bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting SHIP1 for therapeutic intervention in Alzheimer’s disease
Authors: Obst Juliane , Bradshaw William , Roberts Hazel Hall , Priestley Richard , Jimenez‐Antunez Carmen , Cowley Sally A. , Gileadi Opher , Mead Emma , Daniel Elena Di , Davis John B.
Published: December 2020

Background

Genome wide association studies (GWAS) and systems biology approaches have identified several Alzheimer’s disease (AD) risk associated genes expressed in microglia. SHIP1, an inositol phosphatase, has been identified as a regulator of TREM2 signalling, inhibiting the cascade by opposing SYK and PI3K phosphorylation. A SHIP1 variant (rs39349669) confers AD risk by increasing SHIP1 expression, thereby inhibiting TREM2 signalling and reducing beneficial microglial phenotypes including phagocytosis. We hypothesise that SHIP1 inhibition may restore the protective signalling pathway associated with TREM2.

Method

Utilising human iPSC macrophages, we aim to understand the role of SHIP1 in regulating TREM2 signalling. We are able to stimulate TREM2 signalling using an activating antibody, and we have measured SYK phosphorylation and Ca2+ flux in the presence of SHIP1 modulators. As development of small‐molecule inhibitors of phosphatases is challenging due to polar active sites, we hope to identify allosteric binding sites on SHIP1. We have determined the structure of SHIP1 and aim to use crystallography to promote the development of potent modulators. We have performed a crystallographic fragment screen of 597 compounds to identify SHIP1 binders, which will be used as starting points for medicinal chemistry.

Result

The SHIP1 inhibitor 3AC increases SYK phosphorylation and intracellular Ca2+ flux following TREM2 stimulation. We are now working with an isogenic SHIP1 KO iPSC line to validate these findings. We have determined the structure of the phosphatase and C2 domains of SHIP1, both in the apo form and with a phosphate and a magnesium ion bound to the active site. We are working towards further structures. The fragment screen revealed more than 100 binding events. These identify new potential binding pockets outside of the active site and work is ongoing to perform SAR.

Conclusion

We have demonstrated that SHIP1 regulates TREM2 signalling and is a druggable target. Furthermore, we are working towards identifying inhibitors that will increase TREM2 mediated protective signalling in microglia. We have improved understanding of the structural basis of the reaction catalysed by SHIP1, which will inform the development of novel and selective compounds. Targeting SHIP1 could represent a novel therapeutic strategy for the treatment of AD.
Preclinical features of familial FTD
Authors: Jiskoot Lize C.
Published: December 2020

Background

Up to 40% of frontotemporal dementia (FTD) cases carry an autosomal dominant mutation, the majority in the progranulin (GRN), microtubule‐associated protein tau (MAPT) or chromosome 9 open reading frame 72 (C9orf72) genes. Familial FTD offers a unique window for observing the earliest disease‐related changes, as mutation carriers can be identified in their presymptomatic stages.

Method

We performed a systematic review of discoveries from major European prospective longitudinal cohorts of presymptomatic mutation carriers, particularly the Rotterdam FTD Risk Cohort (FTD‐RisC) and the GENetic Frontotemporal dementia Initiative (GENFI).

Result

In the last 10 years, biomarker changes that begin many years before symptom onset have been identified. Presymptomatic neuropsychological assessment have demonstrated executive dysfunction as a common feature of all the genetic groups, as well as mutation‐specific patterns in GRN (memory), MAPT (language) and C9orf72 (attention). Grey matter atrophy and hypometabolism appear around 10 years prior to symptom onset. White matter tract abnormalities signify the first disease‐related changes, seen as early as three decades before symptom onset, again with mutation‐specific patterns in GRN (internal capsule), MAPT (uncinate fasciculus) and C9orf72 (posterior tracts). Several fluid biomarker candidates have been identified. Neurofilament light chain provides a reliable measure of disease staging, progression and survival, with levels being highest in C9orf72‐associated ALS and lowest in MAPT mutation carriers. Two of the biggest challenges are identifying and conceptualizing the transitional (conversion) stage between presymptomatic and overt disease, similar to mild cognitive impairment in the evolution to Alzheimer’s Disease dementia, and the use of estimated years to symptom onset as a proxy for actual symptom onset—which varies widely between and within families and across mutations. Conversion seems to be a relatively rapid process, and there are no clinical tools to capture this transition. There is also a lack of reliable disease‐staging markers.

Conclusion

The pathological heterogeneity in FTD warrants a multimodal approach, and future challenges lie in finding sensitive clinical markers that are able to identify the earliest cognitive and behavioural features, as well as neuroimaging and fluid biomarkers that can reliably differentiate between clinical and pathological FTD subtypes.
Latent disease models estimate symptom onset in familial frontotemporal lobar degeneration and enable novel designs for early‐stage clinical trials
Authors: Staffaroni Adam M. , Quintana Melanie , Wendelberger Barbara , Heuer Hilary W. , Rojas Julio C. , Cobigo Yann , Goh Sheng‐Yang Matthew , Wolf Amy , Onyike Chiadi U. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L.
Published: December 2020

Background

Measuring changes in the earliest phases of familial frontotemporal lobar degeneration (f‐FTLD) and estimating symptom onset has important implications for clinical care. Early stage clinical trials have begun for f‐FTD, but the low prevalence of f‐FTLD mutation carriers and heterogeneous symptomology challenges trial design. Bayesian disease progression models (DPM) incorporate clinical data, neuroimaging metrics, and fluid biomarker concentrations to estimate latent disease age, providing estimates of symptom onset and progression status. Such models may facilitate enrollment in studies (i.e., inclusion of presymptomatic individuals) and provide more powerful analysis methods for trials.

Method

A Bayesian latent variable repeated measures model was used to estimate disease progression, conditional on latent disease age (proximity to symptom onset), in 275 participants with mutations in GRN (n=68), MAPT (n=80) and C9orf72 (n=127). Median follow‐up was one year (range: 0‐4). Jointly modeled longitudinal variables included neuropsychological scores, CDR®+NACC‐FTLD box score, 3T MRI frontotemporal brain volumes, and plasma levels of neurofilament light chain (NfL). Sample size estimates for detecting treatment effects were generated by varying thresholds of estimated proximity to symptom onset.

Result

The Bayesian DPM provided a clear picture of clinical and neurological progression within each mutation group. Neuroimaging and NfL captured early progression rates (1 SD from controls) 5‐10 years before symptom onset. After symptom onset, CDR®+NACC‐FTLD box score was the most sensitive measure of disease progression. GRN mutation carriers had the largest annual progression rates (and lowest variability) compared to MAPT and C9orf72. Between 5 years pre‐ and 10 years post‐onset, CDR®+NACC‐FTLD box score progressed by 2 units/year (SD=2.7) in GRN mutation carriers ‐ almost twice the rate of progression in MAPT (M=1.2;SD=2.5) and C9orf72 (M=1.1;SD=2.2) mutation carriers. Compared to a trial enrolling only early symptomatic cases (CDR®+NACC‐FTLD=0.5 or 1), utilizing latent disease age would facilitate enrollment of asymptomatic cases with the same power.

Conclusion

Based on an estimation of symptom onset, Bayesian DPMs suggest clinical trials in GRN mutation carriers would require the smallest sample sizes. Furthermore, leveraging these DPMs would allow novel, powerful trial designs that may facilitate greater participant enrollment.
Elevated systolic blood pressure is associated with episodic memory decline in healthy aging
Authors: Solé‐Padullés Cristina , Vaqué‐Alcázar Lídia , Abellaneda‐Pérez Kilian , Ros Emilio , Bartres‐Faz David
Published: December 2020

Background

Elevated blood pressure (BP) is associated with poorer cognitive performance in ageing but not in the very old (Obisesan et al., 2008). Likewise, hypertension causes vascular dysregulation and eventually decreased blood flow in several regions including the hippocampus (Glodzik et al., 2019) and is associated with faster cognitive decline in Mild Cognitive Impairment (MCI) patients (Goldstein et al., 2013). However, the association between BP and memory performance remains controversial with studies finding different results (reviewed in Forte et al., 2020). Longitudinal examinations are also non‐conclusive. One study showed association between poorer memory performance and higher systolic BP (SBP) at baseline, but not at follow‐up examination (Waldstein et al., 2005); and a previous one found that elevated SBP predicted greater number of errors in a memory task over time (Glynn eta l., 1999). We aim to explore the association between baseline SBP and memory change in healthy aging.

Method

77 healthy elders (age range 65‐78) were selected from the Institute of Aging (Barcelona). Rey Auditory verbal learning Task (RAVLT) was administered at baseline and follow‐up examination (mean interval period was 4.15 years, SD=0.44). Partial correlations were conducted between SBP and percent of change in RAVLT total learning and delayed scores. Control variables included age at baseline, interval period between assessments, medication for hypertension (medicated versus unmedicated) and years of education. All individuals presented normal global cognitive function (Mini Mental state Examination ≥ 25) and RAVLT delayed scores ≥ 5, to exclude possible MCI cases.

Result

A significant negative correlation was found between SBP at baseline and percent of change in delayed episodic memory (r=‐0.338, p=0.003, Bonferroni corrected p=0.021). Interestingly, no significant associations were found between SBP and cross‐sectional measures of delayed RAVLT.

Conclusion

Elevated SBP was associated with increased decline in delayed verbal memory in healthy aging. Delayed episodic memory is a key factor for characterizing subjects at risk of dementia and therefore, targeting measures to maintain optimal levels of BP should be a priority for primary care medicine.
Genome‐wide DNA methylation signatures of tau and amyloid neuropathology
Authors: Castanho Isabel , Murray Tracey K. , Leung Szi Kay , Hannon Eilis , Jeffries Aaron , Lunnon Katie , Ahmed Zeshan , Mill Jonathan
Published: December 2020

Background

The onset and progression of Alzheimer’s disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and the accumulation of β‐amyloid (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD, the regulatory genomic mechanisms involved in disease progression are not fully understood. DNA methylation (DNAm) is the most widely studied epigenetic modification in human disease, with recent work by our group robustly linking methylomic variation to AD and other neurodegenerative disorders. To date, no study has systematically profiled DNAm in mouse models of AD. This study aimed to relate progressive changes in DNAm to AD neuropathology in the cortex, using transgenic models of amyloid and tau pathology.

Method

We used transgenic mice harboring human microtubule‐associated protein tau (MAPT, rTg4510) and amyloid precursor protein (APP, J20) mutations to investigate epigenomic and transcriptional changes associated with the development of tau and amyloid pathology. Using sequencing‐based approaches, we quantified changes in DNAm and gene expression identifying genomic signatures paralleling the progression of tau and amyloid across multiple brain regions. Methylomic and transcriptomic changes associated with amyloid and tau pathology were compared to similar data generated from human AD brain.

Result

We identified progressive changes in gene regulation associated with the development of AD neuropathology, including changes in DNA methylation and gene expression at loci previously identified in previous and ongoing human AD studies (Ank1, Hoxa, Abca7, Bin1). Of note, significantly upregulated genes were strikingly enriched for genes involved in immune regulation, and significantly downregulated genes were enriched for synaptic function pathways related to AD. This study represents the most systematic analysis of progressive changes in gene expression and DNA modifications in mouse models of AD pathology and the first to focus specifically on the entorhinal cortex, a key region affected early in human AD.

Conclusion

Our data provide further evidence for an immune‐response to the accumulation of tau and Aβ, and reveal novel genomic pathways associated with the progression of AD neuropathology.
Stroke, genetic risk and incidence of dementia
Authors: Ranson Janice M , Lourida Ilianna , Hannon Eilis , Littlejohns Thomas J , Ballard Clive , Langa Kenneth M , Hyppönen Elina , Kuzma Elzbieta , Llewellyn David J
Published: December 2020

Background

Stroke is a strong, independent and modifiable risk factor for all‐cause dementia. However, the extent to which stroke adds to or moderates genetic risk is unknown.

Method

In this cohort study, we used data from UK Biobank including adults aged 60 years and older of European ancestry without cognitive impairment or dementia at baseline. Participants joined the study between 2006 and 2010 and were followed until 2016 or 2017. Genetic risk was estimated using a polygenic score for dementia incorporating 249,273 single‐nucleotide polymorphisms with low (lowest quintile), intermediate (quintiles 2‐4), and high (highest quintile) categories. Stroke was a binary variable based upon history of stroke occurring before dementia diagnosis or end of follow‐up in participants who remained dementia‐free. The outcome was incident all‐cause dementia, ascertained through hospital inpatient and death records.

Result

196,383 individuals (mean [SD] age, 64.1 [2.9] years; 52.7% were women) were followed up for 1,545,433 person‐years (median [interquartile range] follow‐up, 8.0 [7.4‐8.6] years). Overall, 3.8% of participants had a history of stroke. 20.0% had high polygenic risk scores, 60.0% had intermediate risk scores, and 20.0% had low risk scores. Of the participants with high genetic risk, 1.2% developed dementia compared with 0.63% of the participants with low genetic risk (adjusted hazard ratio, 1.94 [95% CI, 1.66‐2.27]). Of the participants with stroke, 2.7% developed dementia compared with 0.8% of participants without a stroke (adjusted hazard ratio, 2.73 [95% CI, 2.35‐3.17]). Of the participants with a high genetic risk and stroke, 3.4% developed dementia compared with 0.57% of participants with low genetic risk and no stroke (adjusted hazard ratio, 5.02 [95% CI, 3.67‐6.86]). There was no significant interaction between genetic risk and stroke (P = 0.633). Among participants with high genetic risk, 1.2% of those without stroke developed dementia compared with 3.4% of those with stroke (hazard ratio, 0.40 [95% CI, 0.29‐0.53]).

Conclusion

Among older adults without cognitive impairment or dementia, both stroke and high genetic risk were significantly associated with higher dementia risk. Stroke prevention should be a key element of risk reduction strategies for the prevention of dementia, particularly amongst those with a high genetic risk.
Impact of psychosis on quality of life and well‐being in dementia
Authors: Choi Aaron , Ballard Clive , Martyr Anthony , Collins Rachel , Morris Robin G. , Clare Linda
Published: December 2020

Background

This study aimed to: 1) Examine the impact of psychotic symptoms on the quality of life, wellbeing and satisfaction of life in people with dementia(PwD) living in the community, and 2) determine whether other symptoms known to affect quality of life in PwD would confound any effect detected.

Method

The Neuropsychiatric Inventory Questionnaire was completed by informant interview. Mean differences between the absence and presence of each psychotic symptom (delusions, auditory hallucinations) were then compared for each of three validated measures of living well and quality of life: Quality of Life in Alzheimer’s scale, World Health Organization‐Five Well‐being Index and Satisfaction with Life Scale. Analysis of co‐variance was used to determine the confounding contributions of cognition via Mini‐Mental State Examination, depression via Geriatric Depression Scale‐10, carer stress via Relative Stress Scale and antipsychotic usage.

Result

Presence of delusions was not associated with quality of life, wellbeing or satisfaction with life. Presence of auditory hallucinations was associated with lower scores for QoL [p<0.001, η2=0.013], wellbeing [p<0.001, η2=0.016] and satisfaction with life [p<0.001, η2=0.010]. After controlling for confounding factors, the relationship between auditory hallucinations and Qol [p=0.003, pη2= 0.011] and wellbeing p <0.001, pη2= 0.018] remained significant, but there was no significant association with satisfaction with life.

Conclusion

Presence of auditory hallucinations but not delusions is associated with lower quality of life and wellbeing in people with dementia living in the community.
Application of two‐graph receiver operating characteristics for defining intermediate amyloid‐beta CSF cutoffs
Authors: Brum Wagner Scheeren , De Bastiani Marco Antônio , Souza João Pedro Ferrari , Bieger Andrei , Therriault Joseph , Benedet Andréa Lessa , Pascoal Tharick A. , Povala Guilherme , Ferreira Pamela C.L. , Souza Diogo O. , Rosa‐Neto Pedro , Zimmer Eduardo R.
Published: December 2020

Background

The NIA‐AA 2018 Research Framework envisioned Alzheimer's disease (AD) as a biological construct, dichotomizing individuals into normal and abnormal for each biomarker category. Furthermore, it suggests that developing intermediate‐range cutoffs would aid in advancing AD research. However, few statistical methodologies have been proposed to define what would constitute an intermediate range for an AD biomarker. Here, we apply a three‐range method for defining cutoff in amyloid‐β (Aβ) cerebrospinal fluid (CSF) measurements to assess intermediate range's predictive value over clinical progression. Considering it is expected that a biomarker loses its predictive value in the perithreshold zone, we hypothesized that Aβ‐intermediate (AbInt) status of cognitively unimpaired (CU) would not be able to predict progression to symptomatic stages of AD.

Method

For defining intermediate‐range cutoffs with two‐graph receiver operating characteristics (TG‐ROC) method, 807 individuals with baseline [18F]AV45 Aβ‐PET and CSF Aβ1‐42 Elecsys® biomarkers were selected from the ADNI. Mean standardized uptake value ratio cutoff of 1.11 for [18F]AV45 was employed to stratify individuals into true‐positive (n=433) and true‐negative (n=374). Based on TG‐ROC cutoffs, 336 CU individuals with baseline CSF Aβ1‐42 Elecsys® were divided into Aβ‐, Aβint and Aβ+ and followed‐up for 6 years. Predictive values of baseline biomarker status for clinical progression were assessed using Cox proportional hazards models adjusted for age, gender, APOE and baseline MMSE.

Result

TG‐ROC analysis yielded cutoffs for Aβ‐ (>1131 pg/mL; n=199), AβInt (820.1<Intermediate<1131 pg/mL; n=55) and Aβ+ (<820.1 pg/mL; n=82), as shown in Figure 1. A total of 52 individuals progressed clinically to mild cognitive impairment (n=50) or to dementia (n=2). Adjusted hazard ratios (HR) for progression, compared to the Aβ‐ group, were, as expected, significantly elevated for Aβ+ individuals (HR=2.428; 95% CI 1.299‐4.537; p=0.005), whereas non‐significant for AβInt (HR=‐0.375; 95% CI 0.259‐1.826; p=0.452). Kaplan‐Meier survival curves illustrate these trajectories (Figure 2).

Conclusion

Our findings support the notion that biomarker measurements lose their ability to significantly predict cognitive decline within the perithreshold zone, emphasizing the need for further investigation of these individuals. As an alternative for operationalizing this matter of pivotal importance, we propose further investigation about the clinical utility of TG‐ROC, a well‐established method for defining three‐range cutoffs.
Exercise as a strategy to prevent APOEε4‐dependent phenotypes
Authors: Foley Kate E. , Diemler Cory , Garceau Dylan , Moore Annah M. , Hohman Timothy J. , Sasner Michael , Howell Gareth
Published: December 2020

Background

Human data suggest cerebrovascular dysfunction precedes and exacerbates Alzheimer’s disease (AD). APOEε4 contributes to cerebrovascular decline with age, and APOE status interacts with angiogenesis pathways including the VEGF family to modify cognitive decline. However, the precise nature of this relationship is not known. Research suggests that running provides substantial health benefits that reduce risk for AD. Previous data from our lab showed that, transcriptionally, cerebrovascular processes such as vascular remodeling and angiogenesis terms can be altered short term running in young mice. Here, we are combining human and mouse studies to (i) understand the relationship between APOE status and the VEGF pathway in AD, and (ii) determine whether the effects of exercise on the cerebrovasculature are modified by APOE status.

Method

To assess cerebrovascular health, we took several approaches: (i) transcriptional profiling, (ii) immunofluorescence of basement membrane, and (iii) immunofluorescence of leakage (fibrin). To assess exercise and metabolic differences, B6.APOEε4/ε4 (risk) and B6.APOEε3/ε3 (neutral) mice were run from 1‐4 months (mo) and 1‐12mos, as well as metabolic phenotyping including circulating plasma lipid levels, food intake, water loss, running speed, and gas exchange. Heterozygous B6.APOEε3/ε4 mice are included to evaluate the potential hypomorphic/ hypermorphic function of the APOEε4 allele on cerebrovascular health. Human data from ROSMAP and ADNI cohorts is being compared to mouse data.

Result

Cerebrovascular dysfunction was evaluated in 2mo and 12mo B6.APOEε3/ε3 and APOEε4/ ε4 mice for basement membrane coverage and fibrin leakage which revealed an increase in COL4 and increased leakage, in 12mo female APOEε4/ε3 compared to B6.APOEε3/ε3 mice. Analysis of 1‐4mo running data showed no transcriptional evidence that the cerebrovasculature was altered in young APOEε4 or APOEε3 carriers, suggesting longer term interventions are necessary. Human data shows patients that suffer a more severe cognitive decline have increasing levels of angiogenesis markers in the brain and blood. Our ongoing work aims to identify the mechanism between APOEε4 and angiogenesis/cerebrovascular integrity.

Conclusion

Recreated APOEε4mice recapitulate age‐dependent cerebrovascular deficits however running at a young timepoint will likely not affect cerebrovascular health. Longer term studies are underway to determine whether chronic running mitigates age‐dependent effects of APOEε4.
Functional characterization of an Alzheimer disease‐associated deletion in SORL1
Authors: Dykxhoorn Derek M. , Simon Shaina A. , Kunkle Brian W. , Cuccaro Michael L. , Vance Jeffery M. , Cukier Holly N. , Pericak‐Vance Margaret A.
Published: December 2020

Background

Over 20 genetic loci have been consistently associated with Alzheimer disease (AD) with accumulating evidence pointing to alterations of the endolysosomal pathway as playing key roles. The sortilin‐related receptor 1 (SORL1) gene has been associated with AD through multiple genetic studies and has been suggested to function by guiding APP to the endocytic pathway. We recently identified a family with multiple AD affected individuals that bear a single base pair deletion (g.4292delG) predicted to result in a frameshift alteration and early termination of the protein (p.Cys143Ser*1). Previous studies have implicated SORL1 variants in AD pathogenesis, but it remains unclear how this deletion impacts SORL1 protein function and AD development.

Method

Induced pluripotent stem cells (iPSC) lines were developed to examine the cellular and molecular consequences in neuronal and glial cell (astrocytes and microglia) populations, which can otherwise only be collected postmortem. Each iPSC line generated was validated for pluripotency through immunocytochemical staining and shown to be negative for any large‐scale chromosomal abnormalities via karyotyping. The patient iPSC lines and control lines were differentiated into cortical neurons and glia cells for functional analyses, including amyloid beta production and uptake, vesicular trafficking, and neurite outgrowth.

Result

We have generated iPSC lines from two individuals bearing this deletion in SORL1 and have confirmed their pluripotency by immunocytochemistry. These cells were differentiated into cortical neurons whose identity was confirmed by staining for forebrain markers. The SORL1 variant bearing cortical neurons showed enlarged endosomes compared to the neurons derived from control iPSCs, as measured by the staining with an anti‐RAB5 antibody and fluorescent microscopy. In addition, the SORL1 deletion bearing neurons showed an upregulation of pathogenic amyloid beta 42 measured by ELISA. Glial cells have emerged as pivotal players in the maintenance of brain homeostasis. Therefore, we will assess the functional impact of this deletion of SORL1 in microglial cells and astrocytes.

Conclusion

In summary, our results support that the p.Cys143Ser*1 variant is indeed pathogenic. iPSC‐derived neurons and glia cells bearing the deletion in SORL1 p.Cys143Ser*1 variant shows cellular deficits associated with AD pathology which could serve as new avenues for therapeutic development.
Aortic pulse wave velocity as a predictor of cognitive decline in older adults
Authors: de la Torre Paola Garcia , Almeida‐Gutiérrez Eduardo , Torres‐Rosales Jorge , Sanchez‐Garcia Sergio , Cuadros‐Moreno Juan , Garcia‐Dominguez Juana A.
Published: December 2020

Background

Global aging has caused a demographic transition that has had an effect on health systems all over the world. Together with dementia, cardiovascular disease is a common health concern in older adults and is the first cause of death globally. The contribution of an unhealthy vascular system to the development of dementia has been stated before.

Method

Using a cross‐sectional analysis, we performed vascular non‐invasive measurements in older adults with (n=101) or without (n=65) detectable cardiovascular disease using a commercial device. All subjects were evaluated for cognitive decline.

Results

We found 54.83% cognitive impairment in the free‐cardiovascular disease group and 41.58% for the cardiovascular disease group. Aortic pulse wave velocity was significantly higher in patients with cognitive decline (p<0.05) independently of their cardiovascular health. However, a higher wave return velocity (p<0.05) and aortic wave velocity (p<0.05), and a lower augmentation index (p<0.001) was found in older adults with cardiovascular disease compared to cardiovascular disease free subjects.

Conclusion

Aortic pulse wave velocity is associated with cognitive decline regardless of the presence of cardiovascular disease. Furthermore, subjects with cardiovascular disease have higher wave return velocity and aortic wave velocity, and lower aortic pulse wave velocity.
Increased 18F‐flortaucipir load correlates with changes in MEG functional connectivity and network topology, as well as oscillatory slowing
Authors: Schoonhoven Deborah N. , Coomans Emma M. , van Nifterick Anne M. , Ossenkoppele Rik , Scheltens Philip , Stam Cornelis J. , Golla Sandeep S. V. , Arjan Hillebrand , Van Berckel Bart N. M. , Gouw Alida A.
Published: December 2020

Background

Recent fMRI studies have provided evidence that tau proteins may spread through the brain in stereotypical patterns following functional connections. However, fMRI is an indirect measure of neuronal activity, and has limited temporal resolution, contrary to magnetoencephalography(MEG). We aimed to investigate whether changes in neuronal activity, functional connectivity and network organization mirror regional tau retention in (preclinical) Alzheimer’s disease(AD), using MEG and in‐vivo 18F‐flortaucipir (tau) PET.

Methods

Twenty participants with AD pathology according to the ATN‐criteria (CSF‐Aβ42 and/or amyloid‐PET) were recruited from the Amsterdam Dementia Cohort, classed as subjective cognitive decline (SCD; n=10) and probable AD dementia (n=10), Table‐1. Participants underwent dynamic 130‐minutes 18F‐flortaucipir PET, and 10‐minutes eyes‐closed, task‐free 306‐channel MEG recordings. Neuronal activity and 18F‐flortaucipir non‐displaceable binding potential(BPND) were reconstructed for 52 regions‐of‐interest(ROIs) in an adjusted version of the probabilistic Hammers atlas. Associations between 18F‐flortaucipir BPND and MEG spectral measures (peak frequency, relative delta(0.5‐4Hz); theta(4‐8Hz); alpha(8‐13Hz); beta(13‐30Hz); gamma(30‐48Hz) power); connectivity (volume conduction‐corrected amplitude envelope correlation(AEC‐c) in delta, alpha and beta band); and network measures (minimum spanning tree betweenness centrality(BC)) were investigated using generalized estimating equation(GEE) models, for SCD and AD dementia combined. To investigate possible group effect, the GEE was repeated using only the AD dementia‐group.

Result

Increased regional 18F‐flortaucipir binding correlated strongly with oscillatory slowing in both the total sample and AD‐group, reflected by negative correlations with peak frequency, relative alpha and beta power, and positive correlations with relative delta and theta power, most pronounced in parietal and occipital regions (Fig‐1A+B). Regional 18F‐flortaucipir binding correlated with loss of connectivity for both groups mainly in the occipital regions (average β=‐0.677±0.16, β=‐0.660±0.23 resp.) for the beta band, Fig‐2A+B. The delta band showed an opposite effect in frontal and occipital regions. Higher 18F‐flortaucipir binding was associated with lower centrality in temporal (delta) and subcortical regions (alpha, beta), and higher centrality in the parietal region (alpha), Fig‐2A+B.

Conclusion

We provide putative evidence that increased regional 18F‐flortaucipir binding associates to reduced neuronal activity, as well as loss of connectivity in higher frequency bands, which could be replicated in a separate AD analysis. Furthermore, tau deposition seems to be related to damage to highly connected hub nodes.
Targeting the Moesin‐CD44 pathway for therapeutic intervention in Alzheimer’s disease
Authors: Katis Vittorio , Bradshaw William , Betarbet Ranjita , Jimenez‐Antunez Carmen , Seyfried Nicholas T. , Slakman Belinda , Mulhern Christopher , Guie Marie‐Aude , Keefe Anthony , Guilinger John , Zhang Ying , Huguet Christelle , Levey Allan I. , Brennan Paul E. , Mangravite Lara M. , Gileadi Opher ,   The Open‐AD Consortium
Published: December 2020

Background

Investigation of the Alzheimer’s Disease (AD) brain proteome, along with weighted co‐expression network analysis, revealed a module enriched with proteins involved in inflammation (PMID: 27989508). This module progressively increases in brains from Controls to Asymptomatic AD to those with Symptomatic AD. Moesin (MSN) and CD44 emerged as key inflammation module hub proteins. MSN is a cytoskeletal protein with roles in focal adhesion‐mediated cell motility; CD44 is a transmembrane receptor that interacts with MSN. This project aims to develop chemical tools to disrupt this pathway.

Method

To investigate the AD‐relevant distribution of MSN, tissue sections and cells were stained with MSN‐specific antibodies as well as with Iba1, 4G8 and pHF‐Tau antibodies. Purified FERM domains of MSN and EPB41L3 were produced in E. coli and co‐crystallized or soaked with ligands after crystallization. The CD44 ectodomain was expressed in bacteria and refolded or secreted from HEK293 cells.

DNA‐encoded library screens were performed as described (http://www.x‐chemrx.com/our‐science/).

Result

MSN‐staining in cortical human brain sections localised to endothelial cells and microglia‐like cells. MSN‐positive cells also stained for microglia‐specific marker, Iba1. In AD brains, MSN‐positive microglia‐like cells were present around amyloid plaques and tangle‐like structures. These immunohistochemical studies confirmed the association of MSN with AD pathology. Co‐crystal structures of Moesin and the related FERM protein EPB41L3 revealed the binding mode of the intracellular tail of CD44 to Moesin. This binding interaction was then used to develop HTRF‐based assays for high‐throughput screening for molecules that disrupt the CD44‐MSN interaction. In parallel, a crystal‐based fragment screen using EPB41L3 identified binding pockets and initial hits. Hits and chemical staring points will be further developed with the Open‐AD Medicinal Chemistry core at UNC. To identify inhibitors of CD44 ectodomain binding to hyaluronic acid we screened DNA‐encoded libraries. The screens identified micromolar hits which are being further developed, aiming to obtain potent brain‐penetrant inhibitors of CD44.

Conclusion

(1) Moesin expression is associated with AD pathology. (2) The CD44‐Moesin signalling axis was targeted for potential points of intervention. (3) We have developed the assays, structural biology and chemical starting points to develop small‐molecule inhibitors of the CD44 ectodomain and the CD44‐MSN interaction.
Validation of a simplified tissue‐to‐reference ratio measurement using SUVR for the assessment of synaptic density alterations in Alzheimer’s disease using [11C]UCB‐J PET
Authors: O'Dell Ryan S. , Naganawa Mika , Toyonaga Takuya , Young Juan , Dahal Rabin , Singh Edward , Waheed Aisha , Banks Emmie R. , Harris Joanna E. , Chen Ming‐Kai , Nabulsi Nabeel B. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H. , Mecca Adam P.
Published: December 2020

Background

Synaptic density PET is an emerging technology with potential as a biomarker for tracking disease progression and therapeutic efficacy in studies of Alzheimer's disease (AD). Simplified methods of image acquisition and quantification would facilitate the use of synaptic density imaging in multicenter longitudinal studies. Therefore, we validated a simplified tissue‐to‐reference ratio method using standardized uptake value ratios (SUVR) for estimating synaptic density using [11C]UCB‐J PET.

Method

[11C]UCB‐J binding was measured in 31 participants with early AD and 16 cognitively normal (CN) participants aged 55‐85 years. All participants underwent 90 minute dynamic PET scans on the HRRT after bolus injection of [11C]UCB‐J. Parametric images of binding potential (BPND
) were generated using SRTM2 (0‐60 minutes) with a centrum semiovale reference region and converted to distribution volume ratios (DVR) with a cerebellum reference region. Parametric images of SUVR were generated by summing frames from 30‐60 or 60‐90 minutes and normalizing to the cerebellum. Regional group differences were assessed using unpaired t tests and Cohen’s d, while associations between DVR and SUVR were assessed using Pearson’s correlation.

Result

Widespread reductions in cortical and subcortical synaptic density were observed in AD (vs. CN) participants using measures of DVR, SUVR30‐60min
, and SUVR60‐90min
. In the entire sample, stronger regional correlations between measures of DVR and SUVR60‐90min
(r=0.97, p<0.00001) were observed compared to DVR and SUVR30‐60min
(r=0.91, p<0.00001; Figure 1). The correlation between DVR and SUVR60‐90min
was also stronger for within‐group correlations (DVR vs. SUVR60‐90min
r
CN
=0.97, r
AD
=0.97; DVR vs. SUVR30‐60min
r
CN
=0.90, r
AD
=0.91). The within‐region correlation between measures of DVR and SUVR60‐90min
ranged from 0.77 to 0.97 (p<0.00001) in the entire sample. Effect sizes to determine group differences in SV2A binding across all regions were highly correlated between both DVR and SUVR60‐90min
(r=0.93, p<0.00001) and DVR and SUVR30‐60min
(r=0.93, p<0.00001; Figure 2).

Conclusion

A simplified method of quantifying synaptic density with SUVR using a shortened (60‐90 minute) scan window and cerebellum reference region is highly correlated with measures of DVR generated with SRTM2 kinetic modeling. This simplified tissue‐to‐reference ratio methodology may be of practical use for multicenter and longitudinal studies seeking to measure synaptic density in AD.
Predicting amyloid status using remote online self‐report and cognitive assessment: The Brain Health Registry
Authors: Ashford Miriam T. , Neuhaus John , Jin Chengshi , Camacho Monica R , Fockler Juliet , Truran‐Sacrey Diana , Mackin R. Scott , Rabinovici Gil D. , Weiner Michael W. , Nosheny Rachel L.
Published: December 2020

Background

The ability to identify older adults with elevated brain amyloid beta (Ab) load can facilitate Alzheimer’s disease (AD) prodromal and preclinical trial recruitment and has possible clinical benefits. Development and validation of non‐invasive, cost‐effective methods to accurately predict brain Ab status are crucially needed. The overall goal of this study was to assess the predictive value of online, remotely‐collected information in determining Ab‐PET status. We compared the predictive performance of online measures to the performance of similar in‐clinic measures.

Method

The Brain Health Registry (BHR) is an online registry for recruitment and longitudinal assessment in cognitive aging research. In BHR participants who had an available Ab status from in‐clinic PET scans, logistic regression was used to determine the optimal combination of online variables to predict Ab‐PET (Ab+ and Ab‐) status in all participants. BHR predictors included: demographics (age, gender, education), self‐reported health information (memory concern, family history of AD, Geriatric Depression Scale (GDS) score, Everyday Cognition Scale score), and a cognitive assessment (Cogstate Brief Battery (CBB)). Area under the receiver operator curve (AUC) evaluated discrimination accuracy. The model with the highest AUC was cross‐validated using 10‐fold cross‐validation.

Result

354 BHR participants had available Ab data and sufficient additional BHR data (see Table 1 for participant characteristics). 48.9% of the participants were Ab+. Model accuracy ranged from AUC 0.55‐0.65 (see Table 2). The most accurate predictive model (AUC=0.65) included demographics, self‐reported health information, and CBB. In this model, GDS score, memory concern, and gender were all significantly associated with Ab status. The cross‐validated estimated AUC was 0.58, which is noticeably lower than the uncorrected estimate. In a larger cohort (n=635) of participants who did not take Cogstate, other BHR variables predicted Ab+ (AUC=0.79). The discrimination ability of our online data was comparable to studies that used similar information collected in‐clinic, with in‐clinic AUCs ranging from 0.59‐0.76.

Conclusion

Our results suggest that a novel, online approach can aid in the prediction of Ab status. Since online variables are low‐cost and non‐invasive, there is an advantage to using this approach to facilitate AD trial screening than prediction models that use in‐clinic measures.
The role of co‐morbid hypertension and depression on cognitive and proteomic outcomes among Mexican Americans
Authors: Large Stephanie E. , Davila Marcela , Petersen Melissa , Hall James R. , O'Bryant Sid , Davis Sandra E. , Johnson Leigh Ann
Published: December 2020

Background

Medical comorbidities are commonly associated with poorer cognition. Hypertension and depression are common comorbidities linked to cognitive decline and Alzheimer’s disease (AD). Mexican Americans experience higher rates of these medical comorbidities and also present with cognitive decline at younger ages as compared to their non‐Hispanic White counterparts. Increased work has expanded to look at reasons for increased risk for neurodegenerative conditions such as AD specifically among this population. The purpose of this study was to examine the role of co‐morbid hypertension and depression on cognitive and proteomic outcomes.

Method

Data from 548 Mexican Americans (415 normal control, 133 MCI/AD) was collected from a community based epidemiological study of aging. The average age was 61 and the average education was 7.7 years. Participants were stratified into 4 groups: no hypertension or depression (N= 101), hypertension only (N= 218), depression only (N=59), and comorbid hypertension and depression (N=170). One‐way ANOVAs were utilized to examine group differences in cognitive performance and proteomics. Cognition was assessed via WMSIII Logical memory 1 & 2, Trails A/B, EXIT, and MMSE. Biomarkers of inflammation (serum TNFα, IL5, IL6, IL7, IL10 and CRP) and neurodegeneration (plasma Aß42/ Aß40, Tau, NFL) were analyzed. A logistic regression was calculated with normal control versus MCI/AD as the outcome variable and comorbid condition, education and age as predicting variables.

Result

In normal controls, comorbid hypertension and depression was significantly associated with poorer executive and global cognitive function; and this comorbidity increased risk of MCI/AD diagnosis (OR= 1.950; 95/5 CI= 1.23‐3.08). Among normal controls, the comorbid group was found to have significantly higher levels of NFL (p<0.032) and IL6 (p<0.018) than the depression only group. Among those with MCI/AD, the comorbid group had significantly higher NFL levels (p<0.002) than the neither condition group.

Conclusion

The results of the study demonstrated that comorbid hypertension and depression was related to poorer cognitive functioning and increased risk for cognitive impairment among Mexican Americans. Findings support that medical conditions likely influence biomarkers of inflammation and neurodegeneration, which lends support for a precision medicine approach to treating MCI and AD specifically among minority populations.
Pathogenesis of degenerative dementia: Emerging role for inflammation
Authors: Arshad Faheem , Alladi Suvarna , Varghese Feba Anna , Ramakrishnan Subasree , Nashi Saraswati , Mahadevan Anita
Published: December 2020

Background

Recent evidence proposes a role for immune‐mediated mechanisms in pathogenesis of neurodegenerative dementias. Contribution of inflammatory processes to the progression of neurodegeneration has also been hypothesized. While deposition of various proteins is recognised as the pathological hallmark for the neurodegenerative dementias, Alzheimer’s disease (AD) and Frontotemporal dementia (FTD), the role of inflammation secondary to immune dysregulation in neurodegeneration remains to be determined. In this study, we aimed to investigate the profile of autoantibodies in patients diagnosed to have neurodegenerative dementia and compare the association between the different subtypes.

Method

We performed immunological screening in a large cohort of neurodegenerative dementias. Diagnosis was based on standard criteria, on review of clinical, MR imaging and laboratory features. Dementia types comprised of Alzheimer’s disease (AD), Frontotemporal dementia (FTD), and Dementia with Lewy Bodies (DLB). The immunological screening consisted of antinuclear antibody (ANA) profile, paraneoplastic and autoimmune encephalitis profile.

Result

Of 274 consecutive patients with degenerative dementia evaluated in the Cognitive Disorders Clinic (AD = 62, FTD = 202, DLB = 10), autoantibody profile was done in 174(63.5%). ANA profile was positive in 18.3%, paraneoplastic panel in 8.3% and autoimmune panel in 2.1% of patients. We observed a significantly higher frequency of immunopositivity in patients with FTD (34.4%) compared to AD(10.4%) and DLBD(14.2%). The range of antibodies detected included antibodies against anti‐Ro 52(SS‐A), anti‐La(SS‐B), PM‐Scl, centromere protein B(CENP‐B), dsDNA, histones and ribosomal P‐proteins in the ANA profile; anti‐Hu, anti‐Ri, anti‐Yo, anti‐CV‐2, PNMA2 (Ma2/Ta), Anti‐amphiphysin, Anti‐ SOX1, anti‐glial nuclear antibody(AGNA), anti‐Tr, Anti‐GAD65, anti‐Zic4, anti‐titin and anti‐recoverin in paraneoplastic and in the autoimmune profile autoantibodies present were N‐methyl‐D‐asparate(NMDA), alpha‐amino‐3‐hydroxy‐5 methyl‐4‐isoxazoleproprionic acid (AMPA), Leucine rich glioma‐inactivated protein‐1(LGI1), Contactin‐associated protein‐2(CASPR2), and GABAB receptor antibody. There were no significant systemic complaints in majority of patients, and no difference was observed in the mean age, gender and duration of illness between immune‐positive and immune‐negative patients.

Conclusion

Our findings further substantiate the emerging role for neuroinflammation secondary to immune dysregulation, in patients with classical neurodegenerative dementias. Establishing the profile of specific autoantibodies that occur in association with dementia subtypes, especially FTD, may aid in understanding mechanisms that underlie role of autoimmunity in neurodegenerative dementias, with therapeutic implications.
Pleiotropy analyses using TADs identify genomic regions affecting risk of AD and stroke
Authors: Greenfest‐Allen Emily , Stoeckert Christian J. , Wang Li‐San , Schellenberg Gerard D. , Naj Adam C.
Published: December 2020

Background

Although stroke is an established risk factor for Alzheimer’s disease (AD), the role vascular factors play in driving AD remains uncertain. Here we leverage GWAS summary statistics to assess the genetic correlation (pleiotropy) between stroke and AD and introduce a novel fine‐mapping approach to pinpoint shared causal variants in the context of higher‐order genome organization.

Method

32 stroke‐risk associated variants identified by the MEGASTROKE consortium (Malik et al. Nat Genet 2018) were mapped to topologically associating domains (TADs) identified in H1‐hESCs (Dixon et al. Nature 2015). Coloc was used to compare GWAS summary statistics for stroke and AD (Kunkle et. al Nat Genet 2019) within the TADs containing each stroke variant. As genes located within the same TAD tend to be coregulated and contacts between enhancers and gene promoters are mainly restricted within TADs, predicted shared causal variants can be functionally linked to genes and their downstream interactants within the same domain. STRING pathway analysis was run on the resultant gene sets to tie putative target genes to processes affecting disease progression.

Result

The strongest evidence for shared genetic risk between AD and stroke is in the promoter region of CDK6 (posterior probability [PP] of common causal variants in the TAD>70%; Figure 1, Tables 1/2), which encodes a serine/threonine‐protein kinase involved in the negative regulation of cell cycle and the promotion of G1/S transition. Levels of CDK6 have been found to be higher in AD patients and affect pathways tied to neuronal cell death in stroke. Genetic correlations supporting pleiotropy due to distinct causal variants were found in TADs containing known interactants of CDK6, including FBXO31 (PPD = 19.1%) and CDKN2A/B (PPD = 66.6%; Table 2). CDKN2A/B is part of a known chromosome 9p21.3 susceptibility locus for both AD and vascular dementia.

Conclusion

We identified several candidate loci affecting AD/stroke pleiotropy, most of which contain no documented variants with genome‐wide significance for AD risk. Pathway analysis of genes contained within TADs reveals a link between the shared risk between AD and stroke and the disruption of neuronal cell cycle at the onset of the G1/S phase.