bluuebunny/crossref_metadata_2025_split huggingface dataset:
White matter hyperintensities across the adult life span: Links with age, amyloid load and cognition
Authors: Garnier‐Crussard Antoine , Bougacha Salma , Wirth Miranka , Andre Claire , Delarue Marion , Landeau Brigitte , Mézenge Florence , Kuhn Elizabeth , Gonneaud Julie , Chocat Anne , Quillard Anne , Devouge Eglantine Ferrand , Sayette Vincent De , Vivien Denis , Salmon Pierre Krolak , Chetelat Gael ,   the Medit‐Ageing Research Group
Published: December 2020

AbstractBackgroundBrain white matter hyperintensities (WMH) are frequent in older adults, including cognitively unimpaired individuals and are associated to decreased cognitive performances. The prevalence of WMH and their links with cognitive performance and with cortical β‐amyloid (Aβ) burden have been rarely assessed in younger adults. The aim of this study was to assess the impact of WMH in younger and older cognitively unimpaired adults on cognitive performances and the possible interaction with cortical β‐amyloid (Aβ) burden.MethodTwo hundred and seventy‐two cognitively unimpaired adults from the community (from the IMAP study and the Age‐Well trial) were enrolled and age‐stratified in 86 younger adults (YA; ≤60 years old) and 187 older adults (OA; >60 years old). All participants underwent i) a comprehensive neuropsychological assessment allowing to obtain composite scores of episodic memory, processing speed, working memory, executive functions, and global cognition; ii) brain structural T1 and FLAIR MRI scans used for automatic segmentation of WMH volumes; and iii) a Florbetapir‐PET scan to measure cortical Aβ. Within each group, the relationships of total and regional WMH to age and cognition were assessed, as well as the impact of cortical Aβ on these relationships.ResultWMH increased with age in both groups but more sharply in OA than YA, particularly in the parietal lobe. Higher WMH volume was associated to worse cognitive performances in both groups. Particularly, working memory, processing speed and global cognition were negatively associated with global and regional WMH in YA and executive functions were negatively associated to occipital WMH in OA. Cortical Aβ differentially impacts the links between WMH and cognition in YA versus OA.ConclusionWMH volume increases with age and is negatively associated to cognitive performances including in YA. This study argues for the clinical relevance of WMH even in middle age.
Effect of beta‐amyloid and tau pathology on neural network segregation and episodic memory in aging
Authors: Cassady Kaitlin , Adams Jenna N. , Maass Anne , Harrison Theresa M. , Baker Suzanne L. , Jagust William J. 
Published: December 2020

AbstractBackgroundFunctional alterations in large‐scale neural networks are consequences of both normal aging and Alzheimer’s disease (AD). Underlying pathological processes in both conditions are the accumulation of beta‐amyloid plaques (Aβ) and neurofibrillary tau tangles, which initially appear in the episodic memory system and track closely with memory loss. Aβ and tau aggregates in aging and AD may lead to memory loss through the disruption, or ‘dedifferentiation’, of episodic memory networks. Neural dedifferentiation refers to the finding that neural networks specialized for different cognitive functions become less segregated or ‘differentiated’ (i.e., reduced within‐ and increased between‐network connectivity) with age. Here, we investigated whether dedifferentiation in two distinct episodic memory networks (anterior‐temporal (AT); involved in object processing and posterior‐medial (PM); involved in scene processing) is associated with the accumulation of Aβ, tau and memory.MethodWe used resting state fMRI to measure functional connectivity (FC) in the AT and PM networks in older (OA; N=97, 76±6 years, 61F) and younger adults (YA; N=55, 25±4 years, 29F), and PIB‐PET (using threshold of 1.065 for PIB+/‐) to measure Aβ and FTP‐PET to measure tau in OA. We also collected cognitive data from OA. Episodic memory was measured with a composite z‐score of the California Verbal Learning Test and Visual Reproduction (short and long delay subtests of each).ResultOA showed decreased segregation in AT and PM networks (decreased within‐network and increased between‐network FC) compared to YA. Furthermore, reduced segregation in the AT network was associated with higher levels of tau in AT regions whereas reduced segregation in the PM network was associated with higher levels of global Aβ. Finally, we found that PIB‐status moderates the association between mean segregation and episodic memory performance, such that less segregated networks correlated with better performance in PIB‐ OA while there was no association between segregation and performance in PIB+ OA.ConclusionThese findings show that AD pathology disrupts the normal AT and PM networks in aging by decreasing within‐network and increasing between‐network FC. They also suggest a compensatory phase (in PIB‐ OA) followed by a dedifferentiation phase (in PIB+ OA) in the relationship between segregation and memory.
Cortical thickness in the Alzheimer’s disease signature regions among superagers
Authors: Dev Sheena Isha , Savoca Paul , Wong Bonnie , Andreano Joseph M , Katsumi Yuta I , Barrett Lisa F , Dickerson Brad C , Touroutoglou Alexandra 
Published: December 2020

AbstractBackgroundNormal aging is usually associated with decline in several cognitive domains and atrophy across most brain regions. Some older adults who show exceptionally preserved memory performance (dubbed Superagers (SA)) exhibit preserved cortical thickness in key regions of the salience and default mode networks, which are important for memory and implicated in both aging and Alzheimer’s disease (AD). Although studies suggest SA have a similar prevalence of cerebral amyloidosis compared with typical older adults (TOA), none have investigated aging‐selective vs. AD‐selective atrophy in these groups. Here we compare cortical thickness in our aging‐selective and AD‐selective cortical signatures in TOA and SA.Method41 young adults (YA), 21 TOA, and 17 SA were included. SA were older adults (aged 60‐80) who a) performed at or above average for YA on the California Verbal Learning Test‐2 long delay free recall; and b) were within expectations for their age group on the Trail Making Test‐B. Structural scans were acquired for all participants and average cortical thickness in Aging‐ and AD‐Signatures were extracted. Independent t‐tests determined differences between young adults (YA) and combined older adult groups in the Aging‐ and AD‐Signature. One‐way ANOVAs examined cortical thickness between all groups. All effects reported met a‐priori alpha value of 0.05 uncorrected.ResultGroups were matched on education and gender. There was no difference in age between TOA and SA. There were large reductions in cortical thickness in the entire older adult sample compared to YA in both Aging‐signature (t=12.5, Cohen’s d=2.8) and AD‐Signature (t=8.14, d=1.84). Compared to YA, TOA showed very large reductions in cortical thickness in Aging‐Signature (t=12.5, d=3.20) and AD‐Signature (t=8.2, d=2.15), while SA showed lesser reductions in Aging‐Signature (t=8.5, d=2.6) and AD‐Signature (t=5.6, d=1.64). SA showed thicker cortex than TOA in both Aging‐signature (t=8.4, d = 0.88) and AD‐signature (t=2.1, d = 0.64).ConclusionSuperagers are resilient to atrophy in regions affected by normal aging and AD. Preliminary analyses suggest that most of these effects were driven by large global effects of age, but work is ongoing to adjust the AD‐signature measure for cortical age as we have done previously.
Phosphorylated tau interactome in the human Alzheimer’s disease brain
Authors: Drummond Eleanor , Pires Geoffrey , MacMurray Claire , Askenazi Manor , Nayak Shruti , Bourdon Marie , Safar Jiri , Ueberheide Beatrix , Wisniewski Thomas 
Published: December 2020

AbstractBackgroundAccumulation of phosphorylated tau (pTau) is a key pathological feature of Alzheimer’s disease (AD). pTau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles (NFTs). The pathological actions of pTau are mediated by surrounding neuronal proteins, however our knowledge of the specific proteins that pTau interacts with in AD is surprisingly limited. Therefore, we used two complementary proteomics approaches to map the pTau interactome for the first time.MethodWe performed quantitative proteomics on NFTs microdissected from patients with advanced AD. Second, we used affinity purification‐mass spectrometry (AP‐MS) to pinpoint which of the proteins identified directly interacted with pTau. Specific proteins of interest were validated using targeted co‐immunoprecipitation (co‐IP) and immunohistochemistry (IHC).Result542 proteins were identified in NFTs including the detection of many proteins known to be present in NFTs (e.g. MAPT, UBB and APOE). AP‐MS confirmed that 75 proteins present in NFTs directly interacted with pTau. 54 of these proteins have been previously associated with tau, therefore validating our proteomic approach. More importantly, 15 of these proteins were previously known to be associated with AD, but not directly linked to tau (e.g. VAMP2, HNRNPA1). Network analysis showed that the pTau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation, and we were able to pinpoint specific proteins that pTau interacts with in these pathways. Importantly, we also identified six novel proteins, not previously known to be associated with pTau or AD. Among these, Secernin‐1 (SCRN1) was selected for validation. Co‐IP of SCRN1 confirmed its interaction with pTau in AD brains, and IHC showed that SCRN1 was uniquely associated with pTau pathology in AD and not in other neurodegenerative diseases such as Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration.ConclusionCombined, our results provide a roadmap for future studies examining the pathological effects of pTau and for identifying possible new drug targets and biomarkers such as SCRN1 for AD.
Plasma IL‐12/IFN‐γ axis predicts cognitive trajectories in cognitively normal older adults
Authors: Yang Hyun‐Sik , Zhang Can , Carlyle Becky C. , Zhen Sherri Y , Trombetta Bianca A. , Schultz Aaron P. , Pruzin Jeremy J. , Fitzpatrick Colleen D. , Kirn Dylan , Rentz Dorene M. , Arnold Steven E. , Johnson Keith A. , Chhatwal Jasmeer P. , Sperling Reisa A. , Tanzi Rudolph E. 
Published: December 2020

AbstractBackgroundThe immune system plays a critical role in Alzheimer’s disease (AD) pathophysiology, and altered peripheral cytokine levels have been reported in AD dementia. However, it remains unclear whether and how plasma cytokines in cognitively normal (CN) older adults predict cognitive decline.MethodWe studied 298 CN Harvard Aging Brain Study (HABS) participants with baseline amyloid‐β (Aβ) measure (Pittsburgh Compound B PET neocortical distribution volume ratio (DVR)), baseline plasma collection, and longitudinal cognitive measures (Preclinical Alzheimer Cognitive Composite 5 (PACC5)). We measured nine plasma cytokines (IFN‐γ, IL‐1b, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, TNF‐α) using the Meso‐Scale Discovery V‐PLEX platform, and the cytokine levels were log‐transformed and normalized. We first screened for the cytokines that modify the association between baseline Aβ and longitudinal PACC5 (linear mixed effect models). We then screened the remaining cytokines for their Aβ‐independent association with longitudinal PACC5 (linear mixed effect models). The identified cytokines’ association with Aβ (“A”), neocortical tau (“T”) (inferior temporal cortex flortaucipir PET standardized uptake value ratio (SUVR) at Year 4), and neurodegeneration (longitudinal hippocampal volume (HV)) (“N”) were tested.ResultHigher baseline plasma IL‐12p70 modified the association between baseline Aβ and longitudinal cognition, whereby higher IL‐12p70 predicted less cognitive decline especially in the setting of higher Aβ (IL‐12p70*Aβ*time: β=0.17, p=3.6×10‐5, FDR=3.2×10‐4): higher IL‐12p70 predicted less cognitive decline in the Aβ+ subgroup (n=72; β=0.085, p=4.0×10‐4), but not in the Aβ‐ subgroup (n=221; p=0.33). IL‐12p70 was not associated with baseline Ab (p=0.79), but its interaction term with baseline Ab predicted lower neocortical tau burden at Year 4 (n=118; β=‐0.15, p=0.040), and less longitudinal hippocampal volume loss (n=244; β=42, p=0.035). On the other hand, higher IFN‐γ was associated with less cognitive decline independent of Aβ (IFN‐γ*time: β=0.026, p=1.5×10‐3, FDR=0.011). IFN‐γ was not associated with Aβ, tau, or longitudinal hippocampal volume.ConclusionPlasma IL‐12/IFN‐γ axis predicted a favorable cognitive trajectory in CN older adults, and plasma IL‐12p70 captured a process that modifies the association of Aβ with neocortical tau and longitudinal neurodegeneration. Our results showing protective effect of upregulated peripheral IL‐12/IFN‐γ axis illustrate complex roles the immune system plays in the progression of AD.
Medial temporal lobe hyperactivity during memory processing in older adults is associated with entorhinal tau deposition
Authors: Adams Jenna N. , Maass Anne , Berron David , Harrison Theresa M. , Baker Suzanne L. , Thomas Wesley P. , Stanfill Morgan , Jagust William J. 
Published: December 2020

AbstractBackgroundAging is associated with memory decline and tau accumulation in medial temporal lobe (MTL) structures that support memory. We hypothesized that age‐related differences in functional activation during an fMRI memory task would be related to tau deposition in the entorhinal cortex (EC) and global amyloid‐beta (Aβ). We investigated repetition suppression and subsequent memory as measures of memory processing.Methods46 normal older adults (OA; 78±6 years, 29F) and 21 young adults (YA; 27±5 years, 12F) underwent high‐resolution 3T fMRI while performing a memory task (Figure 1A). Repetition suppression was defined as the contrast of activity between the first presentation compared to the repeated presentation of a stimulus. Subsequent memory was defined as the contrast of activity for stimuli that were later remembered versus forgotten during a post‐scan delayed recognition test. MTL subregions were defined in native space on high‐resolution T2 images using ASHS (Figure 1B). Tau‐PET was performed with 18F‐Flortaucipir (FTP), and mean FTP SUVR was extracted from native space EC ROIs (PVC corrected). Aβ‐PET was performed with 11C‐PiB, and global PiB DVR was extracted. Age‐related differences in activity were compared with independent samples t‐tests, and correlations controlled for age and sex.ResultsCompared to YA, OA showed reduced repetition suppression in MTL ROIs, including the bilateral hippocampus, anterolateral EC (alEC), and posteromedial EC (pmEC; Figure 2A). Post‐hoc analyses determined that this reduction in repetition suppression was driven by hyperactivity to repeated stimuli in OA (Figure 2B/C). For subsequent memory, OA showed reduced activity for remembered versus forgotten stimuli in pmEC‐L (Figure 3A). Post‐hoc analyses revealed hyperactivity in pmEC‐L that was specific to incorrect stimuli, while bilateral hippocampus and alEC‐R demonstrated consistent hyperactivity across both correct and incorrect stimuli (Figure 3B/C). Finally, increased EC FTP, but not global PiB DVR, was related to hyperactivity in bilateral pmEC and hippocampus for subcomponents of both repetition suppression (Figure 4A) and subsequent memory (Figure 4B).ConclusionsAge‐related reductions in activity for repetition suppression and subsequent memory are driven by hyperactivation of MTL structures in hippocampus and EC. These findings are related to EC tau pathology and to failure of stimulus encoding that reflects age‐related memory decline.
Increased circulating endothelial progenitor cells as a biomarker for cerebral microvascular pathology in cognitively normal older adults
Authors: Kapoor Arunima , Gaubert Aimee , Marshall Anisa J. , Meier Irene B. , Yew Belinda , Ho Jean K. , Blanken Anna E. , Dutt Shubir , Sible Isabel J. , Li Yanrong , Jang Jung Yun , Brickman Adam M. , Rodgers Kathleen E. , Nation Daniel A. 
Published: December 2020

AbstractBackgroundCerebral microvascular pathologies—including white matter lesions, microbleeds and lacunes—are associated with increased risk of vascular dementia and Alzheimer’s disease. Despite the role of cerebral microvascular pathological changes in cognitive decline, such changes often remain asymptomatic until pathology progresses to severe stages, and early‐stage markers of cerebrovascular changes are lacking. Elevated levels of circulating endothelial progenitor cells (EPCs) have previously been observed in response to vascular injury and may represent a protective vascular mechanism. However, few previous studies have examined levels of circulating EPCs in older adults with signs of cerebral microvascular pathology.MethodIndependently living older adults (ages 55‐90) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Mononuclear cells were isolated and stained for EPC surface markers CD34, CD133 and CD309. Circulating EPCs were quantified by flow cytometry as the number of cells in the lymphocyte gate positively expressing all three markers (CD34+CD133+CD309+). MRI changes thought to represent microvascular pathologies (white matter hyperintensities, cerebral microbleeds and lacunes) were evaluated and total microvascular disease load was determined using a previously validated score.ResultFifty‐three older adults (mean age = 69.3 years (SD = 7.5); education = 15.7 years (SD = 2.8); 19 (35.8%) male) were included in this preliminary analysis. Moderate/severe white matter hyperintensity burden was identified by Fazekas scale in 35.8% of participants, small lacunes were identified in 15.1% and microbleeds in 5.7%. Linear regression analyses revealed that older adults with more circulating EPCs exhibited greater total microvascular pathology load (p = .034), after accounting for age, sex and education.ConclusionOur preliminary findings suggest a role for circulating EPCs as an early‐stage biomarker for cerebral microvascular pathology in older adults free of dementia or stroke symptoms. Novel diagnostic approaches to recognize microvascular changes are needed to identify individuals at risk of dementia before the onset of irreversible cognitive impairment. Longitudinal studies examining the association between EPCs and dementia risk are warranted to further explore the utility of EPCs as a biomarker for cerebral microvascular disease.
A singular value decomposition algorithm to identify early dysfunctional molecular pathways in Alzheimer’s disease
Authors: Huseby Carol J. , Delvaux Eliane , Coleman Paul D. 
Published: December 2020

AbstractBackgroundMicroarray technology has been an effective tool to capture gene expression of thousands of genes from multiple molecular pathways in human brain tissue. Many large expression datasets exist maintaining information about differences in gene expression related to Alzheimer’s disease processes. Often groups employ comparative analysis strategies on the data resulting in differential expression between disease and controls.MethodUsing available expression datasets with multiple brain regions as a function of Braak‐staging, we look for expression signatures that do not necessarily increase nor decrease with disease progression, but rather have highly variable patterns indicating a molecular process dysregulation. Here we use a variation on singular value decomposition (SVD) as a rigorous approach to this type of analysis thus providing a characterization of the structure of the data as well as information about the relationship among genes.ResultAnalysis of the sequential singular values generated determines the number of components that capture the data essential features. The magnitude of the singular values identified dysfunctional expressed transcripts at early stage in the disease before the appearance of tau protein neurofibrillary tangles. It follows that by pathway analysis we can determine upstream players in the affected biological processes pathway and design appropriate experiments to validate the early dysregulated molecular pathways.ConclusionUsing a novel approach to analyze expression data, we identified transcripts displaying dysregulated expression signatures at early stages of disease in brain regions not yet affected by neurofibrillary tangles. The relationships of these transcripts and pathways enriched then guided us to explore upstream events in the early disease cascade.
A coral‐derived compound suppresses hippocampal inflammation and improved memory retrieval in triple transgenic Alzheimer’s mice
Authors: Liu Ingrid Y. , Varinthra Peeraporn , Huang Shun‐Ping , Chompoopong Supin , Suresh Pavithra 
Published: December 2020

AbstractBackgroundThe relationship between neuronal inflammation and impairment of memory retrieval is not well established, partially because of the lack of appropriate compound to test this hypothesis. Here we investigated effects of a novel coral‐derived compound on hippocampal inflammation markers and contextual fear memory retrieval using a triple‐transgenic AD (3xTg‐AD) mouse modelMethodThe coral‐derived compound was administered to mice with intraperitoneal injection before subjected to trace fear conditioning. Expression of inflammation markers were measured by western blot analysis or flourescent immunihistochemijcal staining.ResultResults indicate that coral‐derived compound is effective on reducing expression levels of inflammatory markers including TNF‐α, COX‐2, and iNOS in the hippocamapal region, and increased expression of postsynaptic density protein‐95 (PSD‐95) in the hippocampus of 3xTg‐AD mice. It also increased dendritic spine density in hippocampus. Phenotypically, this compound enhanced hippocampadependent retrieval of contextual memory after trace fear conditioning.ConclusionOur results suggest the strong linkage between hippocampal inflammation and memory retrieval in AD, and that the coral‐derived compound may serve as a drug leading for a hippocampal anti‐inflammatory treatment to improve memory retrieval in AD patients.