 hours. Exp 4 ‐ Final versions were compared within participants and against validated CANTAB tasks using Exploratory Factor Analysis (n=155).ResultExp 1 “Serial positioning task”, identified a cognitive load of between 3‐4 items giving good performance‐based variability. Engaging stimuli using emoji and map‐backgrounds increased user ratings without negatively impacting variability. Exp 2 “Biographical association task”, demonstrated good distributions for recall, but only in a forced‐choice format. This was rated the least enjoyable. Exp 3 “Self‐generated pairing task”, showed ceiling effects. This task was rated equally enjoyable as Experiment 1. After comparing the Exp 4 results, the “Serial positioning task” was most predictive of age (tau‐b .256, Bf=113.7), as well as unique according to the factor analysis, and rated as most enjoyable.ConclusionOur agile development pipeline titrated the suitability of three candidate episodic memory tasks for future remote deployment in target clinical populations. By implementing this methodology, it was determined that the "Serial positioning task” was the best candidate for further development and testing for monitoring symptoms of memory decline.
The Cognitive Stress Test (CST): An Innovative Tool to Differentiate Cognitively Unimpaired (CU) Older Adults from those with Pre‐Mild Cognitive Impairment (Pre‐MCI) and Amnestic MCI (aMCI).
Authors: Nahmias Leeron , Beaulieu Ashleigh Nicole , Ortega Alexandra , Hincapie Diana Maria , Kitaigorodsky Marcela , Curiel Rosie E , Loewenstein David 
Published: December 2022

AbstractBackgroundThe CST is a novel assessment that was designed to measure cognitive changes during preclinical and prodromal stages of AD, that include aMCI and PreMCI, where deficits do not meet MCI. The CST employs semantically competing word lists to measure the impact of semantic interference, failure to recover from proactive semantic interference (frPSI), and its persistent effects, despite multiple trials. We hypothesized that frPSI deficits on the CST would be persistent in pre‐MCI and aMCI groups when compared to cognitively unimpaired (CU) controls.Method50 aMCI, 31 pre‐MCI, and 69 CU elders were administered the CST. Participants were presented with List A (18 semantically related words: occupations, household items, or transportation methods) for three initial learning trials, followed by three learning trials of List B, a categorically similar wordlist, to examine PSI and frPSI. Retroactive Semantic Interference (RSI) was assessed by using category cues to elicit recall of List A targets, followed by an additional learning trial to examine failure to recover from RSI (frRSI).ResultSignificant differences were observed between all diagnostic groups across CST Cued Recall trials that measure maximum learning, PSI, frPSI, and persistent frPSI. PreMCI and aMCI participants experienced deficits in learning List B despite two additional opportunities; a deficit that was observed even after adjusting for initial learning strength. Older adults with greater risk (preMCI and aMCI) performed similarly on indices that measures PSI, frPSI, and persistent frPSI as compared to controls. There were differences in RSI among CU and aMCI groups yet measuring frRSI did not differentiate groups. aMCI participants made more semantic intrusion errors on recall trials that cued List B words. Pre‐MCI and CU made a similar number of intrusion errors.ConclusionThe CST extends our work by assessing persistent effects of frPSI, which have been shown to predict neurodegenerative progression and have been associated with multiple biomarkers of AD. The finding that persistent frPSI could differentiate CU from preMCI groups is a promising indicator that semantic interference deficits persist in older adults that present a heightened risk for progression to dementia and is worthy of further research.
Identifying dementia care needs of family physicians, people living with dementia, and care partners in Canada: Results of a national survey
Authors: Sivananthan Saskia , Armstrong Joshua J. , Berall Anna , Santiago Anna , Apostolides Haridos , Iroanyah Ngozi Faith , Guimond Josée , Brookes Jahnel , Ewa Vivian , Grill Allan , Aleong Rosanne , Feldman Sid 
Published: December 2022

AbstractBackgroundThere is consensus that timely detection, diagnosis and ongoing care of people with dementia is primarily the responsibility of family physicians in Canada. Yet evidence indicates low to moderate diagnosis rates and significant challenges in management of dementia. With the growing number of Canadians living with dementia, there is an increasing need to develop effective practice tools for family physicians and to understand the needs of people living with dementia and their caregivers. This nationwide study was conducted to identify the gaps in tools currently being used, and to identify the domains of care that people with lived experience of dementia and their caregivers feel are being done well, and those that require improvement by their family physician.MethodThree nationwide surveys were distributed to target audiences: the 39‐item Dementia Care Needs Assessment Survey for family physicians, the 35‐item Dementia Journey Survey: Caregiver Experience for caregivers, and the 33‐item Dementia Journey Survey: Living with Dementia Experience for persons living with dementia. Survey questions were both multiple choice and open‐ended. Descriptive analyses were conducted on closed‐ended survey questions. Qualitative analyses of open‐ended questions were both inductive, based on observed patterns, and deductive, based on the study objectives.ResultThe surveys received 288 physician, 78 people with dementia, and 485 care partner responses. Preliminary analysis indicates consensus between physicians, people with dementia, and care partners on 15 of 22 barriers to diagnosis and care. Barriers highlighted included gaps in education and support, community resources, and access to specialists, as well as the need for improved communication around care and diagnosis. A further 4 themes were highlighted by physicians and 3 themes by people with dementia that did not overlap, indicating divergent needs. 24.7% of physicians reported using practice tools for dementia care, 10% of whom use only 1 tool for all aspects.ConclusionOptimal primary care is a cornerstone of a comprehensive approach to supporting people with dementia and their care partners. Identifying gaps in knowledge and tools to support practice and developing new educational programs that are aligned with the needs of people with dementia are vital to improve primary dementia care.
Late‐onset AD risk mutation PICALMH458R prevents plaque generation in 5xFAD mice
Authors: Gomez‐Arboledas Angela , Tran Kristine M , Javonillo Dominic I , Phan Jimmy , Milinkeviciute Giedre , Da Cunha Celia , Forner Stefania , Kawauchi Shimako , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N 
Published: December 2022

AbstractBackgroundTo understand the processes that drive late‐onset Alzheimer’s Disease (AD), genome‐wide association studies (GWAS) have uncovered many risk loci. One of these is within the phosphatidylinositol‐binding clathrin assembly protein (PICALM) gene, and a coding mutation has been identified (H458R) which conveys increased risk. PICALM is a cytosolic protein involved in regulating the formation of the lattice during endocytosis. The role of PICALM in AD has not fully defined, however, there are several reports indicating that PICALM affects AD risk primarily by modulating the production, transportation, and clearance of Aβ.MethodWe generated and crossed PicalmH465R
mice with the 5xFAD mouse model of AD, generating 4 groups: wild‐type (WT), PICALM
H458R homozygous (HO), 5xFAD, and 5xFAD/ PICALM
H458R HO, where we named the mice based on the human variant. They were aged to 4 months and 12 months, when plaque loads are being established and plateaued, respectively. Coronal brain sections were immunolabeled with Thioflavin‐S to visualize dense‐core plaques in the hippocampus subiculum and cortex. Plasma neurofilament light chain (NfL), a surrogate measure of brain damage, and soluble and insoluble Aβ levels were measured via meso scale discovery (MSD) technology.Result5xFAD/ PICALM
H458R mice exhibited significant reduction in plaque density in both brain regions compared to 5xFAD mice, as well as reductions in plaque volumes at 4‐month. However, at 12‐month, the opposite is observed with increased plaque density in 5xFAD/ PICALM
H458R compared to 5xFAD but no change in plaque volume. Similar to the observed plaque load at 4‐month, hippocampal insoluble fractions of 5xFAD/ PICALMPlasma NfL levels reflected reduced brain damage at 4‐month in 5xFAD/ PICALM
H458R and a rise to similar level as 5xFAD at 12‐month, consistent with the plaque load.ConclusionThe results indicate PICALM
H458R variant induces age dependent effects on Ab accumulation in 5xFAD mice, with an initial suppression of plaque genesis but ultimately leading to a higher plaque burden with age
Differentially methylated CpG sites between APOE ε4 carriers and non‐carriers in blood and brain from Alzheimer disease cases and controls
Authors: Panitch Rebecca , Au Rhoda , Stein Thor D. , Farrer Lindsay A. , Jun Gyungah R 
Published: December 2022

AbstractBackgroundThe APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer disease (AD). Methylation changes have been shown to occur early in AD, however, the influence of APOE genotype on methylation especially in relation to AD remains largely unknown.MethodWe evaluated differential methylation of genome‐wide CpG sites in brain between 178 APOE ε4 carriers and 511 ε4 non‐carriers in the Religious Orders Study and Memory and Aging Project (ROSMAP), in blood between 276 APOE ε4 carriers and 1118 ε4 non‐carriers in the Framingham Heart Study (FHS), and in blood between 114 APOE ε4 carriers and 187 ε4 non‐carriers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methylation patterns of the top‐ranked CpG sites were further examined in FHS participants with respect to cognitive and brain imaging traits.ResultThe most differentially methylated CpG sites among the autosomes were observed in the APOE region (chr19:45380000‐45430000) in all datasets. Significantly (P<10‐8) hypomethylated CpG sites in APOE ε4 carriers compared to non‐carriers were observed from the APOC1 gene in the FHS (cg23270113, cg05644480) and ADNI (cg07773593) datasets (P=4.6x10‐9) and from the TOMM40 gene (cg02613937, P=1.3x10‐13) in the ROSMAP dataset. Significantly (P<10‐8) hypermethylated CpG sites in APOE ε4 carriers compared to non‐carriers were observed from the APOE gene in the ROSMAP (cg14123992, cg04406254) and FHS (cg06750524) datasets. The two APOC1 CpG sites were significantly associated (P<0.05) with amyloid‐beta 42 level in plasma and several cognitive tests (Trail A, Paired Associate Learning, Verbal Fluency Test, Boston Naming Test). APOE CpG site cg06750524 was significantly associated with MRI volumetric measures of the cerebrum (P=0.01), temporal cortex (P=0.02), and frontal cortex (P=0.05).ConclusionWe discovered novel CpG methylation differences in blood and brain between APOE ε4 carriers and non‐carriers that are associated with AD‐related traits especially involved in executive function and language. Further studies are required to link the methylation patterns to mechanisms leading to AD.