bluuebunny/crossref_metadata_2025 huggingface dataset:
Incorporation of plasma biomarkers for screening and diagnosis in primary care
Authors: Galasko Douglas R. , Chhatwal Jasmeer P. , Wijsman Ellen M , Rumbaugh Malia C. , Mozersky Jessica , Blacker Deborah ,   Shiley‐Marcos Alzheimer’s Disease Research Center
Published: December 2022

Background

Plasma biomarkers that reflect Alzheimer’s neuropathological changes are under FDA consideration for approval as diagnostic tests. Their use in primary care will become feasible, and it will be difficult to limit biomarker screening to symptomatic or high risk individuals, especially as symptoms of cognitive decline are often nonspecific.

Methods

As members of the NIA Advisory Group on Risk Evidence Education for Dementia (AGREED), we have examined analytics of AD biomarkers in asymptomatic and symptomatic contexts, as well as language used in disclosure of biomarker results in research studies. We review recent data and describe key issues in plasma screening for Alzheimer’s Disease in primary care and propose directions for future research.

Results

Critical issues include: 1. Assessing accuracy of biomarker(s) measurement, and sensitivity and specificity of cutoffs to determine presence or absence of amyloid or other AD pathology. 2. Recognizing the critical need to study biomarkers in population‐based settings and among under‐represented individuals to understand factors that may modify cutoffs and normative data, e.g., age, sex, ethnicity, renal and hepatic function. 3. Data and models regarding the value of amyloid positivity to predict the development of Mild Cognitive Impairment (MCI) or dementia in asymptomatic individuals, and for progression of MCI to dementia. 4. Disclosure of APOE genotype if it is part of a biomarker risk algorithm. 5. Selecting nuanced language for describing positive, negative or indeterminate biomarker results, with clear explanations of what the tests measure, and risks associated with positive or negative results. 6. Current plasma biomarkers do not measure other pathologies and cognitions that may contribute to MCI and dementia, e.g., a‐synuclein, TDP43 or vascular pathology; depression, medical comorbidities, sleep disorders or medications that may adversely impact cognition. Together with biomarker results, the impact of these factors on cognition should be considered and discussed. 7. Screening for cognition is underdeveloped, limited by the types of tests currently used for screening and the time typically available to assess patients in primary care.

Conclusions

Further research on these topics and support and education of primary care providers is essential for the deployment of blood‐based biomarkers in primary care.
ILiAD trial of levetiracetam
Authors: Sen Arjune , Mary Akinola , Tai Xin You , Mura Sergio , Galloway Joanne , Hallam Angela , Frangou Eleni , Love Sharon , Chan Jane , Koychev Ivan G , Geddes John , Manohar Sanjay , Symmonds Mkael , VanDerPutt Rohan , Thompson Sian , McShane Rupert , Husain Masud ,   https://www.ndcn.ox.ac.uk/research/oxford‐epilepsy‐research‐group
Published: December 2022

Background

The increasingly appreciated intersection between epilepsy and Alzheimer’s disease offers potential therapeutic opportunity. We therefore initiated a pragmatic pilot study to explore whether the anti‐seizure medication levetiracetam might offer benefit to people with Alzheimer’s disease.

Methods

The Investigation of Levetiracetam in Alzheimer’s Disease (ILiAD) trial is a randomised, double‐blind, placebo‐controlled trial. ILiAD recruits people with mild to moderate Alzheimer’s disease who have not previously had a seizure and in whom a routine electroencephalogram is normal. The primary outcome is change in a touchscreen memory task. Secondary outcomes include effect on mood, alterations in quality of life and carer‐reported outcomes.

Results

ILiAD plans to recruit 30 participants. To date, eight people have completed both arms of the study with no withdrawals from those enrolled. The COVID‐19 pandemic has had multiple severe impacts on both study recruitment and assessments. The primary outcome measure, in particular, has proved difficult to evaluate during the pandemic owing to many assessments being done remotely.

Conclusion

ILiAD is a pilot study that is part of the vanguard of trials exploring the potential role of anti‐seizure medications, particularly levetiracetam, in people with Alzheimer’s disease. Further work seems important to better understand whether drugs specifically designed to modulate cortical excitability may offer improvement in cognition for those with neurodegenerative disorders.
Mediterranean diet and structural neuroimaging biomarkers of Alzheimer’s and cerebrovascular disease: a systematic review
Authors: Gregory Sarah , Ritchie Craig W. , Pullen Hannah , Shannon Oliver , Stevenson Emma , Muniz‐Terrera Graciela
Published: December 2022

Background

Adherence to the Mediterranean diet (MedDiet) has been associated with better cognitive performance, lower incidence of dementia, stroke and lower Alzheimer’s disease (AD) biomarker burden (Scarmeas et al, 2018). Improving dietary patterns in at‐risk populations may improve brain health, reducing incidence of dementia and stroke (Lewis et al, 2014; Feigin et al, 2019). The aim of this systematic review was to evaluate the evidence base for the MedDiet in relation to hippocampal volume and white matter hyperintensity volume (WMHV) (PROSPERO Registration: CRD42021269620).

Method

We systematically searched for studies on MedDiet and hippocampal volume or WMHV in MedLine, EMBASE, CINAHL and PsycInfo. The review was carried out in line with PRISMA methodology. We included studies with adult participants in any setting, time or language. Searches were initially carried out between 21st July 2021 and 19th August 2021. Papers were screened independently by two authors against eligibility criteria. Data on participant demographics, MedDiet calculation and adherence, hippocampal volume and/or WMHV was extracted and narratively synthesised.

Result

Of an initial 112 papers identified, six papers, enrolling 21,750 participants, were eligible for inclusion in the review. The mean age of participants in studies ranged from 53.8 years to 80.3 years and participants were healthy volunteers, had subjective cognitive decline, or dementia. All studies included in the review were cross‐sectional or cohort studies. Four studies reported on hippocampal volume, with inconclusive or no associations seen with MedDiet adherence. One study found a significant association between higher MedDiet adherence and lower WMHV, while two other studies found no significant associations.

Conclusion

Overall, these results highlight a gap in our knowledge about the associations between MedDiet and AD and cerebrovascular related structural neuroimaging findings. Future research is needed including increased frequency of dietary assessments, more sensitive and specific imaging outcomes and the inclusion of data from low‐ and middle‐income countries.
The EuroLaD‐EEG consortium: towards a global EEG platform for dementia, for seeking to reduce the regional impact of dementia
Authors: Parra‐Rodriguez Mario A , Prado Pavel , Moguilner Sebastian , Herzog Ruben A , Birba Agustina , Santamaría‐García Hernando A , Tagliazucchi Enzo , Reyes Pablo A , Cruzat Josefina A , García Adolfo M. , Whelan Robert , Lopera Francisco , Ochoa John F , Anghinah Renato , Ibáñez Agustin
Published: December 2022

Background

The value of Electroencephalography (EEG) to unveil pathophysiological signatures in neurodegenerative diseases that cause dementia has been recently highlighted. To grant EEG tools the necessary validity, reliability, and scalability to support the diagnosis of dementia globally, efforts will need to integrate knowledge developed by EEG labs across diverse countries and develop protocols that can be swiftly implemented by such labs to harmonize research and clinical practices. These are the aims of EuroLaD‐EEG, a consortium that brings together five Latin American (LAC) and five European countries to develop a harmonised EEG database (Aim 1) that can help improve dementia phenotyping and diagnosis (Aim 2).

Methods

EuroLaD‐EEG has developed a global EEG database that comprises 1234 EEG recordings from groups of healthy adults (n=1223), patients with mild cognitive impairment (n=199), and with familial and sporadic variants of neurodegenerative diseases (e.g., AD and FTD) (n=501). We have recently published the harmonization pipeline that will allow EuroLaD‐EEG meet its Aim 1 (Prado et al., 2022, Int J Psychophysiol, 172, 24–38). We have now developed a multi‐feature multimodal approach that combines demographic, neuropsychological, fMRI and EEG data as inputs for a gradient boosting machine‐learning classifier. Multicentric data including those from underrepresented samples will enter such a classification algorithm towards our Aim 2.

Results

Preliminary results with a subsample from LAC (n=282) revealed high classification (AUC > 0.90 for all the classes) and robustness towards heterogeneity, sociodemographic variability, and missing data. We are now planning to combine data from European and LAC to explore sources of phenotypic variability linked to socio‐demographic and cultural factors.

Conclusion

By broadening our understanding of dementia phenotypes, risk factors, and affordable diagnostic approaches, and adding new evidence on variability across developed and developing countries, the EEG will contribute unique evidence that will help enhance both dementia phenotyping and diagnostic strategies.
EEG in the Global Brain Consortium, aiming to strengthen linkages between neuroscientists across borders and disciplines to advance equitable solutions to priority health challenges worldwide
Authors: Valdes‐Sosa Pedro Antonio , Leon Maria Antonieta Bobes , Lopera Francisco , Li Min , Bosch‐Bayard Jorge , Bringas Maria Louisa , Valdes Mitchell
Published: December 2022

Background

The Global Brain Consortium https://globalbrainconsortium.org/ promotes the goals of open science and serves as a clearinghouse to interface synergistically with other initiatives.

Method

Two interacting projects are of interest here: 1) The Harmonized Multinational quantitative EEG norms (HarMNqEEG) project provides open data and software (www.biorxiv.org/content/10.1101/2022.01.12.476128v1) for the first batch‐free Developmental Equations obtained from 1564 EEG cross‐spectral from 9 countries, 12 devices, 14 studies. 2) The Biomarkers of Dementia for Global Health supports Electrophysiology PIA efforts.

Result

As a result of the two projects, we evaluated qEEG discrimination on samples from the Medellin Study. The groups to be distinguished were those without the Preseninin‐1 mutation sample, asymptomatic carriers, and symptomatic carriers. We show that Hermitian Riemannian qEEG descriptive parameters and the HarMNqEEG norms allow the elastic‐net robust classifier to accurate classification (Figure 1) with total AUC in the range of .91‐,93, and acceptable accuracies between groups (Figure 2).

Conclusion

To our knowledge, this is the first report on the use of harmonized Riemannaian norms in the age‐adjusted classification of EEGs from this condition.
Lipidomic analysis of isogenic ApoE‐variant iPSC‐derived glia uncovers coupling between inflammatory signaling and lipid metabolism.
Authors: van der Kant Rik
Published: December 2022

Background

ApoE is the major genetic risk factor for Alzheimer’s disease and the major regulator of brain lipid metabolism. In the brain ApoE is primarily expressed in glia. How different damaging or protective ApoE variants exactly affects glial lipid metabolism, and/or how this correlates with inflammatory signaling is not known.

Method

We generated iPSC‐derived astrocytes and microglia from isogenic induced pluripotent stem cells (iPSC) with ApoE3/3 (reference), ApoE4/4 (increased risk), ApoE2/2 (decreased risk) and ApoEnull/null (control) genotypes. On these cells we performed unbiased lipidomics and transcriptional profiling to measure inflammatory pathways.

Result

We observed strong accumulation of stored lipids in human ApoE4/4, E2/2 and ApoEnull/null glia compared to ApoE3/3 glia. The composition of the exact species of accumulating lipids differed between ApoE4/4, E2/2 and Enull/null glia, and between astrocytes and microglia. At the transcriptional level, lipid accumulation in some genotypes was associated with increased proinflammatory signaling in astrocytes and microglia.

Conclusions

ApoE genotypes has a major effect on glial lipid metabolism and specific changes in lipid metabolism associate with inflammatory signaling pathways. Using lipid‐targeting interventions we are currently probing a causal relationship between altered lipid metabolism and downstream increases inflammatory signaling
Suppression of epileptiform activity by treatment with antiepileptic drugs or by genetic ablation of tau in aged human amyloid precursor protein transgenic mice
Authors: Das Melanie ,   Gladstone Institute of Neurological Disease
Published: December 2022

Background

Neural network dysfunction, including subclinical epileptiform activity, occurs in a substantial proportion of Alzheimer’s disease (AD) patients and related mouse models. Treatment with the anti‐epileptic drug levetiracetam (LEV) or genetically ablating the protein tau effectively reduces epileptiform activity and behavioral abnormalities in human amyloid precursor protein (hAPP) transgenic mice. These findings support the hypothesis that network dysfunction may promote cognitive deficits in AD. While LEV treatment and tau reduction have beneficial effects in young adult hAPP mice, it is not known whether there are similarly beneficial effects in aged mice, whose pathological condition may be more similar to that of AD. To address this gap, we tested the efficacy of LEV treatment and tau reduction in preventing or reversing network, immune and cognitive dysfunctions in aged hAPP mice.

Method

We treated 22–26‐month‐old, male hAPP mice and age‐ and sex‐matched wildtype (WT) controls with placebo or LEV for four months using chow formulations. To genetically ablate tau, we generated a cohort of male and female Mapt
+/+ and Mapt
–/– mice that did or did not express hAPP. Mice were assessed by electroencephalography (EEG) and behavior. Brain tissues were subjected to transcriptome analysis and immunohistochemistry.

Results

Intracranial EEG recordings revealed that placebo‐treated hAPP mice had aberrantly increased epileptiform activity as compared with placebo‐treated WT controls and that this neural network dysfunction was effectively suppressed by chronic LEV treatment or by tau ablation. Both manipulations reduced behavioral deficits detected in aged hAPP mice. Hippocampal levels of inflammation‐related transcripts were analyzed using a NanoString Neuroinflammation panel. Compared to WT mice, more inflammation‐related transcripts were increased than decreased in hAPP mice. LEV treatment reversed and tau ablation prevented the altered expression of many inflammation‐related genes in the hippocampus of hAPP mice. Immunolabeling tissues with an antibody against human Aβ revealed extensive amyloid deposition in aged hAPP mice but LEV treatment nor tau ablation changed the number or size of amyloid plaques.

Conclusion

LEV treatment and tau ablation reduce network, immune and cognitive dysfunctions, but not amyloid load, in aged hAPP mice. These findings demonstrate that LEV treatment and tau reduction counteract AD‐related pathophysiological abnormalities independent of age.
Mapping individualised patterns of atrophy in Alzheimer’s disease using neuroanatomical normative models
Authors: Verdi Serena , Kia Seyed Mostafa , Schott Jonathan M , Marquand Andre F , Cole James H ,   for The Alzhemer's Disease Neuroimaging Initiative
Published: December 2022

Background

Alzheimer’s Disease (AD) is highly heterogeneous, with marked individual differences in clinical presentation and aspects of its neurobiology. Neuroanatomical normative modelling is an emerging technique that reveals individual patterns of neuroanatomy by quantifying deviations from normative ranges (Verdi et al., 2021). Using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, we applied a hierarchical Bayesian regression (HBR) normative model to account for site effects (Kia et al., 2021). We assessed individual patterns of cortical thickness (CT) heterogeneity in AD patients, people with mild cognitive impairment (MCI), and healthy controls.

Method

CT across 148 regions of interest (ROIs) was generated using FreeSurfer from 1492 T1‐weighted MRI scans across 63 sites. A reference HBR normative model was trained on a separate healthy dataset of 34,490 to index population variability, predicting CT at each ROI using age and sex. This generated CT z‐scores for each ROI, per participant. Here z‐scores < ‐1.96 were defined as outliers. Outliers were also summed across 148 ROIs to give a total outlier score per participant. The influence of the total outlier score on converting from MCI to AD within 3 years was tested using Cox proportional hazards regression.

Result

AD subjects had higher total outlier scores than MCI and control participants (β=10.99,95%CI=[5.55,16.42], p<0.001), with marked differences in temporal regions. Total outlier score predicted memory performance (R2=0.39,p<0.001) and executive function (R2=0.35,p<0.001). Total outlier score was predicted by amyloid‐beta (R2=0.06,p<0.001) and phospho‐tau (R2=0.16,p<0.001). The patterns of neuroanatomical outliers varied markedly between AD patients (Fig.1); the parahippocampal gyrus had the highest rate of AD patients with outliers (47%). Outlier maps of AD patients matched age, sex, cognition and APOE4 genotype, illustrate spatially heterogeneous patterns of outliers (Fig.2). Greater within‐group dissimilarity was seen in AD patients, relative to MCI or control participants (Fig.3). Every 10 points of total outlier score contributed to an 31.4% risk of converting from MCI to AD within 3years (HR=1.028,95%CI=[1.016,1.039],p<0.001) (Fig.4).

Conclusion

Our novel quantitative estimate of the neuroanatomical heterogeneity of CT suggests the impact of AD on the brain is not consistent between patients. Furthermore, quantify outliers in CT may help predict individuals with MCI at risk of converting to AD.
Exploration of the gut‐brain axis through metabolomics identifies serum propionic acid associated with higher cognitive decline in older persons
Authors: Neuffer Jeanne , González‐Domínguez Raúl , Lefèvre‐Arbogast Sophie , Low Dorrain Yanwen , Driollet Bénédicte , Helmer Catherine , Preez Andrea Du , de Lucia Chiara , Ruigrok Silvie R , Altendorfer Barbara , Aigner Ludwig , Lucassen Paul J. , Korosi Aniko , Thuret Sandrine , Manach Claudine , Pallàs Mercè , Urpi‐Sarda Mireia , Sánchez‐Pla Alex , Andres‐Lacueva Cristina , Samieri Cécilia
Published: December 2022

Background

The microbiome is involved in nutrient metabolism and releases metabolites that can influence cognitive aging, likely through the gut‐brain axis. Human studies, generally limited in number of metabolites and follow‐up, have been inadequate to identify early metabolic alterations leading to cognitive aging. The aim of this study was to investigate the association between circulating levels of a large number of microbial metabolites in plasma and cognitive decline.

Methods

We studied participants from the Three‐City study, a cohort study conducted in 3 French cities (Bordeaux, Dijon ad Montpellier). The subjects were free of dementia at the time of blood sampling and provided repeated measures of cognition over 12 subsequent years. We used a targeted metabolomic approach, combining ultra‐high performance liquid chromatography coupled to tandem mass spectrometry. We measured 77 circulating gut‐derived metabolites in a case‐control sample matched for age, sex and educational level, nested within the cohort. Associations of these metabolites to cognitive decline were investigated in the Bordeaux center (discovery sample, n = 418) using logistic regressions conditioned on matching variables. Associations with a P‐value corrected for multiple testing (False Discovery Rate [FDR]) ≤0.15 were tested for validation in the Dijon center (validation sample, n = 424). Models were subsequently adjusted for smoking, alcohol consumption and cardiometabolic health (body mass index, hypertension, hypercholesterolemia and diabetes).

Results

Higher serum levels of propionic acid, a short‐chain fatty acid, were associated with increased odds of cognitive decline (OR for 1 SD = 1.40 [95% CI 1.11, 1.75] in discovery, and = 1.26 [1.02, 1.55] in the validation stage). Associations were attenuated in the validation sample after multivariable adjustment, and additional analyses suggested mediation by hypercholesterolemia and diabetes. Moreover, propionic acid strongly correlated with blood glucose (r = 0.80) and with meat and cheese intakes (r>0.15) but not with fiber intake (r = 0.04).

Conclusion

This exploratory study of the gut‐brain axis suggests a deleterious relationship between circulating propionic acid and cognitive decline. Our results suggest a very weak relation to pre‐biotic foods, but a possible link with processed foods, where propionic acid is often used as a preservative. Thus, the adverse impact of propionic acid on metabolism and cognition deserves further investigation.
Potential Reversal of Alzheimer’s Disease pathology by Antibody TB006 Targeting Galectin‐3, the Root Cause of Oligomerization of Amyloid Proteins
Authors: Rasool Suhail , Patel Pooja , Johansson Jenny , Voloboueva Ludmila , Lee Sangmi , Sun Jessica , Lan Xi , Ahmed Taufeeq , Sun Dongxu
Published: December 2022

Background

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder caused by multiple pathogenic factors including Amyloid‐β (Aβ), phospho‐Tau (pTau), alpha‐synuclein, and ApoE4, etc. It is widely accepted that intermediate oligomeric forms, rather than monomers or mature fibrils, are more neurotoxic. Galectin‐3 (Gal‐3) was reported to be involved in Aβ oligomerization. Here, we show that Gal‐3 promotes oligomerization of Aβ and other pathogenic factors, and TB006, a monoclonal antibody targeting Gal‐3, acts as a possible treatment for AD by degrading neurotoxic oligomers.

Method

We used two anti‐Gal‐3 antibodies, our clinical lead TB006 and a mouse cross‐reactive surrogate, mTB001, to establish the benefits of Gal‐3 neutralization in AD in vitro and in vivo. The effects of mTB001 were tested in three AD mouse models (two transgenic mouse models (APPSwe, 5xFAD) and an Aβ42‐injected mouse model). After two‐week treatment, a spatial memory function test was conducted, followed by biochemical and immunohistochemical characterizations.

Result

Amyloid aggregation is a hallmark of several neurodegenerative diseases (AD, PD and ALS) affecting the brain or peripheral tissues, whose intermediates (oligomers, protofibrils) and final mature fibrils display different toxicity. In vitro, Gal‐3 intrinsically and selectively promotes, while mTB001 and TB006 degrade, oligomerization of only pathogenic proteins like Aβ42/40, α‐synuclein, pTau and ApoE4, but not of normal proteins like normal Tau and ApoE2/3. Gal‐3 enhanced, while mTB001 blocked, Aβ42‐induced microglia activation. Additionally, Aβ42 and Gal‐3 synergistically induced, while mTB001 reversed, neuronal death. In vivo, in three mouse models of AD, cognitive deficits were strongly attenuated after just two weeks of mTB001 treatment. Mechanistically, Gal‐3 antibody blocked the initiating events in AD (Aβ aggregates), reduced inflammation and rescued neuronal damage. Furthermore, microhemorrhages, a potential safety liability seen in clinical stage drugs, were reduced.

Conclusion

Pre‐clinical studies show that TB006 is an efficacious therapeutic entity through degradation of toxic oligomers and blocking or even reversing AD progression. Clinically, TB006 has shown a superior safety profile without any drug‐related adverse events in a nearly finished healthy volunteer trial. Promising efficacious data are expected in Q2/2022 from the ongoing phase I/II AD trial.
The Fractal Geometry of Alzheimer’s disease
Authors: Azizi Tahmineh
Published: December 2022

Background

Human brain is the most dynamic and varied system of the body. The brain is composed of neuron and glia. But how do they interact to generate emergent properties like memory, learning, emotion and sleep is little understood. Many such complex systems that exist in non‐linear dynamics are characterized by the fractal nature. The fractal dimension (FD) is a quantitative parameter that has been extensively used to analyze the complexity of structural and functional patterns of the human brain. The fractal dimension (FD) of the human brain quantifies the inherent complexity.

Method

A non‐linear analysis called the Fractal Dimension (FD) has been performed to quantify the fractal complexity of AD. Our primary goal is to investigate FD to assess whether it can discriminate between different states of AD. We perform multi‐fractal analysis to discover whether AD and its states belong to class of multi‐fractal object for which a large number of scaling exponents are required to characterize their scaling structures. We plot the multi‐fractal spectra of the fMRI images to compare the width of the scaling exponent for each spectrum.

Result

From FD analysis, we noticed that the fractal dimension increases with aging the AD, i.e. the complexity and self similarity of brain structure increases. According to our analysis, we have a wide range of exponents for AD fMRI images, which indicates different states of Alzheimer’s disease have multi‐fractal structure.

Conclusion

As a result, fractal geometry can be considered as a computational framework to characterize different stages of AD and with further analysis, it can be used as a diagnostic tool to fight against Alzheimer’s disease.
Effects of ICT‐Based Multicomponent Program on Body Composition and Cognitive Function in Older Adults: A Randomized Controlled Clinical Study
Authors: Kim Duri , Chang Jae Hyeok , Song Seunghwan , Tak Young Jin , Huh Up , Cho Jeong Su , Sung Min‐ji , Jang Minwoo , Park Jong‐Hwan
Published: December 2022

Background

Information and communication technology (ICT)‐based training devices for older adults’ care related to dementia are being developed to enhance older adults’ cognitive functions. Older adults who require bicycle training devices can improve muscle strength and balance of lower limbs by continuously contracting and relaxing lower‐limb muscles and improving cognitive function to prevent dementia. This study was conducted to investigate the effects of an ICT‐based multicomponent program on body composition and cognitive function in older adults.

Method

In a randomized controlled intervention test on 20 people over the age of 60 (exercise group: n = 10; control: n = 10), the multicomponent program was applied to the exercise group twice per week, once per day for 12 weeks, at 30 min per session, whereas the control group was advised to maintain their usual daily activities.

Result

Comparing body composition changes and cognitive function changes before and after intervention exhibited statistically significant differences in skeletal muscle mass (P = 0.01) and modified Alzheimer’s disease assessment scale–cognitive score (P = 0.01) between the two groups.

Conclusion

It can be difficult to be engaged in a simple repetitive exercise program. Therefore, to meet older adults’ interests and expectations, a customized ICT‐based multicomponent program, which can improve body composition and cognitive function in older adults and is believed to help prevent dementia, is recommended.
Post‐stroke dementia and its determinant factors among Ethiopian stroke survivors: A cross‐sectional study
Authors: Zewde Yared Z
Published: December 2022

Background

Stroke and dementia convene risks for each other and share some of the same, largely modifiable, risk factors.

Method

Adult stroke survivors, who visited the outpatient stroke clinic in Tikur Anbessa Specialized Teaching Hospital in Addis Ababa University, Ethiopia was assessed for cognitive decline. Beside Montreal Cognitive Assessment‐Basic (MOCA‐B) tool, functional recovery and depression were measured using modified Rankin Scale (mRS) and Patient Health Questionnaire (PHQ‐9).

Result

From 67 stroke survivors (mean age: 52.1 ± 12.7 years, 40.3 % female, 25.3% illiterate, rural dwellers 32.8%, 37.3% stoke onset < 45‐year), 68.7% had cognitive impairment in at least one domain and 25.3% had dementia. Hospitalization [OR = 0.22 (0.06 ‐0.74)], right hemisphere stroke location [OR = 0.21 (0.06‐0.77)] and poor function recovery with mRS ³3 [OR = 1.4 (1.06‐1.74)] were independently associated with post stroke cognitive impairment and dementia.

Conclusion

The frequency of post stroke dementia was high in Ethiopia and poor functional recovery negatively impact cognitive outcome.
HIVEP3 variant is associated with increased amyloid deposition and lower hippocampal volume in cognitively unimpaired subjects.
Authors: Dauar Marina Tedeschi , Picard Cynthia , Breitner John , Villeneuve Sylvia , Poirier Judes ,   Prevent‐AD Research Group,   ADNI study
Published: December 2022

Background

A GWAS performed in a Canadian cohort identified, for the first time, the polymorphism rs10493098 C in the HIVEP3 gene to be associated with increased risk for late‐onset Alzheimer’s disease (AD). HIVEP3 is a transcription factor that regulates inflammatory response, neuroregeneration, cell growth and apoptosis. In this project, we examined three different population cohorts (PREVENT‐AD, ROSMAP and ADNI cohorts) to investigate the role of the rs10493098 C polymorphism in the pathophysiology of AD.

Method

In the PREVENT‐AD cohort, 18F‐NAV4694 PET was used to measure amyloid burden, and participants were followed for at least four years. In the autopsied‐confirmed ROSMAP cohort, Aß load and NFT density in the cortex were measured by immunohistorychemistry. Participants were followed throughout most of their adult life, until death. In the ADNI cohort, hippocampal volume was assessed with magnetic resonance imaging, and we evaluated follow‐up for 1 year.

Result

In the Prevent‐AD cohort, participants who are homozygous for the HIVEP3 C variant had higher amyloid index score compared to non‐carriers (p=0.004) (Fig 1). There is an interaction between APOE4 and HIVEP3, and participants who are APOE4 positive and homozygous for the HIVEP3 C variant exhibit even higher amyloid deposition compared to non‐carriers (p<0.001) (Fig 1). Participants who are homozygous for the HIVEP3 C variant have a higher risk of having an amyloid positive scan than participants who are non‐carriers (p=0.04) (Fig 1). There was no association between the HIVEP3 rs10493098 C variant and Braak or Cerad stages in the ROSMAP population. In the ADNI cohort, considering only the participants who had normal cognition, subjects who are homozygous for the HIVEP3 rs10493098 C variant display lower right hippocampus volume compared to heterozygous and non‐carriers (p=0.032) (Fig 2).

Conclusion

The HIVEP3 rs10493098 C variant is associated with higher amyloid deposition and lower hippocampal volume in cognitively unimpaired individuals
Humanoid robots coming to aid in dementia care provision: 16 humanoid robots working to augment care in 8 nursing homes across Minnesota
Authors: Khan Arshia a
Published: December 2022

Background

Dementia is a growing problem that is the cause for an increase in care provision needs. Staff shortages are having an adverse effect by creating an atmosphere where the people affected with dementia feel neglected and isolated. This is resulting in reduced quality of life for the people residing in assisted living facilities and nursing homes. Family members and caregivers have been forced to reduce contact with the residents due to the fear of infection given the vulnerability of the residents. The residents are losing emotional stimulation and this is adversely affecting their disease progression.

Method

Freeing caregivers of mundane caregiving activities that require more patience and less caregiving in activities such as reminding/prompting, watching and monitoring can allow them to focus on activities that require more attention and will benefit the residents. Repetitive activities such as prompting, reminding of daily living activities such as brushing teeth and hair, washing hands, keeping the oxygen or face mask on etc. can be repetitive and stressful for caregivers. If these activities can be performed by a humanoid robot that can repeat the same activity or prompt without getting frustrated or changing the tone, the caregivers will have more time to tend to activities that require more attention such as medication management, tending to finances, medical followup appointments etc. University of Minnesota is collaborating with nursing homes in deploying robots to help augment care in the domains of emotion, cognition and physical wellbeing. These robots will have tasks assigned to them that they will perform throughout the day. They work in conjunction with sensors that will provide them with stimulation and feedback for tracking and monitoring activities of daily living. The sensors will also track the physiological well being to ensure the residents are not adversely affected by the robots.

Result

Humanoid robots are being deployed in nursing homes. A combination of humanoid robots and wearable and spatial sensors track and monitor care provision for residents at nursing homes.

Conclusion

The humanoid robots are helping fill staff shortage gaps. Most importantly residents feel more engaged and have an improved sense of wellbeing.
Deep learning to harmonize MRI scans for better diagnosis and prognosis in multi‐center studies
Authors: Gebre Robel K , Senjem Matthew L. , Schwarz Christopher G. , Gunter Jeffrey L. , Kantarci Kejal , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi
Published: December 2022

Background

Data heterogeneity due to cross‐scanner variations is a major challenge in multi‐center aging and dementia studies. Brain structural measures for the same participant can vary due to scanner differences (manufacturer, scanner age/technology, signal‐to‐noise ratio, pulse sequence design, contrast, resolution) and result in biomarker variability. In this work, we applied basic image processing and deep learning methods (style transfer (ST) and generative adversarial networks (GANs)) for harmonizing T1‐weighted MRI scans across change in vendors (GE to Siemens) and resolution (1x1x1.2mm to 0.8x0.8x0.8mm) and test whether this harmonization improved compatibility of AD biomarker measures.

Method

We utilized training (n=814) and test (n=113 same participants scanned on two scanners close‐in‐time, typically on the same day, with different resolution) data from cognitively impaired and unimpaired participants scanned on GE and Siemens scanners from Mayo Clinic Study of Aging and Mayo ADRC. The harmonization was conducted to translate GE to Siemens. All scans were affine transformed to the same template space, resampled to 1.5 mm3, and bias corrected. Histogram matching was performed using cumulative density functions. A ResNet18 was trained for the ST’s content and style layers. Two types of GANs, conditional GANs (cGAN) and cycle‐consistent GANs (cycleGAN), were constructed. We then measured regional cortical thickness from each image using FreeSurfer‐7.1.1 and compared the thickness measurements from the original and translated scans using intraclass‐correlation (ICC) and Deming regression.

Result

In the test dataset, ST and cycleGAN showed the best performances when comparing the translated GE to Siemens. With ST, the ICC increased (vs. the original scans) slightly for the temporal meta‐ROI (0.956 from 0.954) and more substantially for the frontal pole ROI (0.706 from 0.594). The cycleGAN showed an increase in ICC for the frontal pole ROI (0.610 from 0.594) but not the meta‐ROI (Fig. 1).

Conclusion

Each method leveraged a different strength. Histogram matching captures contrast, ST extracts textural information, and GANs learn combination of contrast, edge and texture properties. We found that deep learning is a promising approach to cross‐scanner variability. Our comparisons revealed anatomical differences across methods; thus, disease specific measure should be considered for selection of the scanner harmonization method.
Longitudinal increase of sTREM2 in CSF and its relationship with other biomarkers and cognition along the evolution of autosomal dominant Alzheimer’s disease
Authors: Morenas‐Rodriguez Estrella , Haass Christian , Network Dominantly Inherited Alzheimer
Published: December 2022

Background

Therapeutic modulation of TREM2‐dependent microglial function provides an additional strategy to slow progression of Alzheimer’s disease (AD). Although studies on animal models suggest that TREM2 is protective, clinical biomarker studies reach different conclusions regarding TREM2 effect on tau pathology and its potential beneficial role in human AD. The longitudinal study of cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) as a biomarker of TREM2 signalling during the evolution of autosomal dominant AD and its relationship with different biomarkers shed additional light on these controversies.

Method

We measured sTREM2 by a novel MSD‐immunoassay selectively detecting ADAM10/17 generated sTREM2 in longitudinal CSF samples from 93 non‐carriers (NC) and 155 mutation carriers (MC) ‐presenilin 1, presenilin 2 and amyloid precursor protein genes‐, participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study, and with available longitudinal data on amyloid‐β (Aβ) and tau‐related CSF biomarkers, structural MRI, Pittsburgh compound B PET (PIB‐PET) and cognition. We based our statistical analysis on univariate and bivariate linear mixed effects models.

Result

Our recent results showed that longitudinal sTREM2 increase was predicted by the earliest Aβ‐aggregation captured by lower CSF‐Aβ42, but not yet by a higher cortical uptake in PiB‐PET. In line with previous cross‐sectional studies, higher sTREM2 increase rate was associated with slower Aβ‐deposition, as measured by CSF Aβ42 in presymptomatic MC, and by PIB‐PET in symptomatic MC. Furthermore, MC with high or low sTREM2 increase rates had opposite associations between CSF Aβ42 and PiB‐PET longitudinal changes, further suggesting that TREM2 modifies Aβ‐plaque deposition and compaction. Regarding tau‐related pathology, we found that lower sTREM2 increase rate enhanced the increase of CSF p‐tau associated with PiB‐PET signal increase. Finally, higher sTREM2 increase rate in presymptomatic MC was associated with slower cortical shrinkage in the precuneus and slower cognitive decline.

Conclusion

The most novel results on longitudinal sTREM2 in CSF position the TREM2 response right after the first pathological changes in Aβ‐aggregation and support its beneficial effect on Aβ‐deposition, Aβ‐dependent tau pathology, cortical shrinkage, and cognitive decline. These findings strongly support ongoing efforts to develop TREM2‐boosting therapies and suggest sTREM2 as a key marker for clinical trial design and interpretation.
Proxy measures of cognitive reserve and trajectories of gait and cognitive decline in older adults
Authors: Jayakody Shanika Oshadi , Ayers Emmeline , Verghese Joe , Weiss Erica , Barzilai Nir , Milman Sofiya , Blumen Helena M
Published: December 2022

Background

Lifestyle interventions are an emerging area of interest in dementia prevention. Education, physical activity, and social interactions are potentially modifiable lifestyle factors that are considered proxies of cognitive reserve. People with greater cognitive reserve could be protected against decline in gait and cognition, two interrelated problems associated with dementia, by coping better with age‐ or pathology‐related brain changes. We examined whether decline in gait and cognitive functions are different in those with higher versus lower levels of education, physical activity, and social interactions.

Method

Gait and cognitive performance in 1,095 LonGenity study participants (mean age = 75.4±6.7 years) that were free of dementia at baseline were examined up to 12 years. Gait speed was measured during usual pace (single‐task walking, STW‐speed) and walking‐while‐talking (WWT‐speed). Cognitive performance was measured with standard neuropsychological tests and a standardized composite global cognitive measure was derived. Years of education, number of blocks walked per day, living with someone and engaging in paid or volunteer work (markers of social interactions) were obtained from self‐report. Linear mixed‐effects models adjusted for sex, parental longevity, cognitive impairment, and global health were used to examine age‐associated changes in gait and cognition in those with and without greater cognitive reserve.

Result

STW‐speed and WWT‐speed did not vary as a function of education, physical activity, or social interactions. Greater number of blocks walked per day was associated with slower decline in global cognition, Trail Making Test (TMT)‐A, TMT‐interference, digit symbol substitution, logical memory, figure recall, free recall, category and phonemic fluency tests. Higher education was associated with slower decline in global cognition, TMT‐interference, TMT‐A and figure copy task. Living with someone was associated with slower decline in global cognition, digit symbol substitution and logical memory. Paid or volunteer work was associated slower decline in global cognition.

Conclusion

Having higher education, more physical activity and social interactions appear to protect against cognitive, but not gait decline, potentially by building up cognitive reserve. The multifaceted etiology and relatively earlier decline of gait may render it less influenced by potentially modifiable risk factors in late life than cognition.
Participant FIRST: Improving Communication With and Support For Participants in Trials that End Early
Authors: Largent Emily A. , Walter Sarah , Edelmayer Rebecca M. ,   The Participant FIRST Work Group
Published: December 2022

Background

In 2019, multiple AD/ADRD trials ended earlier than planned. Participants subsequently stepped forward explaining they first learned their trial ended via news coverage, rather than from a site investigator or research staff. As a result, the issue of participant notification—and the emotional impact of being in a trial that stops early—gained attention. This led to calls to identify better ways to communicate with and support participants after trials end early.

Method

The multidisciplinary Participant Follow‐Up Improvement in Research Studies and Trials (Participant FIRST) Work Group met throughout 2021. Members included research participants and study partners, clinical trialists and study personnel, as well as representatives from academia, industry, patient advocacy organizations, and the National Institutes of Health. The work group’s goals were: (1) improving communication with research participants and study partners when trials end early and (2) identifying supports for those affected by early stopping.

Results

The Participant FIRST Work Group identified 17 key recommendations. Pre‐trial recommendations focus on developing a patient‐centered communication plan and ensuring that participants and study partners understand early stopping (e.g., role of DSMBs, stopping rules) and securities laws that shape companies’ announcements of trial stopping and, thus, how disclosure occurs. Mid‐trial recommendations focus on maintaining up‐to‐date contact information; helping participants and study partners build support networks; and reinforcing education on early stopping. Post‐trial recommendations focus on rapidly communicating with participants via multiple modalities; scheduling a personalized close‐out meeting to provide key information about the trial and discuss next steps; collaborating with patient advocacy organizations to provide support to participants (e.g., via a patient hotline); and ensuring that participants receive top‐line results. The work group calls for funders and sponsors to ensure adequate time and resources are available to communicate with and support participants when trials end early.

Conclusion

Participants and study partners invest time, effort, and hope in their AD/ADRD research participation. The research community should hold itself accountable and take intentional steps towards better means of communicating with and supporting participants when clinical trials end early. The Participant FIRST recommendations are a practical guide for researchers and sponsors embarking on that journey.
Participant experience in a longitudinal online research registry: Associations between ethnocultural identity, educational attainment, and participant feedback in the Brain Health Registry
Authors: Ashford Miriam T. , Eichenbaum Joseph , Jin Chengshi , Neuhaus John , Ulbricht Aaron , Camacho Monica R , Fockler Juliet , Flenniken Derek , Truran‐Sacrey Diana , Mackin R Scott , Maruff Paul , Weiner Michael W. , Nosheny Rachel L
Published: December 2022

Background

Research registries focused on brain diseases, such as Alzheimer’s disease and related dementias (ADRD), have been developed to accelerate clinical study recruitment. Completion of registry components can affect the representativeness of registry populations and data, especially where retention is critical. This study aims to provide insights for online research and retention by studying participants’ perceptions of the Brain Health Registry (BHR), with a focus on those from different ethnocultural and socioeconomic backgrounds.

Method

BHR is a public online registry for recruitment and longitudinal assessment focused on cognitive aging and ADRD research. Participants can provide feedback to the study team about their overall experience at any time using a questionnaire and are asked to complete feedback questionnaires after completing the Cogstate Brief Battery (CBB) (Table 1). Multivariable ordinal logistic regression estimated associations between sociodemographic characteristics (ethnocultural identity and education attainment) and feedback responses. All analyses covaried for age and gender.

Result

Of all participants (N = 89,673), 5,469 (6.1%) provided feedback about their overall BHR experience and 14,676 (16.4%) provided feedback about CBB (Table 2). See Table 3 for associations between sociodemographic characteristics and feedback responses. Identifying as Latino was associated with a poorer experience with the cognitive assessment. Identifying as Latino or non‐White was associated with perceiving the cognitive assessment instructions as less clear and rating that additional help for cognitive assessment instructions would be useful. Higher educational attainment was associated with perceiving BHR site as easier to use and the instructions as clearer, as well as rating additional help for cognitive assessment instructions as less useful.

Conclusion

Our findings highlight the need to improve and/or tailor online cognitive assessment design and instructions to better suit the needs of diverse ethnocultural and educational populations. More research is needed to deepen insight into improvements in cognitive assessment design to facilitate engagement and retention of diverse populations.