bluuebunny/crossref_metadata_2025 huggingface dataset:
MRI visualization of activated monocytes accumulation in the CNS of P301S tau mice by targeted nanoparticle technology: An approach to MRI molecular imaging of neuroinflammation
Authors: Tanifum Eric , Chintakunta Praveen , Badachhape Andrew , Admane Prasad , Srivastava Mayank , Stupin Igor , Devkota Laxman , Annapragada Ananth
Published: December 2020

Background

Chronic neuroinflammation plays a critical role in the pathophysiology of Alzheimer’s disease (AD) and related dementias. The CNS is immune privileged with restricted peripheral leukocyte traffic under normal physiological conditions. Neuroinflammation in disease brains is often accompanied by BBB compromise and increase CNS infiltration by activated peripheral monocytes/macrophages. Part of the inflammatory response in these cells is upregulation of the integrin, very late antigen‐4 (VLA‐4) and present a valuable target for detection and treatment of neuroinflammation.

Method

In vivo MRI scans were performed on 9 to 12 months old P301S mice on a 1 Tesla small animal MR scanner using a 2D fast spin echo inversion recovery (FSE‐IR) scan protocol that approximates a fluid‐attenuated inversion recovery (FLAIR) sequence (scan parameters: TR = 6500 ms, TE = 80 ms, TI = 2000 ms, slice thickness = 2.4 mm, matrix = 192x192, FOV = 30 mm, slices = 6, NEX = 6). Mice were pre‐scanned to obtain a baseline image and then injected with Rhodamine‐labeled VLA‐4 targeted nanoparticles bearing a T1 MR relaxive payload. Four days post‐contrast injections, they were rescanned and then euthanized and brain tissue harvested for ex‐vivo immunohistochemical analysis by confocal microscopy. Test animals included transgenic mice injected with the targeted agent (n = 6). Controls included transgenic mice injected with a non‐targeted agent (n = 6) and wild‐type age‐matched litter mates injected with the targeted agent (n = 6).

Result

MR images 4 days post contrast administration showed on average, higher accumulation of the contrast agent in the brains of the test mice compared to moderate to low levels of accumulation in the control mice. The in vivo MR data is validated by ex‐vivo histology results which also showed higher Rhodamine signal intensity in brain disuse sections from the test mice compared to controls. The high accumulation in the test mice is attributed to both active and active particle uptake mechanisms while only passive mechanisms are possible in the controls.

Conclusion

VLA‐4 targeted MRI sensitive nanoparticles label activated monocytes/macrophages in P301S mice CNS, enabling noninvasive detection of neuroinflammatory activity and highlighting a potentially novel approach to imaging neuroinflammation in AD.
Pharmacological suppression of seizure‐like activity in the PS2APP model of amyloidosis
Authors: Weber Martin , Imperio Jose , Gandham Vineela , Meilandt William , Hanson Jesse E. , Easton Amy E. , Elstrott Justin
Published: December 2020

Background

Seizure activity is significantly increased in patients with Alzheimer Disease relative to healthy controls. Concurrently, the J20 mouse model of amyloidosis has increased seizure‐like activity, and compounds that lower this activity can lead to cognitive benefits in this model. Here we aim to extend these studies to the PS2APP mouse model of amyloidosis.

Method

Locomotor activity was measured for 60 min in C57BL/6J mice with a beam‐break based monitoring system (PAS Open Field, San Diego Instruments) using a between‐subjects design with 9‐10 mice/dose group. EEG/EMG headmounts were implanted into PS2APP mice with amyloid‐beta pathology. Data was recorded for 6h using a Pinnacle Technologies recording system and processed with MATLAB (Mathworks) routines. EEG spikes were detected using a thresholded line‐length algorithm.A within subject crossover‐design was used for vehicle vs. Levetiracetam treatment and data from 13 PS2APP mice was analyzed.

Result

Locomotor activity measures showed that an acute dose of 200 mg/kg of the anti‐seizure medication Levetiracetam did not affect activity levels. EEG recordings demonstrated that the frequency of seizure‐like spikes during sleep was increased from 38 spikes/h in 4 months old PS2APP mice to 75 spikes/h in 13 months old PS2APP mice. This measure was reduced by ∼60% in 13 months old PS2APP mice in response to acute treatment with 200 mg/kg of Levetiracetam.

Conclusion

Seizure‐like activity is increased in patients with Alzheimer’s disease and in mouse models of amyloidosis. Our Levetiracetam studies confirm that pharmacological intervention can normalize seizure‐like activity in PS2APP mice. Medications with different mechanism of action need to be tested for their ability to reduce spike activity and improve cognition in this animal model.Ultimately, it will be important to see if such pharmacological effects translate to humans and if reductions in seizure activity are linked to functional improvements.
Apa I, Taq I and Fok I VDR polymorphisms: Functional effect on mRNA levels of amyloid beta transporters LRP1 and P‐gp in lymphocytes of mild cognitive impairment patients
Authors: Arevalo Nohela , Castillo Daniela , Rogers Nicole , Delgado Carolina , Farías Gonzalo , Behrens María Isabel , SanMartín Carol D.
Published: December 2020

Background

LRP1 and P‐gp are the major efflux transporters of β‐amyloid peptide (Aβ) across the blood brain barrier and the expression of both transporters is mediated by the vitamin D receptor (VDR). Three single nucleotide VDR polymorphisms (SNPs) Taq I, Apa I and Fok I have been related to mild cognitive impairment (MCI); however, their functional effect on the expression of VDR and its target genes remains unclear.

Method

76 MCI patients and 133 elderly volunteers were cognitively screened with the Montreal Cognitive assessment (MoCA) and MoCA‐MIS after signing an informed consent approved by the Ethics Committee of Hospital Clínico Unversidad de Chile. The VDR SNPs Apa (rs7975232), Taq (rs731236) and Fok I (rs2228570) were determined by TaqMan SNP genotyping assay. mRNA levels of VDR, LRP1 and P‐gp were evaluated by qPCR.

Result

The C and T alleles of Apa I and Taq I respectively were more frequent in the MCI (p < 0.05); additionally the odds ratio analysis (OR) was significant for both alleles (C allele OR: 1.5 p = 0.049; T allele OR: 1.89, p = 0.0044). There were no significant differences for Fok I polymorphism between the groups. Furthermore, the homozygous CC of Apa I had significantly lower mRNA levels of P‐gp and VDR than the homozygous AA and heterozygous AC (p < 0.05). The carriers of one copy of the C allele (TC) of Fok I had lower mRNA levels of VDR and of both transporters than the homozygous TT (p < 0.005).

Conclusion

The C and T alleles of Apa I and Taq I respectively might be risk alleles for MCI, as reported in other populations. In addition, we found that SNPs of the VDR gene are related to the decrease of the mRNA levels of the Aβ transporter P‐gp and the transcription factor VDR.
Amyloid propagation in a sporadic model of Alzheimer's disease
Authors: Huynh Kelly Do , Nguyen Marie Minh Thu , Cheung Alwin , Tran Janine Pham , Nuñez‐Diaz Cristina , Forner Stefania , Martini Alessandra Cadete , Trujillo‐Estrada Laura , Da Cunha Celia , Shahnawaz Mohammad , Soto Claudio , Moreno‐Gonzalez Ines , Gutierrez Antonia , LaFerla Frank , Baglietto‐Vargas David
Published: December 2020

Background

Most age‐associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion‐like process of template protein corruption or seeding. In fact, studies in FAD‐based animal models show that Aβ deposition and cerebral amyloid angiopathy may be induced by intracerebral infusion of brain extracts from AD patients or from aged APP‐transgenic mice. These studies have shown that the characteristic of both the seeding agent and the host influence the pathologic signature of the Aβ seeds. In this regard, the majority of the Aβ‐seeding studies have been done in APP‐transgenic animal models that overproduce APP and/or Aβ. However, it remains to be elucidated whether Aβ deposition can be induced by Aβ seeds in an animal model that does not overexpress APP and produces wild type human Aβ and if these aggregates are similar to the human condition.

Method

Here, we used an innovative animal model to better understand the amyloidogenic events that occur in the sporadic form of the disease. Our model, termed hAβ‐KI, expresses wild‐type human Aβ under the control of the endogenous mouse APP gene. Thus, amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer’s Disease Research Center (ADRC) at UCI were administered into 7‐8‐month‐old hAβ‐KI and as positive controls 3xTg‐AD mice were employed.

Result

Our findings demonstrated that amyloid seeds can stimulate Aβ aggregations in both models (the 3xTg‐AD and the hAb‐KI). Moreover, we found that Aβ aggregates occur earlier in the 3xTg‐AD vs hAb‐KI and that a longer term of treatment is necessary to accelerate diffusible Aβ pathology in the hAb‐KI mice.

Conclusion

This knockin model represents an important first step towards the development of next‐generation animal models that hopefully will provide better predictive outcomes for human patients, which can turn into safe and effective clinical applications.
Effects of 12‐week combined cognitive training and physical activity intervention on cognitive and psychosocial outcomes of Brazilian older adults
Authors: Almeida Mariana Luciano , Glymour M Maria , da Silva Rodrigues Guilherme , Sobrinho Andressa Crystine da Silva , Júnior Carlos Roberto Bueno
Published: December 2020

Background

Cognitive training and physical activity provide mental, social and physical stimulation that may reduce dementia risk. However, there is limited evidence on the benefits of interventions to increase cognitive engagement among healthy elderly. The present study aimed to evaluate the effect of combined cognitive training and physical activity on cognitive function and psychosocial well‐being among healthy middle‐aged and older adults.

Method

114 adults with age between 50 to 80 years, recruited by advertisements in the local media, were randomized into four intervention arms: 1) cognitive training + physical activity, 2) cognitive training only, 3) physical activity only, or 4) no‐intervention control group. The interventions had 12 weeks of duration with 90 minutes of cognitive training (groups 1 and 2), and 180 minutes of physical activity (groups 1 and 3) per week. Participants were assessed for cognitive performance (MoCA), social support, depressive and anxiety symptoms, at baseline and follow‐up. Data were analyzed through Generalized Additive Models for Location, Scale, and Shape ‐ GAMLSS, controlling for age, sex and years of schooling.

Result

Most of the subjects were female, mean age of 64.5 years (SD=7.0), and average schooling of 12.1 years (SD=3.7). After 12 weeks we conclude the follow‐up with 88 participants. Following the intervention, MoCA increased in all groups (Coef=.98, 95%CI=.00;1.95, p<.01). There was no evidence of differences between the intervention groups for MoCA (1x2 p=.99, 1x3 p=.94, 1x4 p=.92, 2x3 p=.97, 2x4 p=.95, 3x4 p=.99). Subjects from group 1 and 2 increased the number of people to provide social support comparing to the control group (Coef=.27, 95%CI=.00;.54, p=.04/ Coef=.27, 95%CI=.00;.55, p=.03). There was no evidence of differences between the intervention groups for social support (1x2 p=.99, 1x3 p=.53, 1x4 p=.20, 2x3 p=.50, 2x4 p=.18, 3x4 p=.88). Depression and anxiety symptoms did not show effects or interactions (p=.73/ p=.68). There was no evidence of differences between the intervention groups for depression and anxiety (1x2 p=.99, 1x3 p=.94, 1x4 p=.92, 2x3 p=.97, 2x4 p=.95, 3x4 p=.99/ 1x2 p=.99, 1x3 p=.76, 1x4 p=.74, 2x3 p=.78, 2x4 p=.76, 3x4 p=.99).

Conclusion

Social support showed positive results for combined interventions and cognitive training.
Towards a better understanding of human brain ageing: An RNA sequencing study of neuroinflammatory, neurotransmission‐related and synaptic genes in two key brain regions over the lifespan
Authors: Mohan Adith , Thalamuthu Anbupalam , Mather Karen A. , Sachdev Perminder S.
Published: December 2020

Background

Neuroinflammation, synaptic function, and neurotransmission are implicated in gene expression studies of human brain aging. We examined 869 genes specific to these 3 pathways using RNA sequencing in 2 age‐critical brain regions of the human brain, the dorsolateral prefrontal cortex (DLPFC) and posterior cingulate cortex (PCC) in a post‐mortem cohort of 67 non‐diseased control individuals aged 36‐103 years.

Methods

Post mortem brain tissue was obtained from the Human Brain Collection Core (HBCC), , NIMH (n = 41, mean age 56y, 25 male) and the Sydney Brain Bank (n = 26, mean age 91y, 12 male) with 2 samples (1 each from the DLPFC and the PCC) per control participant. Controls were free of neurological disease at the time of death. Additionally, tissue samples did not meet pathological criteria for neurological or neurodegenerative disease and were stroke free in the regions of interest. RNA extraction and library preparation used standard protocols with rRNA depletion (TruSeq Stranded Ribozero prep). 100 base pair paired end reads were obtained on a NovaSeq S4 (Illumina) with a minimum of 50 million paired reads per sample. Standard bioinformatics pipeline was used to process raw read data into normalised gene expression values. We examined relationship of age with gene expression adjusted for gender, post‐mortem interval and library size using regression analyses corrected for multiple testing. Candidate gene lists were derived from public gene‐ontology databases namely KEGG and PANTHER as well as a previously published set of microglia‐derived genes (Butovsky, et al., 2014).

Results

320 and 204 genes from our candidate pathways showed significant differential expression with age in the DLPFC and PCC respectively. The majority of these were upregulated with age in both cortical regions. More than 80% of upregulated genes across both regions were neuroinflammation related, and most upregulated neurotransmission genes encoded elements of the glutamatergic transmission. Genes related to synaptic elements were almost exclusively downregulated with age. 151 genes were significant in both regions and followed the same age‐related pattern as above.

Conclusions

Our findings support the prominence of neuroinflammation and excitotoxicity as prominent drivers of molecular brain aging. Further network analyses are planned including eQTL analyses.
Novel metrics of semantic fluency as preclinical markers of cognitive impairment
Authors: Vonk Jet M.J. , Geerlings Mirjam I. , Qian Carolyn L. , Schupf Nicole , Mayeux Richard , Brickman Adam M. , Manly Jennifer J.
Published: December 2020

Background

Accurate identification of the preclinical phase of Alzheimer’s disease (AD) is important for intervention and timely diagnosis. Some researchers suggest that this phase is only detectable using biomarkers, but these are expensive and/or invasive. Because not all biomarker‐positive individuals develop AD‐dementia and cognitive impairment is at the core of this diagnosis, there is a critical need for sensitive, low‐cost, and high‐access cognitive markers. This study investigated how novel item‐level metrics of semantic fluency—naming as many animals in one minute—uniquely relate to 1) memory decline and 2) mild cognitive impairment (MCI).

Method

To investigate the effect of traditional and novel metrics of semantic fluency on both outcomes in a diverse community‐based cohort followed up to 24 years (mean age=75), we used 1) growth curve models of memory decline (n=534, modeled up to 4 visits), and 2) Cox regression models of time to incident MCI (n=349, free of MCI at baseline and >1 visit). Each word’s lexical frequency value—how often a word occurs in daily language—was derived from SUBTLEXus. Models with total number score were compared to two novel metrics: ratio of mean frequency:number and mean frequency of the lowest 10 frequency words. Covariates included age, sex/gender, education, race/ethnicity, recruitment wave, and all other neuropsychological scores.

Results

Both novel metrics of ratio (standardized B=‐.049, p=.003) and lowest 10 (B=‐.024, p=.003) predicted rate of memory decline over and above other neuropsychological tasks, while total number did not (B=.015, p=.055). The novel metrics were also predictive of time to incident MCI over and above other neuropsychological tasks (HR ratio =1.43, HR lowest 10=1.54, both p<.05), while total number was not (HR=.74, p=.141).

Conclusion

Novel item‐level metrics of semantic fluency predicted rate of memory decline and incident MCI over and above other neuropsychological tasks, while the traditional fluency score did not. Item‐level data hold a wealth of information that could detect cognitive symptoms in the preclinical phase of dementia beyond our current neuropsychological measures. Future research should investigate more item‐level data to identify optimal metrics that can be used as clinical tools and aid selection of high‐risk individuals for intervention.
Norvaline regulates glucose metabolism and insulin pathway in the brains of Alzheimer’s disease mice
Authors: Polis Baruh , Gurevich Vyacheslav , Samson Abraham O.
Published: December 2020

Background

Alzheimer’s disease (AD) is an insidious, progressive, neurodegenerative disorder and the leading cause of dementia. The disease development is followed by the gradual deposition of amyloid plaques and neurofibrillary tangles in the brain; however, converging evidence points to severe metabolic dysfunction as a cause and a key hallmark of AD. Late‐onset form AD, in particular, is characterized by a clear metabolic signature and caused by numerous etiological factors. Severe brain insulin signaling impairment and a decline in glucose metabolism are important metabolic characteristics of AD. Subsequently, positron emission tomography (PET) with radioactive glucose tracers is a well‐established non‐invasive method for early detection of AD symptoms and a treatment efficacy monitoring tool. Additionally, recent data indicate a critical role of the brain insulin resistance in AD pathogenesis. Accordingly, targeting insulin signaling attracted much attention in the context of AD drug development.

Method

Converging evidence points to arginase inhibition with norvaline as a promising approach to treat various metabolic disorders, including AD. Here, we use 3×Tg‐AD mice, which show age‐dependent brain insulin signaling abnormalities and reduction in brain insulin receptor levels followed by severe brain energy metabolism alterations, to evaluate the effects of norvaline on glucose metabolism in vivo.

Result

We utilize 18F fluorodeoxyglucose whole‐body PET and demonstrate a significant treatment‐associated increase in glucose uptake by various organs, including the brain. Additionally, we apply an advanced proteomics assay to explore the molecular mechanisms underlying the effects of norvaline on glucose brain uptake.

Conclusion

Our findings suggest that norvaline interferes with AD pathogenesis and presents a promising agent for clinical evaluation.
Progression modelling of cognitive decline and associated FDG‐PET imaging features in Alzheimer’s disease
Authors: Prosser Angus , Evenden Dave , Holmes Robin , Kipps Christopher
Published: December 2020

Background

Prognosis for Alzheimer’s disease is difficult, with rates of disease progression varying widely. Despite the extensive use of clinical dementia severity assessment scales to determine dementia diagnosis and to monitor progression, there is no consensus on which imaging factors may accurately predict future decline trajectories on these measures. Determination of baseline imaging patterns that are related to slower, or faster, decline rates could be used to identify those at highest risk of worse outcomes and inform care planning.

Method

Decline trajectories were estimated from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset which contains clinical, imaging, and biological assessment records for 1,736 patients followed‐up over 8 years at 3, 6, or 12 month intervals. Clusters of similar decline trajectories were identified for patients with relevant baseline fluorodeoxyglucose positron emission tomography (FDG‐PET) imaging data (N=530) using mini‐mental state examination (MMSE), clinical dementia rating sum of boxes (CDR‐SB), Alzheimer’s disease assessment scale (ADAS‐13), and functional activities questionnaire (FAQ) assessment scores. Decline trajectories allocated to slow, intermediate, and fast clusters were further analysed to find significant associations with PET imaging features using statistical parametric mapping (SPM12).

Result

When compared to cognitively normal non‐decliners, slow, intermediate and fast cluster groups showed similar topographic patterns of hypometabolism on FDG‐PET for all four clinical assessments (p<0.05 family‐wise error corrected). Slow progressors showed focal hippocampal hypometabolism, which extended into parietotemporal, inferior parietal and precuneal regions for intermediate progressors. Fast progressors showed more extensive hypometabolism in similar regions with additional superior frontal hypometabolism. Although locational deficits were similar on cognitive measures for decline groups, CDR‐SB showed the greatest hypometabolism extent for slow progressors, followed by FAQ, then ADAS‐13, with MMSE showing the least.

Conclusion

Our results suggest a single pattern of pathological progression of functional degeneration in Alzheimer’s disease, with slow, intermediate and fast progressors at different time points on the same decline trajectory. This progression begins with focal medial temporal regional abnormalities, extending to parietotemporal, inferior parietal and precuneus regions, before finally involving the superior frontal lobe. CDR‐SB was the most sensitive in detecting slow progressor abnormality, with MMSE being the least sensitive.
Telomere length, brain tau deposition and cognitive decline: Two‐year follow‐up study
Authors: Byun Min Soo , Yi Dahyun , Lee Jun Ho , Lee Jang‐Seok , Lee Hyun‐Seob , Kim Yu Kyeong , Lee Yun‐Sang , Lee Dong Young
Published: December 2020

Background

Telomere length (TL) is known to be associated with aging and various age‐related diseases. However, previous studies on the relationship between the TL and Alzheimer’s disease (AD) yielded inconsistent results, and the association between TL and in vivo AD pathologies such as cerebral beta‐amyloid (Aβ) and tau deposition remains unclear. We investigated whether TL is related to in vivo AD pathologies and predicts future cognitive decline.

Method

Total 132 older adults recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease were included for analysis. For all participants, absolute TL values (aTL) were measured by a quantitative PCR method using DNA extracted from whole blood at baseline, as aTL can provide more direct comparison between experiments and laboratories compared to traditional TL assays. Global PiB retention measured 11C‐PiB‐PET and global tau deposition in the regions corresponding to Braak stages measured by 18F‐AV‐1451 PET were used in this study. For clinical outcome, conversion of clinical diagnosis and change of MMSE score assessed at baseline and 2‐year follow‐up was used.

Result

Among 132 older adults, 71 of them were cognitively normal and 51 of them were cognitively impaired (39 MCI and 22 AD dementia) at baseline and total 20 individuals converted to MCI or AD dementia during 2 year follow‐up period. No significant group difference in aTL was observed between diagnostic groups at baseline. However, aTL at baseline was significantly longer in converters (N=20) compared to non‐converters (N=112) even after adjusting age, sex, APOE4 positivity and baseline diagnosis. In addition, the difference of MMSE score between baseline and 2‐year follow‐up showed positive association with baseline aTL after adjusting age, sex, education, APOE4 and baseline diagnosis. With regard to in vivo AD pathologies, baseline aTL had a significant positive association with global tau deposition, but not with global Aβ deposition.

Conclusion

Our finding suggests that longer TL relates to greater tau deposition in brain and more rapid cognitive decline in older adults. Further studies to elucidate mechanism underlying the association of TL with tau deposition and cognitive decline will be necessary.
The DEMON Network: The first UK network for deep dementia phenotyping
Authors: Ranson Janice M , James Charlotte , Routledge Carol , Everson Richard , Bauermeister Sarah D , Llewellyn David J
Published: December 2020

Background

Collaborative interdisciplinary research will be key to advances in dementia prevention, identification and treatment. We established the DEMON Network to revolutionise dementia research by bringing innovators together to harness the power of data science and artificial intelligence with funding from Alzheimer’s Research UK and the Alan Turing Institute. Membership is free, and open to data scientists, dementia researchers, clinicians and industry partners. Benefits include a framework for national collaboration, research initiatives and networking events.

Method

The DEMON Network Steering Committee includes Profs David Llewellyn and Richard Everson (both University of Exeter and Alan Turing Institute), Dr Carol Routledge (Alzheimer’s Research UK) and Dr Sarah Bauermeister (University of Oxford). Membership is coordinated using an online marketing platform. Recruitment is ongoing and has included a press release, a National Institute of Health Research Dementia Researcher podcast, Twitter (@DEMONNetworkUK) and partner organisations such as Dementias Platform UK. A website was developed to feature Network opportunities and member profiles (www.demondementia.com). A Clinical Advisory Panel was established to provide clinical support, and recruitment to a Public and Patient Involvement (PPI) Group is underway.

Result

Membership on 20th January 2020 comprised 180 individuals including 19 Clinical Advisory Panellists. 87 members (48%) have expertise in data science, 120 (67%) in dementia research, 48 (27%) clinical, and 16 (9%) in industry. 141 members (78%) are interested in networking events, 136 (76%) in seminars and workshops, 117 (65%) in skills exchange, and 101 (56%) in training and career development opportunities. 17 Regional Leads were recruited through Alzheimer’s Research UK Network Centres to support regional activities, and 4 National Theme Leads (Data Science, Clinical and Early Career Development) were recruited to facilitate strategy development in priority areas. Initial activity includes three datathons run in collaboration with Medical Research Council Dementias Platform UK (MRC DPUK).

Conclusion

The DEMON Network has successfully launched and activities are underway reflecting member preferences. A National Strategy Workshop will be convened in 2020. Those interested can join the Network via the website.
Physical activity reduces amyloid‐induced neurodegeneration in non‐demented older adults
Authors: Sohn Bo Kyung , Yi Dahyun , Byun Min Soo , Jeon So Yeon , Lee Jun Ho , Lee Dong Woo , Lee Jun‐Young , Kim Yu Kyeong , Sohn Chul‐Ho , Lee Dong Young
Published: December 2020

Background

Both physical activity (PA) and cognitive activity (CA) are known to reduce the risk of Alzheimer`s disease (AD) and related cognitive decline. However, pathophysiological mechanism underlying their protective effects for AD is still poorly understood. We aimed to investigate the moderation effects of current PA and CA on the relationship between amyloid‐beta (Aβ) and AD‐signature neurodegeneration in non‐demented older adults. Both physical activity (PA) and cognitive activity (CA) are known to reduce the risk of Alzheimer`s disease (AD) and related cognitive decline. However, pathophysiological mechanism underlying their protective effects for AD is still poorly understood. We aimed to investigate the moderation effects of current PA and CA on the relationship between amyloid‐beta (Aβ) and AD‐signature neurodegeneration in non‐demented older adults.

Method

Two‐hundred sixty non‐demented (195 cognitively normal and 65 mild cognitive impairment) participants from the Korean Brain Aging Study for Early diagnosis and prediction of Alzheimer’s disease (KBASE) were included in this analysis. All participants underwent comprehensive clinical and neuropsychological assessment, [11C]Pittsburgh Compound B (PiB) positron emission tomography (PET), [18F]fluorodeoxyglucose (FDG) PET, and magnetic resonance imaging. Using the multi‐modal brain imaging data, in vivo AD pathologies including Aβ deposition, AD‐signature region cerebral glucose metabolism (AD‐CM), and AD‐signature region cortical thickness (AD‐CT) were quantified. Current PA and CA were assessed using well‐validated questionnaires. General linear model analysis was conducted including AD‐CM (or AD‐CT) as a dependent variable and Aβ deposition, PA, CA, Aβ x PA interaction term, and Aβ x CA interaction term as independent variables.

Result

We found significant Aβ x PA interaction effect on both AD‐CM and AD‐CT. Subgroup analyses showed that the inverse association between Aβ and AD‐CM (or AD‐CT) was weaker (i.e., smaller effect size) in higher PA group compared to that in lower PA group. In contrast, Aβ x CA interaction effect was not observed on neither AD‐CM nor AD‐CT.

Conclusion

The findings suggest that current PA reduce AD‐type regional neurodegeneration induced by Aβ deposition, regardless of CA, in non‐demented older adults. When considered with PA, however, current CA appear not have any moderation effect on the relationship of Aβ deposition with the neurodegenerative change.
Decreased plasma clusterin is associated with increased cardiorespiratory fitness as a response to aerobic exercise in older adults with Alzheimer's disease in the FIT‐AD Trial
Authors: Li Danni , Yu Fang , Seidl Claudia
Published: December 2020

Background

A recent study suggests that plasma clusterin increases with exercise and enhances neurogenesis and reduces neuroinflammation in sedentary mice. The same study also reports a positive association between changes in plasma clusterin and walking distance as response to exercise in older adults with amnestic mild cognitive impairment. The objective of this study is to examine whether aerobic exercise increases plasma clusterin and the correlations between changes in plasma clusterin and cardiorespiratory fitness as response to aerobic exercise in older adults with Alzheimer's disease (AD) in the FIT‐AD trial.

Methods

The FIT‐AD Trial is a Phase II randomized controlled trial to investigate the effects of a 6‐month, individualized, moderate‐intensity cycling intervention on cognition in community‐dwelling older adults with mild‐to‐moderate AD. The FIT‐AD subjects were randomly assigned on a 2:1 ratio to cycling and stretching (control) for six months. Fasting blood plasma samples were collected at baseline (n=26), 3 and 6 months. Plasma clusterin concentration was measured by an ELISA kit (R&D Systems, Minneapolis, MN). Symptom‐limited peak cycle‐ergometer test was used to assess VO2peak, a gold‐standard measure of cardiorespiratory fitness. Student t's test was used to examine changes in plasma clusterin concentrations between cycling and stretching groups. Linear regression was used to correlate changes in plasma clusterin concentration with changes in VO2peak.

Results

3‐ or 6‐ month changes in plasma clusterin concentrations did not significantly differ between groups However, correlations between 3‐month changes in plasma clusterin (µg/mL) and 3‐ or 6‐month changes in VO2peak (L/min) were significant regardless group assignment (beta‐coefficients [standard error (SE)]: ‐ 4.2×10‐2 [1.8×10‐2] L/min change in VO2peak per µg/mL change in plasma clusterin and ‐ 4.0×10‐2 [1.4×10‐2], respectively), and in cycling group only (‐ 4.8×10‐2 [1.6×10‐2] and ‐ 3.9×10‐2 [0.9×10‐2], respectively), but not in the stretching (control) group.

Conclusion

This preliminary study does not support the previous findings. Instead, it reports a significant negative correlation between 3‐month change in plasma clusterin concentration and 3‐ or 6‐ months change in VO2peak as response to aerobic exercise with in older adults with AD. Future studies are needed to validate the study findings.
APOE‐stratified, genome‐wide, gene‐based analysis of episodic memory trajectories in a multi‐ethnic sample of 24,769 elderly
Authors: Gao Yizhe , Vardarajan Badri N. , Reyes‐Dumeyer Dolly , Sariya Sanjeev , Mayeux Richard , Tosto Giuseppe , Barral Sandra
Published: December 2020

Background

Understanding genetic modulation of episodic memory will yield insight into the biological mechanisms underlying normal cognitive aging and dementia. Genetic studies based on longitudinal measures of episodic memory are scarce, predominantly focused on candidate genes, and have interrogated common genetic variation. We aimed to identify common and rare genetic variation that may be responsible for uncharacterized genetic risk underlying individual differences in longitudinal performance on memory.

Method

A sample of 24,769 elderly individuals was ascertained from eight independent cohorts (ADGC_NACC, NIA‐LOAD, ROSMAP, WHICAP, LLFS, CHAP, ADNI and UK Biobank). Data on study participants included socio‐demographic variables, longitudinal scores on episodic memory (2 to 15 follow‐up visits), clinical diagnosis of cognitive impairment and genome‐wide imputed genotyped data using the haplotype reference consortium for accurate imputation of low‐frequency genetic variants. The Latent Class Mixed Model was used to derive episodic memory trajectories within each of the study cohorts. The slope of residualized episodic memory scores was used as outcome in an APOE stratified (non‐APOE stratified, APOE_ε4 and APOE_nonε4 sub‐samples) genome‐wide gene‐based analyses. Common (minimum allele frequency, MAF, between 5%‐10%), rare (1% < MAF ≤ 5%) and ultra‐rare variants (≤1% MAF) were analyzed. Association results from each study cohort within each sub‐sample were meta‐analyzed.

Result

Consistent with previous studies, the majority of the study participants maintain their memory performance over time (ranging from 51% to 98%). The strongest association signal for the episodic memory trajectories (p = 4.8 × 10−8) was achieved at chromosomal region 6p22 among in the APOE_nonε4 sub‐sample. Meta‐analysis results in the non‐APOE stratified and APOE_ε4 sub‐samples also yielded several chromosomal regions associated with memory performance over time, although significance level was diminished (p∼ 10−6).

Conclusion

To our knowledge, this is the largest gene‐based GWAS meta‐analysis of high quality imputed common, rare and ultra‐rare variants influence on episodic memory performance over time. Identifying genes associated with progression of episodic memory performance over time in older adulthood provides the possibility of identifying at‐risk population subgroups that can benefit from possible interventions to enhance cognitive function.
Financial awareness is associated with metamemory in cognitively healthy adults
Authors: Sunderaraman Preeti , Chapman Silvia , Barker Megan S , Cosentino Stephanie
Published: December 2020

Background

Metamemory (i.e., awareness of one’s memory abilities) degrades in individuals with dementia and has been found to be associated with poorer everyday outcomes and decision making. Decades of research have established how to measure and detect metamemory changes that may accompany aging or neurologic disease. In contrast, relatively little is known about how to assess the integrity of financial awareness (i.e., awareness of one’s financial abilities), an important construct with tremendous practical implications for avoiding financial loss in vulnerable older adults. The goal of the current study was to apply established metacognitive frameworks in order to examine financial awareness.

Method

Data was collected prospectively using a comprehensive battery of tests examining financial and cognitive abilities. Community dwelling individuals (n=93) with mean age=59 years (SD=15.12); mean education=15.70 (SD=2.39); 60% female were recruited. Financial Decision Making was measured using the Financial Competence Assessment Inventory (FCAI). Confidence ratings were integrated into the FCAI in order to derive a metric of financial awareness. Participants rated their confidence on a 3‐point scale following each item. Memory‐awareness was evaluated using an established 20‐item metamemory task. Awareness on each measure was calculated using a calibration score, wherein average performance across the whole test was subtracted from average confidence, to determine the extent to which individuals were over‐ or under‐confident.

Result

Financial awareness was not associated with age, education or gender. Financial awareness was inversely associated with financial decision making (r = ‐0.38, p < .001), and positively correlated with metamemory (r = 0.36, p < .001).

Conclusion

Mirroring findings from metamemory studies, overconfidence in financial decision making was associated with lower accuracy on this task in healthy adults. Moreover, financial awareness and metamemory were related, suggesting that this construct taps into metacognitive abilities more broadly. Our findings provide preliminary evidence for how to measure financial awareness in both clinical and research contexts.
Phenotype differences between corticobasal syndrome and progressive supranuclear palsy with and without Alzheimer’s disease biomarkers
Authors: Vasilevskaya Anna , Taghdiri Foad , Multani Namita , Anor Cassandra Jessica , Misquitta Karen , Houle Sylvain , Burke Charles , Lang Anthony , Fox Susan , Slow Elizabeth , Rusjan Pablo , Tartaglia Carmela
Published: December 2020

Background

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are usually caused by a tauopathy. Comorbid Alzheimer’s disease (AD) pathology can be seen in PSP and is causative in a number of CBS cases. The contribution of different pathologies to the phenotypes is poorly characterized. Our aim was to compare PSP/CBS without AD biomarker (CBS/PSP‐non‐AD) to CBS/PSP with AD biomarkers (CBS/PSP‐AD).

Method

Twenty‐four patients [11 males, 13 females; age (68.46±7.23)] with a diagnosis of PSP or CBS underwent MRI and PET imaging with tau specific [18F]‐AV1451 tracer as well as cerebrospinal fluid (CSF) analysis. PSP rating scale (PSPRS) and unified Parkinson’s disease rating scale (UPDRS) motor exam were used to assess for motor disturbances. Cognitive testing was completed. Patients were divided into AD and non‐AD based on CSF or PET Tau imaging. Seventeen patients were negative for AD biomarkers (6 CBS, 11 PSP)] while7 tested positive [diagnoses (6 CBS‐AD, 1 PSP‐AD)].

Result

The CBS/PSP‐non‐AD group [age (70.18±6.65)] was significantly older (p=0.028) than the CBS/PSP‐AD group [age (64.29±7.32)]. There were no differences between the groups in terms of gender, education, or disease duration. The CBS/PSP‐non‐AD group compared to the CBS/PSP‐AD group had significantly lower PET [18F]‐AV1451 SUVR values in AD‐specific brain regions of hippocampus [1.20±0.28 vs. 1.80±0.39; p=0.002] and inferior parietal area [1.49±0.56 vs. 3.26±1.53; p=0.001]. The CBS/PSP‐non‐AD group compared to the CBS/PSP‐AD group scored significantly higher on PSPRS [40.76±18.61 vs. 18.29±6.65; respectively, p=0.004] and UPDRS motor exam [36.06±21.49 vs. 15.71±8.34; respectively, p=0.045]. Finally, CBS/PSP‐non‐AD group compared to the CBS/PSP‐AD group scored significantly higher scores on digit span forward [5.76±1.52 vs. 3.86±1.77; p=0.025]. Two participants refused to complete the sentence repetition task but CBS/PSP‐non‐AD group (N=15) scored significantly higher on sentence repetition compared to the CBS/PSP‐AD group (N=7) [4.13±1.46 vs. 2.43±1.90; p=0.031].

Conclusion

The CBS/PSP‐non‐AD group had higher motor signs but had better working memory and sentence repetition than the CBS/PSP‐AD group despite being older. These results show that the presence of AD biomarkers has an effect on CBS and PSP phenotypes. This has implications for monitoring progression and response to treatment.
Alcohol use patterns and cognitive impairment: A cross‐country comparison
Authors: Funk‐White Makaya , Moore Alison A. , McEvoy Linda K. , Bondi Mark W. , Bergstrom Jaclyn , Chen Yen‐Ching , Chen Jen‐Hau , Kaufmann Christopher N.
Published: December 2020

Background

Alcohol use is shown to be a risk and protective factor for cognitive impairment. Alcohol use patterns differ across cultures; it is possible inconsistent findings may be partially explained by different drinking patterns across countries. We analyzed datasets from international studies housed in the Global Alzheimer’s Association Interactive Network to examine the association between alcohol use and cognitive performance.

Method

We used baseline data from two countries: a) the United States (National Alzheimer’s Coordinating Center Uniform Dataset; NACC), and b) Taiwan (Taiwan Initiative for Geriatric Epidemiological Research; TIGER), focusing on participants age 65+ years, not currently taking Alzheimer’s disease medications, and who had complete data for cognitive performance (NACC: N=4,443; TIGER: N=605). In both studies, participants self‐reported alcohol use and completed a cognitive battery. We characterized alcohol use patterns by recent use (yes vs. no), and frequency (never, <once a week, 1‐4 times/week, daily/almost daily), and focused on Trail Making A and B and Verbal Fluency tests. Mixed effects models assessed the relationship between alcohol use and cognitive performance including the study (NACC vs. TIGER) as a random effect, and controlling for participant age, sex, and education in main effects. We also tested interactions for associations between studies.

Result

Two‐thirds of the combined sample reported alcohol use (18% <once a week, 25% 1‐4 times/week, and 19% daily/almost daily). In mixed effects models, those reporting recent alcohol use showed better cognitive performance than those reporting no use (Trail Making A: 46.4 [SD=10.1] vs. 51.7 [SD=10.1]; Trail Making B: 122.1 [SD=18.0] vs. 144.6 [SD=18.0]; Verbal Fluency: 29.7 [SD=3.4] vs. 27.3 [SD=3.4]; all p’s<0.001), and greater frequency was associated with better cognitive performance (all p’s<0.001). There were differences across studies in the association between alcohol use and Trail Making B (interaction p=0.003) and Verbal Fluency (interaction p=0.007); driven by positive associations observed within the NACC dataset. No interactions by study were observed for drinking frequency with cognition.

Conclusion

Both recent and more frequent alcohol use were associated with better cognitive performance; although this association appeared more prominently in the US vs. Taiwan. Identification of specific cultural factors driving associations observed will be explored.
NeMO analytics‐AD: The neuroscience multi‐omic visualization and analysis platform, now extended to support Alzheimer’s disease
Authors: Chrysostomou Elena , Prater Katherine E. , Song Yang , Orvis Joshua , Kancherla Jayaram , Herb Brian , Ament Seth , Bravo Hector C. , Mahurkar Anup A. , White Owen , Garden Gwenn A. , Hertzano Ronna
Published: December 2020

Background

Recent years have resulted in tremendous progress in understanding Alzheimer’s disease via the generation and analysis of multi‐omic data. In addition, the BRAIN initiative has been mapping gene expression in the normal brain, which is important in understanding disease. However, a barrier for the broad usage of these data has been limited access and the requirement for informatics support to allow biologists not trained in programming to meaningfully access this wealth of information.

Method

To address this challenge, we reveal, for the first time, an expansion of the Neuroscience Multi‐Omic (NeMO) Analysis and Visualization platform (NeMO Analytics, nemoanalytics.org) to include a focus on Alzheimer’s Disease. NeMO Analytics gene expression tools are powered by gEAR (umgear.org) and consists of six components: (i) An expression browser, which allows the visualization of gene expression across datasets; (ii) A comparator tool for basic comparison of all of the genes in two groups; (iii) An elaborate single cell workbench; (iv) A dataset uploader, which allows seamless integration with the NeMO Archive data portal for data import, as well as import of user‐supplied datasets in a market exchange format (MEX); (v) A dataset curator that allows the user to define visualization preferences (e.g., data presentation as bar, line, x‐y scatter, violin plot, tSNE, or SVG); and (vi) A dataset manager, which allows the selection of groups of datasets to visualize side‐by‐side and manage dataset sharing. NeMO Analytics also allows the visualization of epigenetic data via integration of the Epiviz tool (https://epiviz.github.io/).

Results

NeMO ‐AD provide biologists with meaningful access to a variety of datasets relevant to Alzheimer’s research with data from different species, including human at different stages of the disease. Users can also create profiles (collections of datasets for visualization side‐by‐side) from additional data originating from the BRAIN initiative and deposited in the NeMO Archive or NeMO Analytics.

Conclusion

The NeMO‐AD offers biologist unprecedented meaningful access to multi‐omic data relevant to Alzheimer’s disease. We propose that broad usage of this platform to share and disseminate data will result in a unique and meaningful repository for biologists studying Alzheimer’s disease.
People with dementia experiencing presence in mixed reality technologies
Authors: Astell Arlene J , Fels Deborah , Desai Shital
Published: December 2020

Background

Mixed Reality Technologies (MRTs) spanning the physical‐virtual continuum offer possibilities for machine‐based prompting to support people with dementia. The effectiveness of MRTs requires users to experience ‘presence’ – the feeling of being there and the illusion of non‐ mediation by the technology ‐ which has not been explored in dementia.

Method

Participants with mild to moderate dementia aged between 63‐90 years of age played games on two MRTs: Tangram on Osmo (Augmented Virtuality) and Young Conker on Hololens (Augmented Reality) in separate sessions to explore their experience of presence and look at their responses to prompts in the games. The sessions were video‐recorded for analysis with Noldus Observer XT 14.1 to identify themes relating to presence and responses to prompts.

Result

Three themes relating to the experience of presence were identified: 1. Affordances and perceptual elements, 2. Degree of realism and 3. Social element. Participants responded differently to visual and verbal prompts in the games.

Conclusion

People with dementia experience presence in MRTs that is mediated by the clues in the visual auditory and material properties of the physical and virtual elements of the games. These findings have design implications for future development of MRTs to support people with dementia.