bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher CSF STREM2/P‐tau ratio levels attenuate effects of polygenic Alzheimer’s disease risk on cognitive decline and neurodegeneration
Authors: Franzmeier Nicolai , Suárez‐Calvet Marc , Frontzkowski Lukas , Morenas‐Rodríguez Estrella , Kleinberger Gernot , Shaw Leslie M. , Trojanowski John Q. , Haass Christian , Ewers Michael ,   Alzheimer's Disease Neuroimaging Initiative (ADNI)
Published: December 2020

AbstractBackgroundLoss of function of TREM2, a key receptor expressed on microglia, is associated with increased Alzheimer’s disease (AD) risk. In biomarker‐defined AD patients, we found previously that higher cerebrospinal‐fluid (CSF) levels of soluble TREM2 relative to the level of p‐tau (sTREM2/p‐tau ratio) are associated with attenuated clinical AD progression. This suggests that higher sTREM2/p‐tau, indicative of more activated microglia at a given level of pathology, may be beneficial in AD. Here, we asked the more general question whether higher sTREM2/p‐tau ratio levels attenuate the general risk to develop AD‐related cognitive decline and neurodegeneration in a large sample of cognitively normal to AD dementia subjects. To assess AD risk, we used a pre‐established polygenic hazard score (PHS) including 31 SNPs that are associated with age of AD onset (e.g. Tan et al., Brain, 2019). We determined whether higher sTREM2/p‐tau levels attenuate the effect of polygenic AD risk (i.e. PHS) on future cognitive decline and neurodegeneration.MethodsWe included 648 elderly cognitively normal to dementia subjects from ADNI with available CSF‐biomarker data (i.e. sTREM2, Aβ1‐42 and p‐tau), longitudinal cognitive assessments and structural MRI (∼4yrs follow‐up). The PHS was determined on GWAS data. Using linear regression, we tested the association between PHS, CSF‐assessed AD biomarkers or sTREM2, controlling for age, gender, education and diagnosis. Second, we determined whether higher sTREM2/p‐tau levels moderated the effect of PHS on annual change rates in global cognition (i.e. ADAS13), memory (i.e. ADNI‐MEM) and MRI‐assessed hippocampal volume, controlling for age, gender, education and diagnosis and baseline cognition.ResultsHigher polygenic AD risk, i.e. PHS, was associated with lower CSF Aβ1‐42 (β=‐0.354,p<0.001) and higher p‐tau levels (β=0.328,p<0.001), but not with sTREM2 (β=0.007,p=0.864; Figure 1). We found significant sTREM2/p‐tau x PHS interactions, such that individuals with higher sTREM2/p‐tau ratios had a lower effect of PHS on global cognitive (β=‐0.210,p=0.002) and memory decline (β =0.258,p=0.002) as well as hippocampal atrophy rates (β=0.262,p=0.002; Figure 2).ConclusionA higher sTREM2/p‐tau ratio is protective against the AD‐related polygenic risk for faster cognitive decline and hippocampus atrophy.
Measuring neurodevelopmental effects of polygenic risk for Alzheimer's disease via longitudinal study of brain and cognitive variables in periadolescent children
Authors: Warren David E. , Phipps Connor J. , Eckel Medea , Rangel Anthony , Heller Abi M. , Maerlender Arthur C. , Phatak Vaishali S. , Cramer Justin A. , Blair James , Murman Daniel L. , Smith Shelley D. 
Published: December 2020

AbstractBackgroundIndividual variability in Alzheimer’s disease (AD) risk is greatly affected by genetic factors, and those factors may exert early influence on brain development. Specifically, genetic/genomic AD risk factors may bias brain development toward vulnerability to late onset AD. We are conducting a five‐year study (funded by the National Institute on Aging) to test the hypothesis that polygenic AD risk alters neurodevelopment of brain systems most affected by AD in ways that increase vulnerability to late‐onset AD. If true, then properties of AD‐vulnerable brain structures (e.g., hippocampus) and AD‐vulnerable brain networks (e.g., default mode network) will vary with polygenic AD risk even during youth. Here, we describe our study aims, approach, and predictions.MethodsWe have implemented our project as the Polygenic Risk of Alzheimer’s disease in Nebraska Kids (PRANK) study. The PRANK study will measure neurodevelopmental effects of AD polygenic risk scores (ADPRS) with three aims: 1) measure effects of ADPRS on development of AD‐vulnerable brain regions; 2) quantify how ADPRS affects development of functional brain networks vulnerable to AD; and 3) evaluate effects of ADPRS on development of AD‐vulnerable cognitive abilities. To address these aims, we are developing a new dataset which combines neuroimaging (brain structure/function), neuropsychology (cognition), and genomics (ADPRS) in a longitudinal design. Our study is currently enrolling healthy youth age 8‐13 years; our multi‐year recruitment goal is N = 270. Participants will return for follow‐up two years after initial participation.ResultsOur study is ongoing, but we will discuss our design and preliminary findings. We predict that higher ADPRS in otherwise typically developing youth will be associated with: 1) smaller hippocampal volume and decreased cortical thickness in AD‐related ROIs; 2) lower connectivity in functional brain networks and less brain activity in memory tasks; 3) lower scores on measures of AD‐related cognitive abilities (e.g., memory and executive functions) after accounting for IQ.ConclusionsFindings from the PRANK study will improve the field’s understanding of how developmental effects of ADPRS relate to clinical and epidemiological challenges of AD. Measuring how genetic/genomic factors associated with late‐onset AD affect brain development will elucidate lifelong trends for AD risk while highlighting new opportunities for early intervention.
Multiple pathophysiological biomarkers are associated with gray matter volume and cerebral glucose metabolism in the early preclinical Alzheimer's continuum
Authors: Gispert Juan Domingo , Salvadó Gemma , Milà‐Alomà Marta , Cacciaglia Raffaele , Falcon Carles , Operto Greg , Grau‐Rivera Oriol , Arenaza‐Urquijo Eider M , Shekari Mahnaz , Minguillón Carolina , Fauria Karine , Kollmorgen Gwendlyn , Eichenlaub Udo , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

AbstractBackgroundThe pathophysiological events that occur early in the preclinical Alzheimer’s disease (AD) continuum are not fully understood. Here, we sought for associations, in cognitively unimpaired individuals, between cerebrospinal (CSF) biomarkers of the main pathophysiological events described in AD vs. patterns of gray matter volume (GMv) and cerebral glucose metabolism (rCMRGlu).MethodThe first consecutive 381 participants of the ALFA+ study with valid T1w MRI, [18F]FDG‐PET scans and CSF samples were included. CSF biomarkers were measured with the NeuroToolKit robust prototype assays and Elecsys® immunoassays (Roche Diagnostics) and related to amyloid (Aβ42, Aβ40) and tau (pTau) metabolism, neuronal and axonal damage (NfL), synaptic dysfunction (neurogranin), neuroinflammation (sTREM2, YKL40, GFAP, S100, IL6), and α‐synuclein. Individuals were staged using the A/T system and pre‐established cut‐offs for the Aβ42/40 ratio and pTau concentrations. Modulated GMv maps were obtained from T1w scans. [18F]FDG uptake was normalized to the pons. Exploratory voxelwise associations between maps of GMv and rCMRGlu vs. CSF biomarkers (and differences between A/T groups in the AD continuum) were assessed with SPM12 (p<0.005, k>50 voxels) after accounting for the effect of age, sex, education, and APOE‐ε4 carriership, as well as for the Total Intracranial Volume (TIV) in the GMv analysis.ResultDemographics are shown in Table 1. Figure 1 shows regional differences in GMv and rCMRGlu between A/T groups and Figure 2 associations with biomarkers. Compared to the A‐T‐ group, A+T‐ individuals presented a widespread pattern of higher GMv. Higher pTau levels were associated with an extensive pattern of higher GMv and rCMRGlu. Higher sTREM2 values were associated with higher GMv in the temporoparietal junction and posterior cingulate cortex overlapping pTau GMv effects (Figure 3). Lower Aβ42/40 values were also associated to lower rCMRGlu in bilateral hippocampus and anterior cingulate. Higher NfL levels were coupled with lower GMv in bilateral parietotemporal cortices.ConclusionResults suggest that pathogenic events in very early stages of the Alzheimer’s continuum are unexpectedly associated with higher GMv and rCMRGlu. The overlap of pTau and sTREM2 effects in GMv may point towards a TREM2‐mediated microglial reaction to initial tau pathology. Interactions between biomarkers and A/T groups will be presented.
Development of monoclonal antibodies specific for the calpain‐generated ∆48 kDa calcineurin fragment, a marker of distressed astrocytes
Authors: Gollihue Jenna L. , Kraner Susan D. , Weiss Blaine E. , Artiushin Irina A. , Sompol Pradoldej , Norris Christopher M. 
Published: December 2020

AbstractBackgroundCalcineurin (CN) is a Ca2+/calmodulin‐dependent protein phosphatase expressed at high levels in brain. In healthy tissue, CN exists mainly as a full‐length (∼60 kDa) highly‐regulated protein involved in essential cellular functions. However, in diseased or injured tissue, CN is proteolytically converted to a constitutively active fragment that has been causatively‐linked to numerous pathophysiologic processes. The 48 kDa CN fragment (DCN) appears at high levels in human brain at early stages of cognitive decline associated with Alzheimer’s disease. DCN tends to show‐up in regions of frank amyloid and cerebrovascular pathology, especially in select subsets of astrocytes, both in humans and in animal models. Our goal was to develop monoclonal antibodies to DCN for use in neuropathology research.MethodA peptide encompassing the calpain sensitive region of the CN carboxyl terminus was used for antibody generation. Antibodies were screened in ELISAs against the immunizing peptide, but decision‐making screens were carried out as a Western analysis of 5XFAD mouse brain extracts, which express high levels of the DCN fragment.ResultWe identified 2 monoclonals, one of which (17E1) was highly reactive to DCN in Western blots, but not in ELISAs, of 5xFAD brain extracts. In contrast, the second antibody (26A6) reacted well against the peptide in ELISAs, but worked only modestly in Westerns. Importantly, neither antibody reacted with full‐length (60 kDa) CN, nor did antibodies detect DCN in extracts from healthy WT mice. In immunostaining assays, both antibodies strongly labeled subsets of GFAP‐positive astrocytes in 5xFAD mice with a high signal‐to‐background. Some GFAP‐negative cells also labeled positively for DCN. Consistent with Westerns, there was no antibody reactivity to WT mouse brain sections.ConclusionNew monoclonals are highly selective for the 48 kDa CN proteolytic fragment and label subsets of astrocytes, and possibly other cell types, under pathological conditions. These antibodies could be a useful tool for marking insidious brain pathology and identifying novel astrocyte phenotypes.
The North American Prodromal Synucleinopathy (NAPS) Consortium: Baseline neuropsychological findings in 136 participants
Authors: Fields Julie A. , Boeve Bradley F. , Forsberg Leah K. , Louis Erik K. St. , Kraft Ruth A. , Nelson Kevin M. , Timm Paul C. , Teigen Luke N , Avidan Alon Y. , Rivera Adreanne , Postuma Ronald B. , Gagnon Jean‐François , Pelletier Amelie , Howell Michael J. , Schenck Carlos H. , De Kam Josh , Ryberg Kelly J. , Summers Rebekah L. , Bliwise Donald , Huddleston Daniel , Wood‐Siverio Cathy , Videnovic Aleksandar , Stauder Matthew , Hersh Samantha , Criswell Susan R. , McLeland Jennifer S. , Ju Yo‐El ,   NAPS Consortium
Published: December 2020

AbstractBackgroundIt is important to determine the natural history of individuals with RBD and generate clinical and neuropsychological data for planning disease‐modifying trials to delay or prevent phenoconversion of RBD to an overt synucleinopathy such as dementia with Lewy bodies, Parkinson’s disease, or multiple system atrophy. Our objective is to present initial neuropsychological data on 136 participants with REM sleep behavior disorder (RBD) without an overt synucleinopathy who are in the North American Prodromal Synucleinopathy (NAPS; R34AG056639) Consortium.MethodAs part of the NAPS protocol (www.naps‐rbd.org), investigators at 10 centers in North America are enrolling a target of 360 participants with RBD. A comprehensive clinical battery and a set of neuropsychological measures (using the National Alzheimer Coordinating Center Uniform Data Set version 3 or UDS3) are performed at each visit.ResultParticipants were 82% male, ranging in age from 35‐85 (Mean=65.9, SD=15.9) and education from 8‐20 years (Mean=15.9, SD=3.1). Only 17 participants (13%) were impairment‐free across all tests administered. The proportions of participants with impaired scores were tabulated as follows (< ‐1.5 SD after adjustment for age, sex, and education): global cognition – 17%; attention/executive functioning – 10‐20% across measures; language – 14‐24% across measures; visuospatial – 16%; and episodic learning/memory – 18‐25% across measures. Of all participants, 79 (58%) showed impairments < ‐2 SD. Moreover, 53% of those with cognitive impairment involved impact in 2 domains, an additional 20% in 3 domains, and another 4% was impaired in all domains. The combination of attention/executive and language was most often observed.ConclusionCollection of a comprehensive set of clinical and neuropsychological measures is feasible and tolerated in RBD patients. Using the UDS3 neuropsychological test battery, impairment in one or more measures was present in 87% of participants, and 58% showed impairments greater than 2 SD below the mean in the absence of a clinical diagnosis of dementia. Impairments in > 2 domains was common, most frequently involving attention/executive and language. Future longitudinal assessments will be required to determine the predictive utility of neuropsychological performance for phenoconversion of RBD to an overt synucleinopathy.
MRI‐assessed locus coeruleus integrity is heritable and associated with cognition, Alzheimer’s risk, and sleep‐wake disturbance
Authors: Elman Jeremy A. , Puckett Olivia K. , Beck Asad , Panizzon Matthew S. , Sanderson‐Cimino Mark E. , Gustavson Daniel E. , Lyons Michael J. , Franz Carol E. , Kremen William S. 
Published: December 2020

AbstractBackgroundThe locus coeruleus (LC) is one of the earliest sites of Alzheimer’s disease (AD) pathology, and it experiences extensive neurodegeneration through the disease course. The LC has long been associated with arousal and the sleep‐wake cycle, which are commonly disrupted in AD. Recent research implicates the LC in modulating cognitive function, suggesting an additional path by which LC dysfunction can contribute to cognitive decline in AD. Recent advances in MRI allow for in vivo measures of LC integrity, which may detect early effects of AD or other diseases. We examined whether an MRI measure of LC structural integrity was heritable and whether it was associated with cognitive performance, mild cognitive impairment (MCI), and sleep‐wake disruption.MethodParticipants were 481 late‐middle‐aged men (mean age=67.5; range=62‐71.7) from the Vietnam Era Twin Study of Aging. Rostral LC structural integrity was indexed by contrast‐to‐noise ratio (LCCNR) in manually marked regions of an FSE T1‐weighted MRI scan. We determined heritability with the classical twin method comparing monozygotic and dizygotic twins. Cognitive performance was assessed using factor scores across multiple domains, and amnestic MCI (aMCI) was diagnosed according to Jak‐Bondi criteria. The Pittsburgh Sleep Quality Index was used to measure sleep‐wake disruption.ResultGenetic influences (heritability) accounted for 62% of variance in LCCNR. The remaining variance was accounted for by unique environmental variance. Participants with aMCI showed significantly greater daytime dysfunction on the Pittsburgh scale compared to cognitively normal participants. Lower LCCNR was associated with increased odds of aMCI and greater daytime dysfunction. Lower LCCNR was also associated with lower episodic memory, general fluency, semantic‐specific fluency, and processing speed factor scores.ConclusionThese results demonstrate that MRI‐assessed LC integrity is a meaningful biological index. They suggest that LC damage may contribute to sleep‐wake disturbances and cognitive impairment among those with aMCI. Further research is needed to determine whether and how these factors are causally linked. Associations with factor scores across multiple domains highlight the potentially widespread impact of reduced LC integrity on cognition. Furthermore, these findings in late‐middle‐aged adults highlight the potential utility of MRI‐based measures of LC integrity in early identification of AD risk.
Study partner factors on cognitive function index scores among participants screened for the A4 study
Authors: Voeller Emily K , Choi Jiyoon , Sperling Reisa A. , Aisen Paul S , Raman Rema 
Published: December 2020

AbstractBackgroundThe Cognitive Function Index (CFI) is an evaluation of participants’ cognitive and functional decline. Alzheimer’s disease (AD) clinical trials, including Preclinical trials, require participants to have a study partner (SP) to help evaluate participant cognitive and functional performance. Past studies in early AD dementia and Mild Cognitive Impairment populations have shown that spousal SPs are more accurate at providing cognitive information than non‐spousal SPs. We aimed to investigate if SP variables are associated with participant and SP reported CFI score among cognitively normal participants screened for the A4 Study.Method6155 Participants and 5953 Study Partners completed the screening CFI in the A4 Study. The CFI is a 14‐item questionnaire completed by both the SP and the participant with higher scores meaning increased decline over the past year. SPs were categorized as: Spouse, Adult Child, Friend/Companion, and Other. SPs were also categorized based on the number of weekly hours spent with the participant in‐person (more vs less than 68 hours per week). Associations with participant and SP reported screening CFI were assessed using a multiple regression model adjusting for participant age, gender and education, but without adjustments for multiple comparisons.ResultsSPs were female for 40% of female participants and 90% of male participants. Spousal SPs report spending 103 +/‐ 42 hours per week with the participants, while the other groups reported much fewer hours (Adult child: 17 +/‐30, Friend/Companion: 21 +/‐ 35, Other: 27 +/‐ 40). There was no association between SP group and participant CFI score. There was an observed association between SP group and SP CFI score (F=6.54, p < 0.001). Friends/Companions (beta=‐0.30+/‐0.19, p<0.001) and Other (beta=‐0.19 +/‐0.11, p=0.07) groups reported lower scores on the CFI than Spouses. There were no differences by SP gender or number of hours spent in person per week.ConclusionThis cross‐sectional analyses showed preliminary evidence that SP type can influence the SP score on the screening CFI although there is no evidence of SP influence on participant reported CFI. Longitudinal data, when available at trial end, will help assess these associations over time and if study partner type can predict future cognitive decline.
Mechanism for the protective effect of APOE ε2 against Alzheimer disease is linked to tau and the classical complement pathway
Authors: Jun Gyungah R. , Zhu Congcong , Panitch Rebecca , Chung Jaeyoon , Hu Junming , Wang Li‐San , Lunetta Kathryn L. , Haines Jonathan L. , Mayeux Richard , Pericak‐Vance Margaret A. , Schellenberg Gerard D. , Stein Thor D. , Farrer Lindsay A. ,   The Alzheimer's Disease Genetics Consortium
Published: December 2020

AbstractBackgroundRecent reports suggest that the rare APOE Christchurch mutation and APOE2 allele protect against Alzheimer’s disease (AD) pathology by reducing the burden of tau pathology. However, the mechanism(s) underlying the APOE2 protective effect linking to tau is largely unknown.MethodWe conducted a genome‐wide association study (GWAS) for AD among 2,120 APOE2 carriers from the Alzheimer Disease Genetics Consortium (ADGC), and prioritized by gene network analysis and methylation profiling of CpG sites in the locus using the Religious Orders Study and Memory and Aging Project (ROSMAP) data. We also performed differential gene expression analysis among APOE2/3 subjects in prefrontal cortex tissue from 44 AD and 75 control brains of the Framingham Heart Study (FHS), Boston University Alzheimer’s Disease Center (BUADC), and ROSMAP. We validated the relationships between protein levels of the top‐ranked genes and levels of tau and amyloid beta proteins in prefrontal cortex area of 193 FHS/BUADC brains.ResultOf the significant genetic associations with AD (P < 10−6), PPP2CB was the key node in APOE2‐related gene networks and contained the most significant CpG site (P = 5.2 × 10−4) located 2,814 bp upstream of the top‐ranked GWAS variant. The complement genes C4A and C4B were the top‐ranked differentially expressed genes (P < 2 × 10−4) with reduced expression in APOE2/3 controls compared in APOE2/3 cases or other carriers. Furthermore, the level of PPP2CB protein was significantly associated with increased levels of C4B protein (P = 8.2 × 10−7), and the C4A level was associated with increased pTau231/tTau ratio (P = 0.006). Protein levels of C4A, C4B, and PPP2CB were not associated with amyloid beta 42 (Aβ42) or pTau181/tTau ratio. We were unable to confirm previous reports on the role of C1q, since the C1q level was not associated with any of these phenotypes.ConclusionThis is the first to report the molecular link between a tau phosphatase and the classical complement pathway, especially C4, as a mechanism for the ε2 protective effect against AD. Our findings may lead to the development of novel therapeutic targets for AD by mimicking the neuroprotective effect of APOE2.