bluuebunny/crossref_metadata_2025 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

Background

Brain 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.

Method

Two 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.

Result

WMH 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.

Conclusion

WMH 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

Background

Functional 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.

Method

We 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).

Result

OA 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.

Conclusion

These 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

Background

Normal 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.

Method

41 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.

Result

Groups 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).

Conclusion

Superagers 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

Background

Accumulation 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.

Method

We 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).

Result

542 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.

Conclusion

Combined, 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

Background

The 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.

Method

We 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.

Result

Higher 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.

Conclusion

Plasma 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

Background

Aging 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.

Methods

46 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.

Results

Compared 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).

Conclusions

Age‐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

Background

Cerebral 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.

Method

Independently 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.

Result

Fifty‐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.

Conclusion

Our 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

Background

Microarray 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.

Method

Using 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.

Result

Analysis 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.

Conclusion

Using 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

Background

The 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 model

Method

The 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.

Result

Results 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.

Conclusion

Our 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.
Assessing whole genome sequencing variation for Alzheimer’s disease in 4707 individuals from the Alzheimer’s Disease Sequencing Project (ADSP)
Authors: Peloso Gina M. , Wang Yanbing , Lin Honghuang , Sarnowski Chloé , Pitsillides Achilleas N. , Lim Elise M. , Beecham Gary W. , Hamilton‐Nelson Kara L. , Ramos Jairo , Martin Eden R. , Naj Adam C. , Thornton Timothy A. , Wang Li‐San , Boerwinkle Eric , Farrer Lindsay A. , Haines Jonathan L. , Mayeux Richard , Pericak‐Vance Margaret A. , Seshadri Sudha , Schellenberg Gerard D. , Wijsman Ellen , Fornage Myriam , Dupuis Josée , Destefano Anita L. , Kunkle Brian W. ,   Alzheimer’s Disease Sequencing Project
Published: December 2020

Background

The Alzheimer’s Disease Sequencing Project (ADSP) seeks to identify genomic variants contributing to increased risk of and/or protection from Alzheimer’s disease (AD) in multi‐ethnic populations. Here we report on statistical modeling considerations and results from 4707 diverse individuals including 2076 non‐Hispanic White, 1030 Black, 1304 Hispanic, and 297 of other ancestry with whole genome sequencing (WGS) in the ADSP.

Methods

A total of 4789 individuals were sequenced across 4 sequencing centers and 2 sequencing platforms. Joint calling was carried out by the ADSP data coordinating center GCAD. We evaluated a series of models to explore technical covariate adjustment related to study, sequencing center, and platform and then performed single variant association analysis for AD status adjusting for principal components associated with AD, technical covariates, and a genetic relatedness matrix, limiting to variants with a minor allele count > 30 and a missingness rate ≤ 10%. We also performed gene‐based association of rare (both MAF < 1% and MAF < 5%) coding variants.

Results

After quality control, we included over 95 million variants across 4707 individuals (2209 cases, 2498 controls). We replicated association at the APOE locus and identified a locus on chromosome 15 that has a suggestive association with AD status (freq = 0.8%, p‐value = 1 × 10−7). Despite joint genotype calling, adjustment for study, sequencing center and platform are necessary to control type‐I error. In gene‐based tests, we found evidence (p < 0.05) of association for 4 of 8 AD candidate genes with low‐frequency or rare variant associations implicated for AD (TREM2, ABI3, SORL1, and MAPT) as well as suggestive associations (P < 5 × 10−5) for seven genes (ZGRF1 on chr4; C1RL on chr12; NAA30 on chr14; NIPA2 on chr15; and ABCC3, BIRC5 and HIC1 on chr17).

Conclusion

We explored covariate models for the WGS data from ADSP and established that despite joint calling, it is necessary to account for technical effects in the model. We found suggestive novel associations with AD status that will require confirmation.
The function and composition of brain tissue derived exosomes in human Alzheimer’s disease
Authors: Vella Laura J. , Su Huaqi , Koukoulis Tiana , Cheng Lesley , Purnianto Adityas , Beauchamp Leah , McLean Catriona , Bush Ashley I. , Masters Colin L. , Reid Gavin , Hill Andrew F. , Barnham Kevin J.
Published: December 2020

Background

Exosomes are extracellular vesicles (EVs) found in all bodily fluids. They carry the unique biological fingerprint of the parental cell they were released from, making them an ideal source of tissue and disease specific biomarkers and they are key players in cell‐to‐cell communication. Identification of brain derived exosomes (BDEs) in the periphery, for the purpose of AD diagnosis, requires knowledge of the composition of exosomes in the CNS. Moreover, an appreciation of the technical complexities associated with the isolation and characterisation of exosomes. We have taken a rigorous approach to the study of exosomes in AD frontal cortex. We have determined their Aβ and tau content, in addition to uncovering their omic profile.

Method

EVs were isolated from human frontal cortex as previously described by us (Vella et al JEV 2017), according to ISEV guidelines. Vesicles from neurological control or AD subjects were systematically assessed for morphology, density, size distribution, proteomic, lipidomic, genomic and metal content. The potential of BDE tau to cause conversion was assessed in tau biosensor cells.

Result

Exosomes are hypothesised to be a source of extracellular Aβ and p‐tau in AD and responsible for the ‘spread’ of these proteins. Here, we identified a pool of extracellular p‐tau and Aβ in AD brain, not associated with exosomes. In aggregation assays however, exosomes from AD subjects caused aggregation in tau biosensor cells, despite the absence of detectable p‐tau. Findings from some of our omic approaches revealed that BDEs recapitulate the lipidomic changes in the tissue, with remodelling in PE lipids in AD BDEs relative to control. While genomic profiling identified 26 highly enriched miRNA.

Conclusion

We determined the composition of brain exosomes in AD with the goal of identifying disease relevant biomarkers and identification of BDEs in the periphery. Lipid and RNA changes in AD frontal cortex were not only recapitulated in BDEs from this region but the dynamic range between disease and control tissues was extended, highlighting the advantage of this approach. Our functional studies suggest that BDEs can corrupt tau in the brain, potentially moving through the CNS in the absence of connected neuronal networks or detectable aggregated tau.
Retinal vascular occlusions are associated with increased risk for vascular dementia in APOE ε4 carriers in a community‐based cohort
Authors: Lee Cecilia S , Lee Michael L. , Gibbons Laura E , Larson Eric B , Crane Paul K
Published: December 2020

Background

We previously reported that several eye conditions were associated with increased risks of developing Alzheimer’s disease (AD). Retinal vascular occlusions (RVO, i.e. retinal vein and artery occlusions) are one of the leading sight‐threatening retinal vascular disorders. In this study, we sought to determine whether RVO are associated with increased risks of AD and other types of dementia. A few previous studies suggest that APOE is associated with RVO and vascular dementia.

Method

Participants aged ≥ 65 and dementia‐free were recruited in a prospective, observational cohort (Adult Changes in Thought [ACT] study). Self‐reported smoking history, hypertension, congestive heart failure, diabetes, and history of cardiovascular or cerebrovascular disease were obtained at study visits, and APOE genotype was obtained from consenting participants. Cognition was evaluated every two years with extensive neurological and neuropsychological testing when cognitive scores fell below normal range. All data were reviewed at consensus conferences for diagnosis of AD and various types of dementia such as vascular dementia (VasD). Eye diagnoses were obtained using ICD‐9/10 codes. We used adjusted Cox survival models to compute hazard ratios (HR) for developing dementia.

Result

A total of 4,743 participants had 1,037 incident cases of AD. 439 (9.3%) participants had retinal vascular occlusions. In participants with any APOE ε4 alleles, the HR of developing VasD was 3.03 (95%CI 1.37, 6.71, p‐value=0.0064) in participants diagnosed with retinal vascular occlusions compared to those without [Figure, Table 2]. This strong relationship persisted after further adjustment for diabetes, hypertension, and cardiovascular disease. No significant association was found between retinal vascular occlusions and VasD in participants (HR=1.05 95% CI 0.54, 2.03 , p= 0.89) who were negative for APOE ε4. No associations were found between RVO and AD or all‐cause dementia.

Conclusion

Increased risk of vascular dementia was found in participants diagnosed with RVO in participants who are APOE ε4 carriers. Further research about the relationship between APOE, dementia, and eye conditions is warranted.
[18F]MK‐6240 depicts early and late Braak stages of neurofibrillary tangles in preclinical and symptomatic subjects
Authors: Pascoal Tharick A. , Therriault Joseph , Benedet Andréa Lessa , Savard Melissa , Lussier Firoza Z. , Chamoun Mira , Tissot Cécile , Qureshi Muhammad Naveed Iqbal , Kang Min Su , Mathotaarachchi Sulantha , Stevenson Jenna , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

Postmortem Braak staging provides an index of disease stage and has therefore been incorporated as a core neuropathological criterion for the diagnosis of Alzheimer’s disease (AD). Recent in vivo studies using the tau positron emission tomography agent [18F]flortaucipir have shown low sensitivity to detect tau pathology in early Braak stages. These studies report Braak I‐II or greater in ∼20% of cognitively unimpaired elderly, in contrast to the ∼70‐90% of non‐zero Braak stage reported in postmortem studies. Here, we tested whether the novel high‐affinity tau tangles tracer [18F]MK‐6240 (6 fold > [18F]flortaucipir)can better identify individuals in the early stages of tau accumulation.

Method

To this end, we studied 301 individuals (30 young adults, 138 cognitively unimpaired (CU) elderly, 67 mild cognitive impairment (MCI), 54 AD dementia, and 12 frontotemporal dementia (FTD)) with amyloid‐b[18F]NAV4694, tau [18F]MK‐6240, magnetic resonance imaging, and clinical assessments.

Results

[18F]MK‐6240 discriminated AD from FTD dementia as well as predicted amyloid‐b positivity with the highest area under the curve in Braak I‐II region (=∼95‐100%)(Fig.1 and 2). [18F]MK‐6240 accumulation hierarchically followed the 6 Braak stages (Fig.3)in 98% of our population (Fig.4).91% of the elderly amyloid‐b positive and 46% of the elderly amyloid‐b negative displayed tau deposition, at least in the transentorhinal cortex (Braak I)(Fig.4). Cognition and amyloid‐b status explained most of the Braak stages variance (P<0.0001, R2=0.75). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid‐b, neurodegeneration, and cognitive impairment (P<0.0001). No single region‐of‐interest accurately segregated individuals into the 6 Braak stages (Fig.5). However, classification decision tree analysis suggested that a composite of transentorhinal, entorhinal, and hippocampal cortices(Braak I‐II) was the region‐of‐interest that best represented [18F]MK‐6240Braak stages (capacity of a region’ SUVR cutoff segregating individuals in 7 levels (Braak 0‐VI)) (accuracy=86.2%)(Fig.6).

Conclusion

Our results highlight that the hierarchical 6‐stage Braak model using [18F]MK‐6240 provides a robust index of early and late tau accumulation as well as disease stages in preclinical and symptomatic individuals. Tau positron emission tomography Braak staging using high‐affinity tracers has the potential to be incorporated in the diagnosis of living patients with AD.
Serum metabolome informs neuroimaging biomarkers for Alzheimer’s disease
Authors: Nho Kwangsik , Kueider‐Paisley Alexandra , Arnold Matthias , Dehkordi Siamak Mahmoudian , Risacher Shannon L. , Louie Gregory , Blach Colette , Baillie Rebecca , Han Xianlin , Kastenmüller Gabi , Doraiswamy P. Murali , Kaddurah‐Daouk Rima F. , Saykin Andrew J. ,   Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Metabolomics Consortium
Published: December 2020

Background

Accumulating evidence suggests that Alzheimer’s disease (AD) patients display metabolic dysfunction. Metabolomics is a powerful tool for studying metabolic pathways by mapping biochemical changes in AD, yet little is known about the association between circulating metabolites in blood and the “A/T/N” (amyloid‐β, tau, neurodegeneration) biomarkers for AD.

Method

Serum‐based targeted metabolite levels were measured in the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 1,531; 370 cognitively normal controls (CN), 95 significant memory concern (SMC), 271 early mild cognitive impairment (EMCI), 491 late MCI (LMCI), and 304 AD). The quality control process resulted in 139 metabolites for further analysis. We performed association analyses of circulating serum metabolites with the “A/T/N” biomarkers for AD. Biomarkers of “A” are CSF Aβ1‐42 and cortical amyloid‐β accumulation measured by Florbetapir PET, biomarkers of “T” are CSF phosphorylated tau (p‐tau), and biomarkers of “N” are atrophy on MRI and glucose metabolism on FDG PET. FDR‐based multiple comparison adjustment with the Benjamini‐Hochberg procedure was used.

Result

We found significant associations of multiple metabolites with biomarkers of amyloid‐β (“A”) and neurodegeneration (“N”) including brain amyloid deposition, glucose metabolism, and structural atrophy measured from multimodal neuroimaging scans (MRI, PET) after multiple testing adjustment. We did not observe any significant associations between metabolites and biomarkers of fibrillary tau (“T”) (Figure 1). In particular, higher levels of phosphatidylcholines (PC) were associated with greater amyloid deposition (“A”) and decreased brain glucose metabolism (“N”). Higher levels of propionyl‐L‐carnitine (C3) were associated with less amyloid deposition and increased brain glucose metabolism. Higher levels of two amino acids, two PCs, and three sphingomyelins were associated with less brain atrophy (“N”).

Conclusion

This is the first study to show serum circulating metabolites are significantly associated with neuroimaging biomarkers for AD. Perturbations in PC and acylcarnitine metabolism may play a role in features intrinsic to AD including amyloid‐β deposition and neurodegeneration, but not fibrillary tau suggesting that acylcarnitines and PCs are associated with earlier stages of AD as tau spreading is more closely related to AD progression.
Genome‐wide study of the human lipidome and links to Alzheimer’s disease risk
Authors: Meikle Peter J. , Giles Corey , Cadby Gemma , Huynh Kevin , Mellett Natalie A. , Olshansky Gavriel , Smith Alexander , Nguyen Anh , Chatterjee Pratishtha , Martins Ian , Laws Simon M. , Bush Ashley I. , Rowe Christopher C. , Villemagne Victor L.L. , Ames David , Masters Colin L. , Arnold Matthias , Kastenmüller Gabi , Nho Kwangsik , Saykin Andrew J. , Baillie Rebecca , Han Xianlin , Inouye Michael , Martins Ralph N. , Kaddurah‐Daouk Rima F. , Moses Eric ,   Busselton Health Study, AIBL and ADNI research groups
Published: December 2020

Background

Dysregulation of lipid metabolism is as an important – and modifiable – risk factor for the initiation and progression of Alzheimer’s disease (AD). Although lipid metabolism is established as crucial to numerous biological processes, the genetic factors that influence inter‐individual variation are still not well understood. To address this issue, we apply an integrative approach to link genetic variants with altered lipid metabolism and AD.

Method

Lipidomic profiling was performed using liquid chromatography coupled electrospray‐ionization tandem‐mass spectrometry on 4,492 genotyped individuals from the Busselton Family Health Study. We performed genome‐wide association analysis of 596 lipid species and 33 lipid classes using linear‐mixed models, correcting for age, sex, their interactions, 10 genomic principal components and an empirical genetic relatedness matrix. To account for lipoprotein mediated associations, the analysis was repeated with HDL‐C, triglycerides and total cholesterol as covariates. Additionally, collider bias was avoided by conditioning using multi‐trait‐based conditional and joint analysis. Validation of genome‐wide significant associations is supported by replication in the Australian Imaging, Biomarker & Lifestyle Study of Ageing (n = 1,112) and Alzheimer’s Disease Neuroimaging Initiative (n = 757) cohorts.

Result

Over 70,000 genome‐wide significant (p<5e‐08) associations were identified, with 451 lipid species having at least one significant association. Approximately 70% of the observed associations are independent of lipoprotein measures. We observed associations (p<1.0E‐6) between lipid species and seven loci containing genes previously identified as risk factors for AD, including ApoE, ABCA7 and SLC24A4. We further identify 1252 variants (92 independent gene regions) that associated (p<5.0E‐8) with the 71 lipid species we identified as significantly associated with incident AD in a combined meta‐analysis of the AIBL and ADNI cohorts.

Conclusion

By linking lipid species to AD, through genetic associations, we highlight potential therapeutic targets for monitoring, prevention and treatment.
Alteration of perivascular spaces in early cognitive decline
Authors: Sepehrband Farshid , Barisano Giuseppe , Sheikh‐Bahaei Nasim , Choupan Jeiran , Cabeen Ryan P , Crawford Malcolm S , Mack Wendy J , Chui Helena C , Ringman John M , Toga Arthur W ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Vascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular space (PVS). Here we investigated the association between PVS volume fraction and early cognitive decline, neurofibrillary tau and Amyloid‐b uptake and APOE status.

Method

Data were obtained from the ADNI‐3 database. A total of 685 participants with magnetic resonance imaging (MRI) data were assessed, and 596 participants (326 female [54.6%]) with complete data that passed quality control and inclusion criteria were included (cognitively normal participants age: 73.04 ± 7.36; mild cognitive impairment participants age = 75.56 ± 8.16). PVS volume fraction and brain volume were estimated from MRI using an automated in‐house pipeline; Amyloid‐b and Tau status were determined from PET images and CSF samples; Demographic, cognitive information and cardiovascular risk factors were also collected. Cognitive assessment scores were used to categorized individuals into cognitively normal and mild cognitive impairment subjects. Analysis models were adjusted for age, sex and years of educations.

Result

A significantly lower PVS volume fraction in mild cognitive impairment was observed compared to the cognitively normal group in both left (p=0.00047) and right (p=0.0009) anterosuperior medial temporal lobe (Figure 1). PVS volume fraction of the centrum semi‐ovale of the white matter was higher in mild cognitive impairment compared to cognitively normal participants, but not statistically significant after adjusting for age, sex, education and brain volume (p=0.07). PVS volume fraction in anterosuperior medial temporal lobe was significantly associated with Tau PET standardized uptake value ratio in right entorhinal cortex (beta (SE) = ‐0.02 (0.007); p=0.006). PVS volume fractions across different regions were independent of Amyloid load or APOE e4 status.

Conclusion

We show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered PVS presence and distribution, irrespective of Amyloid‐b. Surprisingly, we noted decreased PVS presence in the anterosuperior medial temporal lobe, which was associated with neurofibrillary tau tangle deposition in the entorhinal cortex, one of the hallmarks of early Alzheimer’s disease pathology. Our results suggest that anatomically‐specific alteration of the PVS may provide an early biomarker of cognitive impairment in aging adults.
The effects of mesial temporal tau in Ab‐negative cognitively normal older adults
Authors: Groot Colin , Dore Vincent , Robertson Joanne S , Burnham Samantha C , Savage Greg , Ossenkoppele Rik , Rowe Christopher C , Villemagne Victor LL
Published: December 2020

Background

Many older adults have some degree of tau aggregation, which is often regarded as a part of the process of aging. We assess the effects of mesial temporal tau on neocortical tau and on cognition in Ab‐negative, cognitively healthy older adults.

Method

Subjects were 47 cognitively healthy subjects from the AIBL cohort who had negative Ab‐PET scans and underwent [18F]flortaucipir‐PET to examine tau load. Regional tau was assessed using the MeTeR template and we determined mesial temporal (Mecomprising entorhinal cortex, hippocampus, parahippocampus and amygdala) tau‐positivity at SUVR>1.2 (n=10/47 [21.3%]). The associations between Me‐tau, voxelwise tau‐burden and cognition (MMSE, composite memory, composite non‐memory and the pre‐Alzheimer’s cognitive composite) were assessed. Furthermore, we examined the effect of Me tau on age and Ab burden.

Result

Voxelwise contrasts between Me+ and Me‐ subjects revealed that Me+ subjects had more tau in the neocortex (Figure 1). Furthermore, Me+ subjects had worse performance compared to Me‐ subjects on all cognitive tests assessed (Figure2). Me‐tau was marginally associated with higher age, but there was no association with Aβ burden (Figure 3).

Conclusion

These results indicate that, within a group of Ab‐negative subjects performing within normal ranges of cognitive performance, high Me tau is associated with more neocortical tau, suggesting that Me tau is a harbinger of tau in the neocortex. This high Me‐tau is associated with worse cognition and while likely age‐related (PART) might not be as benign as the term “ageing” implies.
The effects of peripheral lipoprotein metabolism on cerebrovascular inflammation in APP/PS1 mice
Authors: Button Emily B. , Boyce Guilaine K. , Wilkinson Anna , Stukas Sophie K. , Hayat Arooj , Cheng Wai Hang , Wadsworth Brennan J. , Fan Jianjia , Robert Jerome , Martens Kris M. , Wellington Cheryl L.
Published: December 2020

Background

Although Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaques and neurofibrillary tangles, most AD patients also exhibit cerebrovascular dysfunction. Therefore, strategies promoting cerebrovascular resilience have potential as therapeutic or preventative interventions against AD. High‐density lipoproteins (HDL) have several known beneficial functions on peripheral vessels. Further, increased plasma HDL concentrations have been associated with reduced dementia risk and HDL supplementation reduces both amyloid pathology and cognitive deficits in AD model mice. We therefore hypothesized that HDL may promote cerebrovascular health to protect against AD. We investigated the effects of HDL specifically on the cerebrovasculature in APP/PS1 mice, an AD model, using two methods.

Methods

First, we reduced plasma HDL levels by creating APP/PS1 mice genetically deficient for apolipoprotein (apo)A‐I, the primary protein component of HDL. Second, we treated 12‐month old APP/PS1 mice with a non‐brain penetrant liver X receptor (LXR) agonist for seven days to selectively upregulate the HDL biogenesis pathways in peripheral tissues. We measured cognitive deficits using cued and contextual fear conditioning tests. Fluorescent amyloid staining was used to assess vascular amyloid deposition. Immunofluorescent imaging evaluating glial fibrillary acidic protein (GFAP) and intercellular adhesion molecule 1 (ICAM‐1) association with CD31 positive area was used to assess vessel‐associated astrogliosis and endothelial inflammation, respectively.

Results

At 12 months of age, apoAI‐null mice had increased cognitive deficits in cued and contextual fear conditioning tests, increased vascular amyloid burden, increased vessel‐associated astrogliosis, and increased brain endothelial cell inflammation. Seven days of LXR agonist treatment had no effect on amyloid pathology or astrogliosis. However, LXR agonist‐treated APP/PS1 mice displayed reduced cognitive deficits in cued fear conditioning tests and reduced endothelial cell inflammation.

Conclusions

Circulating HDL promotes cerebrovascular health in APP/PS1 mice by limiting both Aβ‐induced vascular inflammation and vascular Aβ deposition resulting in reduced amyloid pathology and cognitive deficits.
Healthy subjects with abnormal levels of amyloid‐B and tau have lower cortical volumes in the mesial temporal region
Authors: Huang Kun , Dore Vincent , Li Shenpeng , Krishnadas Natasha , Bourgeat Pierrick , Burnham Samantha C. , Fripp Jurgen , Villemagne Victor L.L. , Rowe Christopher C.
Published: December 2020

Background

Post‐mortem studies on Alzheimer's disease (AD) have shown that the stereotypical pattern and density of tau deposition is strongly associated with cortical loss. In this study, we investigate if cognitively healthy elderly subjects with abnormal level of tau in the mesial temporal lobe and/or of Ab in the brain as measure with PET have lower cortical volumes in parahippocampal, entorhinal, inferiortemporal, fusiform, hippocampus and amygdala which are the early region of atrophy.

Method

232 healthy cognitively normal control (CN) participants from the AIBL cohort underwent an Ab PET scan (18F‐NAV6240) and a tau scan (18F‐MK6240), . Ab and MK6240 scans were spatially normalized and scaled to the cerebellar cortex using CapAIBL. Threshold for Ab abnormality was 20CL, and two standard deviations above the SUVR mean in the mesial temporal region on Ab‐ CN subjects for tau. Three groups were then defined A‐T‐ (n = 180, 74.5 ± 5 yrs), A+T‐(n = 32, 77 ± 6 yrs) and A+T+(n = 16, 78 ± 7 yrs). From T1w MRI, cortical volumes in the parahippocampus, hippocampus, entorhinal, amygdala, inferior temporal and fusiform were computed. Volumes were controlled for intracranial volumes and normal aging and compared between the different group using standard T‐tests.

Result

There were no significant differences in age between 3 groups. However, A+T+ cohort had lower MMSE scores than A‐T‐. In addition, the CDR scores for A+T+ were significantly higher than in the other two groups. A+T+ had a significant lower cortical volume in all examined regions compared to A‐T‐ and A+T‐, (p < 0.05). There were no significant difference in cortical volumes between A‐T‐ and A+T‐.

Conclusion

In CN, Ab pathology alone is not associated with lower cortical volumes. However, Ab and tau deposition in the mesial temporal lobe is associated with GM loss, even at the presymptomatic stages.