bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of a multi‐session cognitive training combined with brain stimulation on age‐associated cognitive decline
Authors: Thams Friederike , Antonenko Daria , Li Shu‐Chen , Flöel Agnes
Published: December 2020

Background

Research on non‐invasive methods of modulating age‐associated cognitive decline has yielded promising results. Current evidence shows that transcranial direct current stimulation (tDCS), if administered with concurrent cognitive training, may successfully modulate cognitive performance. In the TrainStim‐Cog trial, we investigated in healthy older adults if longer‐term training combined with tDCS, versus sham, would lead to higher increases in performance on the trained tasks, and to larger transfer to non‐trained domains. Moreover, we aimed to elucidate neural mechanisms underlying these effects.

Method

Fifty‐six participants (20 men; mean age / SD = 69.8 / 4.0 yrs) underwent nine sessions of cognitive training over a period of three weeks with concurrent administration of either tDCS stimulation over 20 min (1mA current) or sham stimulation. The cognitive training consisted of two tasks targeting executive functions: a letter‐updating task was used to train working memory updating and, reward‐based decision‐making was trained with a three‐stage Markov decision‐making task. Prior to the intervention and immediately after the intervention, performance on training and transfer tasks was assessed and neural correlates were recorded using structural, functional and diffusion tensor MRI.

Result

At the time of submitting this abstract, assessment of primary endpoint has just been completed; data base lock, and unblinding of intervention type will be conducted in February 2020. The trial has been registered at clinicaltrials.gov (ID NCT03838211), the study protocol of the trial has been published (Antonenko et al., 2019, Frontiers in Aging Neuroscience), and a statistical analysis plan has been uploaded at clinicaltrials.gov. Results of the analyses will be presented at the AAIC conference.

Conclusion

Our results will determine if a 3‐week combined cognitive training and tDCS approach may not only enhance trained functions, but also transfer to non‐trained tasks. Moreover, we will determine if effects are sustained over longer periods of time, and we will aim to identify predictors of response to the intervention on the individual level. Thus, our trial will hopefully contribute to the development of non‐medical interventions in the field of age‐associated cognitive decline.
Development and evaluation of 0.5 mm isotropic resolution T1‐weighted and DTI templates of the older adult brain
Authors: Niaz Mohammad Rakeen , Ridwan Abdur Raquib , Wu Yingjuan , Qi Xiaoxiao , Zhang Shengwei , Bennett David A , Arfanakis Konstantinos
Published: December 2020

Background

Human brain MRI templates with low spatial resolution lack important fine details due to partial volume effects. The purpose of this work was to introduce a novel approach for high‐resolution template construction based on principles of super‐resolution, and using this technique, to develop high‐resolution T1‐weighted and DTI templates of the older adult brain.

Method

T1‐weighted (222 images,1mm isotropic) and DTI (202 images,2mm isotropic) brain MRI data from non‐demented older adults (65‐95 age‐range, male:female=1:1) participating in the Memory and Aging Project were used in this work (Fig.1). The raw images were spatially normalized in a 0.5mm isotropic resolution space using conventional template building methods. The resulting non‐linear deformations were utilized to map the signals from raw space to exact physical locations in the 0.5mm template space, minimizing interpolations that occur in conventional template‐building method. The final signal in a 0.5mm isotropic voxel in template space was calculated as the weighted average of all signals included in that voxel using a Gaussian kernel. The new T1‐weighted template, MIITRA_0.5mm_T1, was compared to MCALT_0.5mm, ICBM2009b_0.5mm, Colin27_0.5mm, and MIITRA_1mm_T1 (Fig.2A). The new DTI template, MIITRA_0.5mm_DTI, was compared to ICBM81, NTU, IIT_v5.0, EVE, and IXI (Fig.4A). The templates were evaluated in terms of image quality and spatial normalization accuracy achieved when used as references for alignment of MRI data from a large number of older adults.

Result

Fine structures were resolved in MIITRA_0.5mm_T1 in contrast to MCALT_0.5mm and MIITRA_1mm_T1 (Fig.2B). Visual inspection revealed atypical brain features in the cortex of MCALT_0.5mm (red circles). MIITRA_0.5mm_T1 has higher image sharpness (Fig.3A) and allowed higher inter‐subject spatial normalization accuracy of older adult T1‐weighted data (Fig.3B,C,D) compared to other templates. Fine white matter structures such as the anterior commissure, posterior commissure, inter‐thalamic adhesion and optic chiasm were clearly resolved in MIITRA_0.5mm_DTI (Fig.4B), in contrast to other DTI templates. MIITRA_0.5mm_DTI exhibits higher image sharpness (Fig.5A) and allowed higher inter‐subject spatial normalization accuracy of older adult DTI data (Fig.5B,C,D,E,F) compared to other templates.

Conclusion

MIITRA_0.5mm_T1 and MIITRA_0.5mm_DTI are high‐quality, high‐resolution templates of the older adult brain and allow higher spatial normalization accuracy of older adult data compared to other available templates.
Atrial fibrillation and the interaction with stroke in relation to white matter lesion volumes: A population‐based study in 70‐year‐olds
Authors: Rydén Lina , Sacuiu Simona , Wetterberg Hanna , Najar Jenna , Zettergren Anna , Kern Silke , Pereira Joana B , Wahlund Lars‐Olof , Westman Eric , Skoog Ingmar
Published: December 2020

Background

Atrial fibrillation (Afib) increases the risk of stroke and dementia. However, the mechanisms underlying the association between Afib and dementia in the absence of manifest stroke are not that well understood. The aim of this study is to investigate the association between Afib and white matter lesion (WML) volumes in a population‐based sample of 70‐year‐olds.

Method

Data were obtained from the Gothenburg H70 birth cohort studies (H70). In 2014, 1203 participants were examined (response rate: 72%) and a subsample (n=791) underwent structural MRI using a fluid‐attenuated inversion recovery (FLAIR) sequence. WML volumes were measured on FLAIR images using the Lesion Segmentation Tool (LST) and subsequently log transformed for further statistical analyses. Afib was diagnosed through self‐report, ECG, and hospital register. Stroke was diagnosed through self‐report, proxy‐report, hospital register, and large infarctions (>15mm) on brain‐MRI. Linear regression was used to analyze the association between Afib and WML volumes, while adjusting for potential confounders.

Result

After excluding individuals with neurodegenerative diseases, valvular heart diseases, and incorrect WML segmentation, 779 individuals remained for statistical analyses. Of these, 65 individuals (8.3%) had Afib. Individuals with a history of Afib had larger WML volumes than individuals without Afib after adjusting for total intracranial volume and sex. However, after additional adjustments for cardiovascular and metabolic diseases, smoking, alcohol risk‐consumption, education and stroke, this association was no longer seen (β 0.1 (95% CI ‐0.2‐0.3); p=0.697). A significant interaction was found between Afib and stroke (p<0.001) regarding the association with WML volume. Therefore, we stratified the material by stroke and found that Afib was associated with increased WML volumes in individuals with stroke (β 1.1 (95% CI 0.0‐2.2); p=0.047) but not in those without.

Conclusion

This study suggests that Afib is associated with larger WML volumes in individuals with stroke but not in those without.
Integrative analysis identifies copy number variations and their controlled causal molecular networks in Alzheimer’s disease
Authors: Zhang Bin
Published: December 2020

Background

The pathogenic mechanism of late‐onset Alzheimer’s disease (LOAD) remains elusive despite intensive studies in the past few decades. Even though ‐27 AD risk loci have been identified through genome‐wide association studies, they explain only a small fraction of the heritability of LOAD. LOAD is such a complex disease that more types of genetic variations need to be studied. Copy number variation (CNV), as one primary type of genomic variation, has been found to play a significant role in many neurological diseases such as Parkinson’s disease, schizophrenia, mental retardation, and AD. A systematic functional study of CNVs through omics‐levels can provide valuable insights into the mechanism of LOAD.

Method

In this study, we employed four complementary CNV calling approaches including CNVnator, Pindel, MetaSV and Delly2 to comprehensively identify CNVs in the WGS data from 1,662 individuals (including 827 LOAD, 330 mild cognitive impairment, and 505 control subjects) across three LOAD cohorts including the Mount Sinai/JJ Peters VA Medical Center Brain Bank (MSBB) AD cohort, the ROSMAP cohort, and the Mayo Clinic cohort. Integrative analysis of the identified CNVs and the matched transcriptomic, proteomic, clinical and pathological data was then performed to determine the functional impacts of these CNVs.

Result

Genes associated with CNVs at the transcriptomic level in seven different brain regions were consistently enriched for glutathione metabolism and antigen processing and presentation pathways. The mRNA and protein expression levels of two genes (ACOT2, and GSTM1) in the frontal pole were significantly correlated with cis‐regulatory CNVs in AD cases. Rare LOAD specific CNVs were involved in axonogenesis and neurite morphogenesis. The LOAD cases had a higher disease‐specific CNV burden compared with the normal controls. Moreover, the causal networks based on the integration of CNV, transcriptomic, proteomic, and clinicopathological data demonstrated brain region‐specificity.

Conclusion

To our knowledge, this is the first genomic CNV study focused on LOAD by integrating genomic, transcriptomic, proteomic, and clinicopathologic data. The identified CNVs and their downstream molecular networks provide a blueprint for studying the pathogenic mechanisms of LOAD.
Extracellular complex of beta‐amyloid with glyceraldehyde‐3‐phosphate dehydrogenase contributes to neurodegeneration in Alzheimer’s disease
Authors: Kozin Sergey A. , Lazarev Vladimir , Tsolaki Magda , Mikhailova Elena , Benken Konstantin , Shevtsov Maxim , Nikotina Alina , Mitkevich Vladimir , Makarov Alexander , Margulis Boris , Guzhova Irina
Published: December 2020

Background

The discovery of migrating protein complexes armed with β‐amyloid (Aβ) and acting as the driving force of Alzheimer’s disease (AD) mechanism led us to suggest that besides the pathogenic peptide some other proteins may cooperate with the latter and enhance its cytotoxicity and intercellular propagation. One of such proteins was suggested to be glyceraldehyde‐3‐phosphatedehydrogenase (GAPDH), enzyme that in normal conditions maintains cellular glycolysis and under action of oxidative stress is converted to monomers and dimers and forms tight, insoluble complexes with aggregation‐prone polypeptides.

Method

CSF samples were collected from patients of both genders. The cohort comprised four patient groups: (1) mild cognitive impairment (MCI) n = 21; (2) mild AD‐type dementia (‘Mild’), n = 58; (3) moderate AD‐type dementia (‘Moderate’) n = 57; and (4) severe AD‐type dementia (‘Severe’), n = 56. The diagnosis was established according to the NINCDS‐ARDRA criteria for AD and the Petersen criteria for MCI. Patients were assigned to severity subgroups based on their scores on the Mini‐Mental State Examination (MMSE). Two animal models of AD were used in this study: (1) “chemical” model in rats and (2) transgenic 5XFAD mice.

Result

GAPDH is present in cerebrospinal fluid samples of AD patients as covalent complex with Aβ, and the heavier the stage of the disease, the higher is the level of such complexes. The increase of constitutional GAPDH level in AD animal models results in aggravation of cognitive and brain deficits linked to AD progression.

Conclusion

The findings imply a potential role of GAPDH as biomarker and prerequisite of massive neuronal death on the late stages of Alzheimer’s disease Supported by RSF grant #19‐74‐30007.
High‐resolution, genome‐wide, promoter‐focused Capture C in astrocytes implicates causal genes for Alzheimer’s disease
Authors: Burton Elizabeth , Argenziano Mariana , Lu Sumei , Su Chun , Leonard Michelle E. , Hodge Kenyaita M. , Manduchi Elisabetta , Schellenberg Gerard D. , Wang Li‐San , Johnson Matthew E. , Pippin James A. , Brown Christopher D. , Wells Andrew D. , Grant Struan F.A. , Chesi Alessandra
Published: December 2020

Background

Previous studies of Alzheimer’s Disease (AD) have primarily implicated neurons and microglia as disease‐conferring cell types due to obvious links with degeneration and inflammation, respectively. However, astrocytes may also play a role in AD pathogenesis, but have been less studied in this context. Indeed, genome‐wide association studies (GWAS) have identified multiple genomic variants that reside near genes with astrocyte‐related functions, such as lipid processing and synaptic function. However, GWAS only reports genomic variants associated with a given trait and not necessarily the precise localization of culprit genes. High resolution chromatin conformation capture‐based techniques detect 3D genomic interactions between GWAS‐implicated signals and their effector genes, and allow for the characterization of non‐coding variants in the context of their regulatory activity.

Method

To improve on the low resolution of available Hi‐C data, we employed a high resolution DpnII‐based Capture‐C method to simultaneously characterize the physical genome‐wide interactions of 36,691 baited regions covering human promoters genome‐wide (including non‐coding transcripts) ‐ which we applied to a human primary astrocyte line (NHA, Lonza). Following sequencing, we investigated significant interactions at two different resolutions (1‐fragment and 4‐fragment resolutions; median fragment size = 265bp and 1,441bp, respectively). In parallel, we generated ATAC‐seq open chromatin maps to filter for informative (r2>0.7) proxy single nucleotide polymorphisms (SNPs) for each of the 45 AD independent signals reported to date.

Result

ATAC‐seq fine‐mapping yielded 100 candidate SNPs in open chromatin for 30 of these loci. By further constraining on our promoter Capture C data in astrocytes, at both one and four DpnII fragment resolution (median distance between interacting regions 9kb and 71kb, respectively), we observed contacts to “open” promoters for 6 putative target genes, corresponding to 6 of the original GWAS loci. These included PICALM, FERMT2, CASS4, and CLU.

Conclusion

We observed informative contacts between proxy SNPs and putative effector genes in the human astrocyte context for ∼13% of AD GWAS loci. Further efforts in other relevant cell types, where many of the other loci may in fact be principally operating, should shed light on additional signals. Follow‐up functional studies are warranted to validate these findings.
Design, synthesis and neuroprotective potency of self‐assembling memantine‐docosahexaenoic acid conjugate nanomedicine for the effective treatment of Alzheimer’s disease
Authors: Krishna Kowthavarapu Venkata , Dubey Sunil Kumar , Saha Ranendra Narayan
Published: December 2020

Background

Alzheimer’s Disease (AD) is the most common type of dementia characterized with progressive neurodegeneration and seems to be irreversible, progressive and presently untreatable. Memantine (MEM), a N‐methyl‐D‐aspartate receptor antagonist has been approved by FDA for symptomatic relief in neurodegenerative disorders. Docosahexaenoic acid (DHA) is a brain essential omega‐3 fatty acid that has a vital role in functional development and growth of the brain in infants. It has been reported that the presence of DHA in the diet helps in cognitive enhancement. Hypothesizing the co‐delivery of MEM and DHA for the effective treatment of AD, herein our aim was to design and develop a novel self‐assembling MEM‐DHA conjugate nanomedicine and to investigate its neuroprotective potency on SH‐SY5Y cells. Furthermore, the efficacy of these nanoparticles was assessed in intracerebroventricular‐β‐amyloid1‐42 induced cognitive deficits rats. To the best of our knowledge, this is the first report on self‐assembling nanomedicine of MEM.

Method

MEM‐DHA was synthesized by amide coupling reaction and thoroughly characterized by 1H NMR, 13C NMR and HR‐MS. The synthesized conjugate was self‐assembled into nanoparticles by using nanoprecipitation method and morphological characterization was performed by using dynamic light scattering technique and by FE‐SEM analysis. The neuroprotective activity was performed on human neuroblastoma SH‐SY5Y cells against oxidative stress induced by H2O2. Animals were injected with β‐amyloid1‐42 through intracerebroventricular route and dosage administered for a period of 28 days in separate groups viz control, disease control, MEM, MEM‐DHA conjugate and MEM‐DHA nanoparticles. Learning, behavior, memory assessment and biochemical parameters were estimated.

Result

The formation of MEM‐DHA conjugate was confirmed by 1H NMR, 13C NMR and HR‐MS. MEM‐DHA conjugate has a property to self‐assemble into nanoparticles due to its amphiphilic nature. The average hydrodynamic size of the self‐assembled nanoparticles was found to be 144.30 ± 3.91 nm with a polydispersity index 0.181 ± 0.02 and zeta potential was ‐6.82 ± 0.51 (Fig.1.). Cell culture and animal studies revealed MEM‐DHA conjugate nanoparticles are having strong potential as a therapeutic delivery to restore memory impairment in AD.

Conclusion

The MEM‐DHA conjugate nanomedicine was successfully prepared, thoroughly characterized and has shown improved neuroprotective efficacy in cognitive induced rats.
Effect of L‐type calcium channel blocking drugs on microglia during inflammation and amyloid pathology
Authors: Hopp Sarah C. , Wickline Jessica , Smith Sabrina
Published: December 2020

Background

During Alzheimer’s Disease (AD), microglia accumulate near amyloid plaques where they acquire a non‐homeostatic phenotype, lose essential neuroprotective functions, and take on an “activated’ phenotype that can induce neurotoxicity. Microglia intracellular calcium orchestrates these functions including cytokine production and formation of neurotoxic reactive oxygen species. Notably, other groups have demonstrated that activated, non‐homeostatic microglia in mouse models of AD display dysregulated intracellular calcium that may mediate their dysfunction. Epidemiological evidence suggests that using calcium channel blocker (CCB) drugs is associated with a reduced incidence of neurodegenerative diseases such as AD. However, the mechanism by which CCBs reduce AD risk is currently unknown. We hypothesize that CCBs reduce AD risk via modulation of microglia, the immune cells of the brain.

Method

Using cultured microglia in vitro, we tested whether CCBs that target L‐type voltage‐dependent calcium channels (L‐VDCCs) could prevent microglia activation in response to lipopolysaccharide (LPS), as measured by cytokine production. We also use the calcium indicator Fluo‐8 to measure directly whether L‐VDCCs could prevent LPS‐induced calcium flux. We then tested whether one of the CCBs, isradipine, could prevent microglia response to LPS in vivo in wild‐type animals. Finally, we used the 5xFAD mouse model of AD to examine whether isradipine could alter microglia phenotype in the presence of amyloid pathology in vivo.

Result

We found that L‐VDCC antagonist CCBs significantly reduce gene expression of inducible nitric oxide synthetase, interleukin 1β (IL‐1β), and tumor necrosis factor α (TNFα) in response to LPS in vitro, regardless of the structural class of the CCB, suggesting these drugs do target microglia L‐VDCCs. We also found that during microglia activation, microglia upregulate gene expression of the L‐VDCC subunits Cav1.2. Similarly, isradipine was able to reduce microglia activation in vivo.

Conclusion

Overall these data suggest that the reduced incidence of AD in humans treated with L‐VDCC‐targeting CCBs may be via their modulation of microglia. However, further work is required to understand how these drugs may be utilized as an intervention for AD.
Combined treatment with the microdose lithium formulation NP03 and S‐adenosylmethionine reduces cognitive decline and Alzheimer’s‐like amyloid pathology in Mcgill‐R‐Thy1‐APP rats
Authors: Carmo Sonia Do , Emmerson Joshua T. , Foret Morgan K. , Welikovitch Lindsay A. , Cuello A. Claudio
Published: December 2020

Background

By engaging several targets simultaneously, combination therapeutics hold promise for the prevention and treatment of complex conditions such as Alzheimer’s disease. We have previously shown that monotherapy using either NP03, a microemulsion formulation of lithium, which can reach the CNS when applied on mucosae, or S‐adenosylmethionine (SAM), a global methyl donor, can blunt amyloid‐driven pathology and cognitive impairment. Here, we explored the potential therapeutic value of a combination of NP03 and SAM in pre‐plaque McGill‐R‐Thy1‐APP transgenic (Tg) rats.

Method

We administered NP03 (rectal administration; 40 ug Li/Kg; 5 days per week), SAM (orally; 20 mg/Kg; 3 days per week), a combination of NP03‐SAM, or vehicle to 3‐month‐old Tg and non‐Tg control rats for 12 weeks. Behavioral testing and tissue harvest were performed 3 weeks after ceasing treatment.

Results

Combined NP03‐SAM treatment had a greater impact in reversing cognitive impairments in the auditory fear‐conditioning task compared with either the NP03 or SAM treatment alone. Moreover, NP03‐SAM‐treated McGill‐APP rats exhibited lower abundance of amyloid‐β peptides. Beneficial effects of NP03‐SAM treatment also included a reduction in neuroinflammation, BACE 1 expression and activity, and global DNA demethylation. Furthermore, combined treatment amplified the rescue of neurogenesis already observed in NP03‐treated rats.

Conclusion

Our findings provide preclinical evidence suggesting that combined treatment with NP03 and SAM may be of therapeutic value in the early stages of Alzheimer’s disease.
Early dementia diagnosis from spoken language using a transformer approach
Authors: Wahlforss Alfred , Jonasson Alexander Aslaksen
Published: December 2020

Background

Diagnosing dementia early is a critical factor in order to apply ameliorating factors. Currently, it is both difficult and costly to make an accurate diagnosis of early dementia. We present an approach where an accurate diagnosis is achieved using a machine learning model that analyses the spoken language of patients describing the cookie‐theft picture.

Method

The dataset used is Dementia Bank, which is the largest public dataset of spoken word dementia diagnostics. The experiments were carried out on the cookie‐theft section of the DementiaBank Pitt Corpus, which is a dataset containing audio and transcripts of patient interviews in which the patients perform the cookie‐theft test, a commonly used tool for diagnostics. The dataset consists of 243 control samples and 309 samples from patients with dementia. Although the dataset includes transcripts along with parts‐of‐speech tags produced by linguists, the goal of this study was to automate the process of diagnosis. As such, automatic speech recognition (ASR) was used to generate text transcripts from the audio files. The generated transcripts were split into two sets; one training set consisting of 70% of the original transcripts, and a test set containing the remaining 30%. The training set transcripts were then used as input to various transformer models, including BERT and ROBERTA. These models were then trained on the training set to fine‐tune their parameters. During evaluation, the transcripts from the test set are fed into the transformer model, which then classify the transcript as either belonging to the control group or the dementia group. Accuracy is used as an evaluation metric.

Result

We achieve an accuracy of 90% on the Dementia Bank dataset using the transformer model BERT, which according to a review study by Lyu, Gang (2018) is state‐of‐the‐art when using the entire dataset.

Conclusion

These results give the possibility to introduce a cost‐effective screening method for signs of early dementia. These results give the possibility to introduce a cost‐effective screening method for signs of early dementia. Hopefully, our approach could put an end to the current subjective diagnostics which is expensive and has varied results.
Pre‐fall prognostics, prevention and management of frailty in geriatrics: A personalized intelligent system approach (ALL‐FrAAgile)
Authors: Marinescu Mihaela , Bartolome Inaki , Marzan Mircea , Mashayekhi Kaveh , Spiru Luiza
Published: December 2020

Context

Frailty is a clinical state in which there is an increase in an individual’s vulnerability for developing an increased dependency and/or mortality when exposed to a stressor”. Frailty can occur in 15% of adults aged 65 years and over as the result of a variety of medical and socio‐demographic conditions such as living alone, depression, polypharmacy, malnutrition or sedentary lifestyle, etc. Even small stressors may increase the risk of developing significant health complications such as falls, dependency and hospitalizations. Nevertheless this state can be reversed through personalized intervention. So screening, evaluation and management are highly important.

Objectives

Frailty detection and prevention.

Methods

The FrAAgile is an ICT based personalized Ambient Assisted Living (ALL) intelligent system aimed at pre‐fall prognostics, identification, prevention and management of physical and mental frailty and multimorbidity and transition to robust health status. A personalized intelligent role‐based service is offered to access and improve the physical and the mental state of the individual through physical and cognition‐enhancing games based exercises. Intelligent system applications accessing the individual’s behavior, cognition, mood, agility, onset/lack of outside activities, balance, gate etc. to define a personalized role for that particular person to improve his/her physical and mental condition avoiding fall incidents due to frailty. This approach can be implemented and offered as a service directly to an individual user or to his/her informal and formal caregivers.

Results

During the CO‐creation phase, more than ninety End‐Users in Cyprus, Spain, Switzerland and Romania sites are identified and started to be recruited since Jan 2020. The ICT architecture of the project has been defined, considering required hardware, web‐connection, cloud database, data collection modules, video, and game applications and libraries.

Conclusion

The mild cognitive impairment individuals (MCI) would be accompanied across three phases of pre‐trial pilot lab‐testing, adaptation, and optimization, which leads finally to field trails. The main focus of the role‐based intervention aims to prevent clinical frailty and falls incidence through augmenting physical and mental health condition considering a holistic personalized view of the individual lifestyle and condition (EU AAL‐frAAgiLe project, Active Assisted Living, Ageing Well in the Digital World, aal‐2018‐5‐152‐CP).
Quantification of tau phosphorylated at threonine 217 using a novel ultrasensitive immunoassay distinguishes Alzheimer’s disease from healthy controls
Authors: Kvartsberg Hlin , Hanes Jozef , Benedet Andréa Lessa , Ashton Nicholas J , Pascoal Tharick A. , Rosa‐Neto Pedro , Hansson Oskar , Zetterberg Henrik , Zilka Norbert , Blennow Kaj
Published: December 2020

Background

One of the major neuropathological hallmarks of a brain affected by Alzheimer’s disease (AD) is neurofibrillary tangles (NFTs), which are composed of aggregated, and sometimes truncated, hyperphosphorylated tau protein. Clinical diagnosis of AD is often aided by the use of biomarkers. One of the three core cerebrospinal fluid (CSF) biomarkers for AD, tau phosphorylated at amino acid 181 (p‐tauT181), shows quite a high sensitivity and specificity for AD but there is also a relatively large overlap between AD non‐demented subjects. Recently, tau species phosphorylated at amino acid 217 (p‐tauT217) quantified by mass spectrometry was shown to correlate with amyloid and tau lesions in the brain and clinical disease progression, and thus seem to be a new potential AD biomarker. Here, we present a novel immunoassay used to quantify p‐tauT217 in CSF and show that it outperforms the classical AD biomarkers.

Method

CSF samples from AD, healthy controls (Co) (cohort1 [Lund University] and cohort2 [TRIAD cohort, McGill University]), frontotemporal dementia (FTD) and mild cognitive impairment (MCI) (cohort2) were analysed by a novel ultrasensitive immunoassay on the Single molecule array (Simoa) platform. The Simoa assay was based on two in‐house generated monoclonal antibodies.

Result

CSF levels of p‐tauT217 were significantly increased in AD compared with Co in both cohort1 (p<0.0001, 4.3‐fold increase) and cohort2 (p=0.0003, 3.5‐fold increase). In cohort2, p‐tauT217 was also increased in AD compared with FTD (p=0.0059) and amyloid PET‐negative MCI (p=0.0203, 4.8‐fold increase), and in amyloid PET‐positive MCI compared with Co (p<0.0001, 3.9‐fold increase), amyloid PET‐negative MCI (p=0.0035, 5.2‐fold increase) and FTD (p=0.0011).

Conclusion

We present performance data on a novel ultrasensitive immunoassay capable of quantifying p‐tauT217 in CSF. There was much less overlap between AD patients and healthy controls, as well as between amyloid PET‐positive and ‐negative MCI when using p‐tauT217 compared with p‐tauT181 in both cohorts, thus indicating that p‐tauT217 reflects the presence of AD pathology better. In conclusion, p‐tauT217 is a very promising new biomarker for AD, which potentially could be used to aid clinical diagnosis, even at pre‐dementia stages of the disease.
Cerebrovascular amyloid angiopathy in bioengineered vessels is reduced by high‐density lipoprotein particles enriched in apolipoprotein E
Authors: Robert Jerome , Button Emily B. , Martin Emma , McAlary Luke , Gidden Zoe , Gilmore Megan , Boyce Guilaine K. , Caffrey Tara M. , Agbay Andrew , Clark Amanda , Silverman Judith M , Cashman Neil R. , Wellington Cheryl L.
Published: December 2020

Background

Several lines of evidence suggest that high‐density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta‐amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood.

Methods

Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding.

Results

We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)‐BI, in contrast to the SR‐BI‐dependent mechanism by which HDL prevents Aβ‐induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen‐I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen‐I protein levels produced by smooth‐muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE.

Conclusion

The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally‐acting apoE in AD.
Exploring the pathologic synergy between amyloid β and tau
Authors: Ibanez Kristen R. , Koller Emily J. , De La Cruz Elsa Gonzalez , Weinrich Mary J. , Ryu Daniel H. , Giasson Benoit I. , Borchelt David R. , Chakrabarty Paramita
Published: December 2020

Background

Alzheimer’s disease is mainly characterized by amyloid β (Aβ) plaques and tau neurofibrillary tangles (NFTs). The amyloid cascade hypothesis provides a hypothetical link between these two proteinopathies and posits that Aβ can trigger tauopathy.

Method

To understand the temporal relationship between Aβ and tau and also to probe whether specific forms of misfolded tau preferentially interact with Aβ to induce the neurodegenerative cascade, we used an adeno‐associated model (AAV) of tauopathy combined with the TgCRND8 mouse model of Aβ deposition. We used three different types of tau variants in TgCRND8 mice – wild type (WT) tau, FTD‐associated P301L mutant tau and Pick’s disease‐associated S320F mutant tau. In prior studies, we demonstrated that while both WT and P301L tau expression results in accumulation of soluble phosphorylated tau in nontransgenic mice, only the S320F mutant readily formed insoluble intracellular NFTs allowing us to test the relative vulnerability of the Aβ mouse model to different types of misfolded tau.

Result

In the first cohort, we injected the AAV‐tau constructs into the brains of neonatal TgCRND8 mice. At 3 months post‐injection, when Aβ deposits first begin to appear, we found ‐ that expression of S320F tau produced NFT and surprisingly also exacerbated Aβ deposition. Expression of WT or P301L tau had no effect. The intracellular tau pathology in all these mice resembled the patterns observed in nontransgenic CRND8 littermates, suggesting no obvious cooperativity between Aβ and tau. In the second cohort, we delivered these AAV‐tau in the hippocampus of adult TgCRND8 mice with pre‐existing Aβ pathology and analyzed after three months of AAV expression. Here, we observed that the presence of pre‐existing Aβ induced formation of NFT pathology in the P301L tau expressing mice but not in the WT tau expressing mice. The levels of tau pathology from expression of S320F tau induced NFTs were essentially similar to that found in the first cohort that was injected neonatally.

Conclusion

Taken together, our data demonstrate gradations in the ability of pre‐existing Aβ deposits to secondarily induce tau misfolding, with the P301L tau variant showing the greatest response.
Engaging the Down syndrome community: Overcoming barriers to clinical trial recruitment
Authors: Hendrix James A.
Published: December 2020

Background

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly with a life expectancy of >55 years of age compared to just 25 year of age in the 1980’s. It is estimated that there are 210 K people with DS in the USA and 40% are over the age of 30 years old.1 However, with longevity comes a very high risk of Alzheimer’s disease (AD). It is estimated that by age 55–60 years at least 70% will develop Alzheimer’s dementia.2, 3 Despite the Alzheimer’s crisis facing the DS population, very few people with DS have participated in clinical trials.

Method

This talk will explore common barriers and potential solutions to the recruitment of adults with DS. DS organizations, such as LuMind IDSC, continuously work to gain the trust of participants and their families in ethical research which is a key component for successful recruitment.

Result

The NIH, LuMind IDSC, and other DS advocacy organizations are developing tools to engage, support and educate adults with DS and their caregivers about the risk of AD to help solve the issue of DS recruitment into trials.

Conclusion

Unique recruitment strategies are needed for successful enrollment of adults with DS in AD trials. References: 1. de Graaf, G.; Buckley, F.; Skotko, B. January 28, 2019 | https://dsuri.net/us‐population‐factsheetLemere, al. Neurobiol Dis, 1996, 3(1):16‐32. 2. Hartley, al. Alzheimer’s Dementia, 2015, 11(6):700‐9.
Functional considerations in the conduct of clinical investigations in the adult Down syndrome population
Authors: Bell Joanne M.
Published: December 2020

Background

With a lifespan buildup of amyloid beta in individuals with Down Syndrome (DS), comes the opportunity to study Alzheimer’s disease (AD) related pathological processes in potentially smaller sample sizes and shorter duration trials.

Method

There are multiple differences between these groups that require attention in designing investigational trials in the DS population. Primary is that DS participants constitute a vulnerable population.

Result

There is a wide range of intellectual disability (ID), and not all participants will have similar understanding of the informed consent/ assent process. Respecting the individuals perspective will be necessary to ensure open communication and build trust. These differences in ID translate into cognitive capacity which reflects upon reaction time, verbal working memory and mental flexibility. The variation in ID applies to mental health concerns as anxiety over novel situations and depression over life/environmental changes are frequent and require accommodation by both the family and the trial site. While many physical problems associated with DS are corrected in childhood, more problems arise during succeeding decades: obstructive sleep apnea, epilepsy (bimodal occurrences), poor visual and/or auditory acuity, and heightened immune responses are some co‐morbidities which will need to be addressed.

Conclusion

More overwhelmingly is a need for the investigational site to build a strong, long‐term trusting relationship with DS individuals and their families or caregivers. Investigators will need to encourage DS parents or their study partners to take an active role in preparing and soothing the participants while allowing some degree of autonomy to boost confidence and increase tolerance to clinical assessments.
APOE genotype and multimorbidity in the FINGER multidomain lifestyle trial
Authors: Turunen Heidi , Marengoni Alessandra , Antikainen Riitta , Helisalmi Seppo , Laatikainen Tiina , Soininen Hilkka , Strandberg Timo , Kivipelto Miia , Solomon Alina , Ngandu Tiia
Published: December 2020

Background

A growing burden on healthcare systems is the increasing amount of chronic diseases in single person (multimorbidity), especially in the elderly population. Multimorbidity leads to many problems, such as higher use and cost of healthcare, polypharmacy and poorer quality of life. The present study reports exploratory analyses of APOE genotype and multimorbidity in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER, ClinicalTrials.gov NCT01041989).

Method

FINGER was a 2‐year randomized controlled trial with 1260 participants at risk for dementia from the general Finnish population, aged 60‐77 years. Beneficial effects of the multidomain intervention (diet, exercise, cognitive training and monitoring of vascular risk factors) versus control (regular health advice) have been previously reported on the primary cognitive outcome and several secondary outcomes. APOE and multimorbidity data at baseline and the 2‐year follow‐up were available for 532 participants in the intervention group and 527 in the control group. Multimorbidity was assessed through a standardized questionnaire, and an interview by the study physicians. The questionnaire entailed 17 diseases. Associations between APOE genotype (carrier vs non‐carrier of the ε4 allele) and multimorbidity after 2 years were assessed using logistic regression analyses, adjusted for randomization group, age, sex, education, smoking, alcohol consumption and baseline multimorbidity.

Result

At baseline APOE was not related to multimorbidity. However, in longitudinal analyses carriers of the APOE4 allele were more likely to develop 3 or more new chronic diseases during follow‐up, with OR (95%CI) 2.2 (1.04‐4.87), p=0.04. No significant associations were found between APOE and multimorbidity defined as one or more new chronic diseases (p=0.21) or 2 or more new chronic diseases (p=0.59).

Conclusion

Preliminary findings from the FINGER trial suggest that in this at‐risk general older population the APOE4 allele was related to multimorbidity defined as 3 or more new chronic diseases. To our knowledge this is the first study to link APOE to multimorbidity in the context of a lifestyle intervention to prevent cognitive decline. This is in line with previous findings linking APOE4 to cardiovascular and metabolic conditions.
In‐silico high throughput whole transcriptome screening implicates cardiovascular disease and the immune system in the mechanism of action underlying adverse effects of atypical antipsychotics
Authors: Creese Byron , Malekizadeh Yasaman , Williams Gareth , Whitfield David , Kelson Mark , Ballard Clive , Mill Jonathan , Jeffries Aaron
Published: December 2020

Background

Risks of stroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in people with dementia but specific mechanisms are unclear. In a novel application of a drug repurposing paradigm, we aimed to identify candidate underlying mechanisms in‐silico by leveraging publicly available transcriptomic data.

Methods

Whole transcriptome signatures were first generated for three antipsychotics (amisulpride, risperidone and volinanserin) using RNA‐sequencing in SHSY‐5Y cell lines. These compounds were chosen to represent a range of mechanisms of action relevant to clinically used compounds and novel compounds in development. An unbiased high throughput screen generated correlations between each compound and a public repository of over 100,000 human disease samples. From a long list of statistically significant hits, correlations between each antipsychotic and conditions/diseases related to known side effects of antipsychotic use in dementia were identified and gene set enrichment analysis performed.

Results

Statistically significant associations were found between antipsychotic transcriptional signatures and atherosclerosis (amisulpride p=0.002; risperidone p=6.98x10‐6; volinanserin p=5.5x10‐8), venous thromboembolism (risperidone p=8.13x10‐7; volinanserin p=0.002) and influenza (amisulpride p=0.002). Pathways enriched in antipsychotic signatures were linked to the cardiovascular system, the immune system and inflammation (including brain derived neurotrophic factor, platelet derived growth factor receptor beta, tumor necrosis factor alpha signalling).

Conclusion

Using a novel, high throughput approach, these findings implicate cardiovascular disease and the immune system in the mechanisms of action of atypical antipsychotics, providing a list of priority candidate mechanisms of harm relevant to dementia research. This approach could have implications for drug safety screening of psychotropic drugs in dementia.
Synaptoprotective effects of the novel TNF inhibitor XPRO1595 in 5xFAD mice: Interactions between Western diet and sex
Authors: Weiss Blaine E. , Gollihue Jenna L. , Farr N. Drew , Sompol Pradoldej , Artiushin Irina A. , Kraner Susan D. , Tansey Malu Gamez , Norris Christopher M.
Published: December 2020

Background

The western diet has been repeatedly shown to trigger inflammation and has been implicated as an environmental factor in cerebrovascular disease and Alzheimer’s disease (AD) pathology. Our previous work has shown that inhibition of neuroinflammation by the selective anti‐TNF biologic, XPro1595, ameliorates neurologic dysfunction in a mouse model of amyloid pathology. Unlike other TNF inhibitors, XPro1595 targets only the soluble form of TNF (sTNF), preserving the neuroprotective transmembrane TNF signaling pathways. Here, we investigate whether western diet‐induced chronic inflammation accelerates AD‐like pathology in a mouse with genetic predisposition for amyloid development and the extent to which this synergy is dependent on sTNF signaling.

Method

Three‐month‐old 5xFAD mice received Teklad high fat and high fructose (HFHF) diet (TD 150111) or a balanced control diet (TD 150112) over a two‐month period. At four‐months‐of‐age and halfway through dietary intervention, subcutaneous injections of XPro1595 (10mg/kg, 2x/week) or saline were started and continued for another 4 weeks along with the dietary regimen. At endpoint, brain slices were prepared for electrophysiologic analyses of basal synaptic function and long‐term potentiation (LTP) in hippocampal CA1. Synaptic parameters were compared across diet and drug treatment conditions (n= 9‐14 mice/condition) using ANOVA and, where appropriate, Tukey’s post hoc test.

Result

Slices from XPro1595‐treated mice exhibited an increase in both synaptic strength and LTP, regardless of diet. However, these effects also depended strongly on sex. LTP in males was similar across treatment groups (125‐130% of baseline), but females treated with HFHF showed nearly no LTP. LTP deficits in HFHF‐treated females were reversed by XPro1595 adminitration in vivo. In fact, HFHF females treated with XPro1595 showed the highest LTP levels (∼140% of baseline) of all groups investigated.

Conclusion

Aberration of sTNF pathways have a differential effect on synapse physiology depending on sex and diet. Protective effects of XPro1595 on synapes materialize predominantly in females under conditions of dietary stress, while males responded modestly to treatment regardless of diet conditions. Studies are underway to establish whether sex‐specific differences reflect differences in amyloid burden between the sexes known to occur in this model, or are related to other differences unrelated to amyloid burden.
Exercise intervention differentially induces the expression of cystathionine beta synthase (CBS) in African American with MCI: Implication for endogenous H2S generation and component of aging pathway
Authors: Bedada Fikru B. , Ntekim Oyonumo , Johnson Steven P. , Turner Jillian , Nadarajah Sheeba R. , Ngwa Julius S. , Bond Vernon , Kwagyan John , Obisesan Thomas O.
Published: December 2020

Background

Decline in metabolic fitness, accumulation of undesirable metabolic changes and cellular senescence are the hallmarks of aging [1,2]. The incorporation of lifespan‐extending platforms such as exercise can promote metabolic fitness and delay the process of aging [3]. However, the mechanisms involved are unclear. We hypothesized that exercise intervention can drive beneficial outcome by increasing expression of two enzymes; CBS and CTH involved in the production of H2S, glutathione and taurine as well as splice factors; SRSF2 and HNRNPD [4,5] in African American with MCI.

Method

We used TaqMan gene expression assay to investigate mechanistic link between exercise and components of aging pathway by evaluating CBS and CTH, enzymes metabolizing sulfur containing amino acid. We also evaluated if CBS and CTH expression correlate with SRSF2 and HNRNPD splice factors by virtue of endogenous H2S production.

Result

Comparison of CBS and CTH at baseline, 3‐ and 6‐month exercise time points revealed that 3‐month exercise intervention doubled the expression of CBS. However, CTH showed a decreasing trend, suggesting differential expression. Interestingly, expression of CBS correlated with SRSF2 splice factor whereas expression of CTH correlated with HNRNPD at all time points tested.

Conclusion

In this study, we provided mechanistic insight through which exercise drive beneficial outcome by investigating component of aging pathway at baseline and exercise intervention in African American with MCI. Our data suggest differential effect of exercise on the expression of CBS, CTH; and the splice factors linked to delay pace of cellular senescence and aging by way of H2S [4,5]. Thus, our study implicates exercise‐induced CBS expression and endogenous H2S as drivers of benefit of fitness adaptation on metabolic fitness and life span with potential for clinical translation.