bluuebunny/crossref_metadata_2025 huggingface dataset:
Classification of AD/MCI/HC based on amyloid‐PET using Random Forest Ensemble
Authors: Bao Yiwen , Chiu Patrick Ka‐Chun , Shea Yat Fung , Kwan Joseph S.K. , Chan Hon Wai Felix , Mak Henry
Published: December 2021

Background

Positron emission topography (PET) and magnetic resonance imaging (MRI) are two common in‐vivo techniques for supporting clinical diagnosis of dementia. The correlated neuropathological changes including amyloid‐beta (Aβ) deposition, and cortical atrophy may have the potential to predict conversion from cognitively normal elderly adults (HC), to mild cognitive impairment (MCI) and eventually Alzheimer’s disease (AD). In order to overcome the complex interactions among these biomarker datasets, random forest (RF) as one of the machine learning algorithms is usually used in data classification. In current study, we aim at evaluating the accuracy of RF model in distinguishing HC, MCI from AD and the importance of various neuropathological features in selection.

Method

Three cohorts were included in our study. We recruited 94 AD, 82 MCI and 85 HC from GAAIN (The Global Alzheimer’s Association Interactive Network) database, AIBL (Australian imaging, biomarkers and lifestyle) database, and our memory clinic database. Based on Centiloid pipeline, we processed the co‐registered MRI and PET images of each subject. Additionally, to compare quantitative amyloid load across different tracers, we converted SUVR (Standardized Uptake Value Ratio) values into standard Centiloid units. RF algorithm was performed on Python via scikit‐learn package. Finally, 122 regional volumes, 68 regional cortical thicknesses, 16 small regional amyloid distribution and 1 global amyloid load were input as features.

Result

In Table 1, the AUC value was highest (AUC=0.82) in the classification between HC and AD, intermediate (AUC=0.78) between HC and MCI and lowest (AUC=0.65) between AD and MCI. In each binary classification, sensitivity‐71%, specificity‐85%, accuracy‐78%; sensitivity‐88%, specificity‐76%, accuracy‐81% and sensitivity‐86%, specificity‐44%, accuracy‐66% were achieved in differentiating MCI from HC, AD from HC and AD from MCI respectively. For importance ranking of features within the model, 6 features of regional cortical thickness and 4 features of regional volume were found in the classification between HC and MCI, while all 10 essential features belong to regional Aβ ‐ROI in classification between HC and AD as well as MCI and AD (Table 2).

Conclusion

Random forest model using regional volume, regional cortical thickness and amyloid load (in Centiloid unit) had moderate to high accuracy in differentiating AD from HC and MCI.
Social behavior assessment in cognitively impaired older adults using a passive and remote smartphone application
Authors: Muurling Marijn , Reus Lianne M. , de Boer Casper , Jagesar Raj , Vorstman Jacob A , Kas Martien JH , Visser Pieter Jelle
Published: December 2021

Background

In Alzheimer’s Disease (AD), loss of social interactions has a major impact on well‐being. Therefore, AD patients would benefit from early detection of symptoms of social withdrawal. Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone applications, which measure social behavior passively and objectively. Here, we examine social interactions through passive remote monitoring with the smartphone application BEHAPP in cognitively impaired participants. This study aims to investigate (1) the association between demographic characteristics and BEHAPP outcome variables in cognitively normal (CN) older adults, (2) if social behavior as measured using the passive smartphone app BEHAPP is impaired in cognitively impaired (CI) participants compared to subjects with subjective cognitive decline (SCD), and CN older adults. In addition, we explored in a subset of individuals the association between BEHAPP outcomes and neuropsychiatric symptoms.

Method

CN (n=209), SCD (n=55) and CI (n=22) participants, older than 45 years, installed the BEHAPP app on their own Android smartphone for 7‐42 days. CI participants had a clinical diagnosis of mild cognitive impairment or AD‐type dementia. The app continuously measured communication events, application usage and location. Neuropsychiatric Inventory (NPI) total scores were available from 20 SCD and 22 CI participants.

Result

We found that older cognitively healthy participants called less frequently and made less use of apps. No sex effects were found. Linear models corrected for age, sex and education showed that compared to the CN and SCD groups, CI participants called less unique contacts and contacted the same contacts relatively more often (Figure 1). They also made less use of apps, visited less unique places and traveled less far from home. Higher total NPI scores were associated with more unique stay points and further travelling. Similar behavior patterns were found when correcting for multiple comparisons.

Conclusion

Cognitively impaired individuals show reduced social activity, as measured by the smartphone application BEHAPP. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with BEHAPP. This research shows that a passive and remote smartphone application is able to objectively and passively measure altered social behavior in a cognitively impaired population.
Community paramedic‐delivered care transitions intervention reduces emergency department revisits among cognitively impaired patients
Authors: Shah Manish N , Green Rebecca K , Jacobsohn Gwen C , Jones Courtney MC , Caprio Thomas V , Cochran Amy L , Cushman Jeremy T , DuGoff Eva , Lohmeier Michael , Kind Amy J
Published: December 2021

Background

Up to half of community‐dwelling older adults with impaired cognition who are discharged home from the emergency department (ED) return for further care within 30 days. We examined the effects of delivering the Care Transitions Intervention (CTI) to older adult patients with impaired cognition discharged home from the ED, hypothesizing that the CTI would decrease ED revisits in the following 30 days.

Method

We conducted a pre‐planned sub‐analysis of community‐dwelling older adults (age≥60 years) with impaired cognition participating in a single‐blind, randomized controlled trial testing the effectiveness of the CTI adapted for use following ED discharge. The parent study recruited ED patients from three university‐affiliated hospitals from 2016–2019. Subjects eligible for this analysis had to: 1) have a primary care provider within these health systems; 2) be discharged to a community residence; 3) not receive care management or hospice services; and 4) be cognitively impaired in the ED, as determined by a score>10 on the Blessed Orientation Memory Concentration Test. Intervention group subjects received a home visit from a trained paramedic coach within 72 hours of discharge, and up to three follow‐up phone calls during the following month. Our primary outcome was occurrence of any ED revisit within 30 days of discharge. Secondary outcomes included any ED revisit within 14 days and outpatient clinic follow‐up. We evaluated intervention effects using multivariate logistic regression.

Result

Of our sub‐sample (N=81, 36 control, 45 treatment), 57% were female and the mean age was 78 years. Bivariate comparison of primary and secondary outcomes found no significant differences. Multivariate analysis, adjusted for the presence of moderate to severe depression and inadequate health literacy, found that the CTI significantly reduced the odds of a repeat ED visit within 30 days (OR 0.25, 95%CI 0.07‐0.90) but not 14 days (OR 1.01, 95%CI 0.26‐3.93). Multivariate analysis of outpatient follow‐up found no significant effects.

Conclusion

Community‐dwelling older adults with cognitive impairment receiving the CTI following ED discharge experienced fewer ED revisits within 30 days compared to usual care. Further studies must confirm and expand upon this finding, identifying features with greatest benefit to patients and caregivers.
Plasma P‐tau181 levels predict amyloid pathology in cognitively unimpaired individuals after 10 years
Authors: den Braber Anouk , Verberk Inge M.W. , Den Dulk Ben , Tomassen Jori , Dage Jeffrey L , Stoops Erik , Willemsen Gonneke , Nivard Michel G. , Van Berckel Bart N.M. , Scheltens Philip , Visser Pieter Jelle , de Geus Eco J.C. , Teunissen Charlotte E.
Published: December 2021

Background

Plasma levels of phosphorylated‐tau (P‐tau) are able to identify core Alzheimer’s Disease (AD) pathologies, but its value in cognitively unimpaired individuals needs further study. We aimed to investigate the value of plasma P‐tau at threonine‐181 (P‐tau181) for predicting amyloid pathology in cognitively unimpaired individuals followed over 10 years.

Method

From the EMIF‐AD PreclinAD study we selected 74 individuals, aged 60 years and older (Table 1) with normal cognition, that had plasma samples available that were collected at time of amyloid status assessment, as well as 10 years earlier (median (IQR) = ‐9.7 (2)). Amyloid status was defined using visual read of dynamic [18F]flutemetamol‐PET images or CSF amyloid‐β1‐42/1‐40<0.065 (Euroimmun). Simoa assays were applied to measure plasma P‐tau181 levels (Eli Lilly). ROC curve analysis was used to determine the value of plasma P‐tau181 in predicting amyloid status. Further, linear mixed models, adjusted for age and sex, were applied to assess longitudinal change in plasma P‐tau181, using time and the interaction between time and amyloid status as a predictor.

Result

Amyloid‐positive individuals had higher plasma P‐tau181 levels compared to amyloid‐negative individuals, both at time of amyloid status assessment and 10 years earlier. Plasma P‐tau181 obtained 10 years prior to amyloid status assessment was able to discriminate amyloid status with similar high Area Under Curve, sensitivity and specificity as plasma P‐tau181 obtained at time of amyloid status assessment (Figure 1). Longitudinally, we observed a general increase in plasma P‐tau181 levels over time (β=0.10, p<.001). Interestingly, amyloid‐positive individuals showed a steeper increase in plasma P‐tau181 levels over 10 years compared to amyloid‐negative individuals (time*amyloid‐β‐interaction: β=0.16, p=.005 (Figure 2)).

Conclusion

Our data suggest that plasma P‐tau181 can be used to predict AD pathology in cognitively unimpaired individuals. The high discriminative value observed, even using plasma P‐tau181 collected 10 years prior to amyloid status assessment, indicates the potential of this marker as an early amyloid pathology pre‐screening tool in the normal aging population. The observed amyloid dependent longitudinal increases in plasma P‐tau181 levels indicates this marker to be eligible for disease monitoring.
Memory impairments in Tg19959 and APP/PS1 AD model mice are alleviated by eEF2K inhibitor A‐484954
Authors: Kasica Nicole P , Yang Wenzhong , Zhou Xueyan , Ma Tao
Published: December 2021

Background

Mounting evidence indicates synaptic failure as an early and key event in Alzheimer’s Disease (AD) pathophysiology. Maintenance of long‐term memory and synaptic plasticity requires de novo protein synthesis. Phosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis. Previous studies have shown elevated levels of eEF2 phosphorylation in post mortem AD human brain tissue and in AD mouse models. Here we investigated whether suppression of eEF2 phosphorylation via eEF2K inhibitor A‐484954 can alleviate AD‐associated synaptic failure and memory impairments

Method

Aged Tg19959 mice (6‐9 months), APP/PS1 (12‐16 months) and age‐matched controls were treated with a subcutaneous pellet containing A‐484954 or vehicle. The pellet continuously releases treatment over 30 days. Starting two weeks after pellet placement, the mice underwent cognitive assessment via the Novel Object Recognition (NOR) and Morris Water Maze (MWM) tasks. Golgi‐Cox Stain, Amyloid Beta immunohistochemistry, Western blots, SUnSET Assays, and a variety of other experiments were performed on the mice after sacrifice.

Result

We found that cognitive impairments displayed in aged Tg19959 and APP/PS1 mice were alleviated with treatment of A‐484954. Brain tissue from these mice also underwent high performance liquid chromatography (HPLC) to assess drug concentration. In addition, Golgi‐Cox stain was done to assess dendritic spine density and morphology. Spine analysis indicates a rescue in levels of mature spines in the CA1 region of the hippocampus in APP/PS1 mice treated with A‐484954.

Conclusion

Taken together, our results suggest that treatment with a eEF2K inhibitor, A‐484954, alleviates cognitive impairments and restores synaptic morphology in two mouse models of AD.
Single‐particle characterization of tau oligomers in solution
Authors: Awasthi Saurabh , Mayer Michael
Published: December 2021

Background

Protein aggregation is the hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD), and oligomeric species of microtubule‐associated protein Tau are implicated as neurotoxic species as well as promising biomarkers. The size and shape of the oligomers are critical to their toxicity. Currently existing, sensitive immunoassays for biomarker detection do, however, not provide information on the size‐ or shape‐distribution of Tau aggregates. This limitation reduces the information content from tau analyses since specific sizes and shapes of oligomeric Tau aggregates are more toxic than others. Hence, a novel approach that reveals the size‐, and the shape‐distribution of Tau oligomers rapidly in solution would be ideal.

Method

Here, we use resistive‐pulse sensing with solid‐state nanopores to detect and characterize Tau oligomers on a single particle basis in solution with respect to their size and shape.

Result

The nanopore‐based approach facilitates single‐particle detection and fingerprinting of tau oligomers with regard to their size and shapes. We can determine the heterogeneity among oligomers with respect to their sizes and shapes, which is usually overlooked by averaging. We follow and compare the aggregation kinetics of wild type and AD‐associated variants of Tau.

Conclusion

Resistive‐pulse sensing using nanopores allows rapid fingerprinting Tau oligomers in solution in a label‐free manner. The size and shape information of oligomeric species can improve the general understanding of their toxicity and facilitate the development of new prevention strategies.
Neural correlates of cognitive resilience differ between experiences of bilingualism and education: A cortical surface‐based morphometry study in dementia
Authors: Alladi Suvarna , Arshad Faheem , Kenchaih Raghavendra , Surampudi Bapiraju , Paplikar Avanthi , Varghese Feba Anna , Ramakrishnan Subasree , Saini Jitender , SrInivasan Narayanan , Khokhar Sunil , Bak Thomas H
Published: December 2021

Background

Life‐course experiences such as education and bilingualism can be protective against dementia. The cognitive effects of bilingualism are specific while education has a more pervasive effect on general cognitive abilities, indicating that there is a likelihood of a variability in mechanisms underlying resilience. India is characterised by educational diversity and bilingualism. Importantly, bilingualism is not always associated with confounding effects of education, socioeconomic class or immigration. This makes the population uniquely suited for the study of resilience and opens up the possibility to disentangle the independent effects of bilingualism and education. Recent evidence indicates that surface‐based morphometric features of the cortical thickness and surface area are significantly modulated by life course experiences. Therefore, in this study, the independent influence of bilingualism and education on cortical thickness and surface area in dementia were studied to investigate the mechanisms that underlie resilience.

Method

Forty‐five patients with Frontotemporal dementia (FTD) were enrolled. 27 bilinguals were matched with 18 monolinguals for demographic factors and clinical severity. We examined the independent associations of bilingualism and education with cortical thickness and surface area using a surface based morphometric approach.

Result

Bilinguals with FTD had greater cortical thickness and reduced surface area in bilateral dorsolateral and medial frontal areas, and right parietotemporal cortex, regions associated with executive control. Bilinguals also demonstrated lesser cortical thickness in the language processing areas of left superior temporal, inferior parietal and lateral occipital regions compared to monolinguals. On the other hand, higher education was associated with decreased cortical thickness and increased surface area in bilateral frontal, medial temporal, parietal, occipital, and left temporal regions.

Conclusion

This study explores for the first‐time, associations of two different proxies of resilience with cortical thickness and surface area in FTD. Our findings indicate that the neural substrate underlying the protective effects of bilingualism differ from education in FTD, and can be related to their differential effects on cognition. Results indicate specific neural correlates of resilience for different life‐course experiences.
The Critical Path for Alzheimer’s Disease (CPAD) Consortium: A platform for pre‐competitive data sharing, standardization, and analysis to support quantitative tools for AD drug development
Authors: Sivakumaran Sudhir , Hanan Nathan J , Cui Zihan , Burton Jackson , Lang Patrick , Priest Eileen , White Hazel , Romero Klaus , Karten Yashmin
Published: December 2021

Background

The primary objective of the Critical Path for Alzheimer’s Disease (CPAD) consortium, a pre‐competitive consortium of the Critical Path Institute, is to promote, support, and manage pre‐competitive data and knowledge sharing from Alzheimer disease (AD) drug development stakeholders. Since 2019, CPAD has embarked on a new data sharing initiative to acquire fluid and imaging biomarker‐rich data sources for development of novel tools to quantify Alzheimer’s Disease progression across the AD continuum.

Method

Patient‐level data from contemporary Phase2/Phase3 AD clinical trials and observational studies is acquired through formal data contribution agreements within CPAD, curated in collaboration with data contributors, standardized to common structure and terminology, and input into a relational data model (RDM) tool to generate analysis subsets. Data standardization is being accomplished using Clinical Data Interchange Standards Consortium (CDISC) standards. The RDM was developed using the open‐source software R and converts CDISC structure to analysis ready files for quantitative analyses through user defined primary keys, i.e. unique identifying variables for extracting information. The RDM includes a front‐end data interrogator that provides users with versatile capabilities to visualize and tabulate the data.

Result

As of October 2020, CPAD’s database (https://codr.c‐path.org/) contains 41 studies, standardized to the AD CDISC standards, of which three datasets were used to generate analysis subsets. Four additional datasets were recently acquired and are being standardized. Execution of Data Contribution Agreements (DCAs) is in progress for two contemporary datasets rich in key fluid and imaging biomarkers. Nine additional prioritized datasets are targeted for acquisition. The RDM is currently being used to transform the CDISC standardized data into analysis ready subsets containing patient demographics (age, sex), fluid biomarker information (Aβ 40/42), and clinical outcome assessments (Clinical Dementia Rating Scale – Sum of Boxes).

Conclusion

The data acquisition and analysis platform developed is stimulating pre‐competitive efforts to generate quantitative tools for advancing AD drug development. Previously developed tools, including a regulatory endorsed clinical trial simulation tool, help optimize trial design and advance drug development in AD.
Quantitative electroencephalography features of dysexecutive Alzheimer's disease
Authors: Li Wentao , Varatharajah Yogatheesan , Barnard Leland R. , Allen Kay S. , Brinkmann Benjamin H. , Worrell Gregory A. , Jones David T.
Published: December 2021

Background

Progressive dysexecutive syndrome (dAD) is an atypical presentation of early onset Alzheimer’s disease (AD) with increased frontal and parietal region hypometabolism on FDG‐PET imaging compared to classic amnestic AD. We compared electroencephalogram (EEG) and FDG‐PET in dAD patients to determine if there was a correlation between EEG spectral activity and standard uptake value ratios (SUVR) in those regions.

Method

FDG‐PET and resting state scalp EEG were obtained on AD‐biomarker confirmed, behavioral neurologist diagnosed cases of dAD (n = 11). We isolated awake‐eyes‐closed segments (mean duration: 113s, median:118s, range: 58‐138s) of each EEG and calculated the relative power of delta, theta, alpha, beta, and gamma bands within a wideband of 0.5‐40 Hz. In bilateral frontal and parietal regions, we averaged select channels across 6 to 14 10‐second windows per subject (fig.1). We evaluated the correlation between relative band powers and SUVRs of the regions by linear regression analysis.

Result

There is a strong negative correlation (R2 = 0.54, p < 0.01) between alpha band relative power and SUVR in bilateral frontal regions (fig 2). Delta band relative power showed a strong positive correlation (R2 = 0.54, p < 0.05) with SUVR in the left frontal region. A positive trend was noted in the delta band in the right frontal region but did not reach statistical significance. Beta band relative power was negatively correlated with frontal region SUVR bilaterally, but only the left side reached statistical significance. These findings remained significant after multiple comparisons correction. No statistically significant correlations were noted in the parietal regions. Exploratory analysis revealed negative correlations between alpha bands and temporal region SUVRs bilaterally.

Conclusion

In this small sample of selected individuals with dysexecutive AD, we report a strong correlation between EEG relative spectral power and PET regional SUVR in multiple EEG frequency bands and brain regions. In the bilateral frontal regions, slower delta frequencies and faster alpha and beta frequencies were associated with lower FDG‐PET signal. Future studies are needed to determine if this spectral power pattern and other EEG properties of dAD differ from other clinical dementia phenotypes and its clinical significance.
Using academic detailing to enhance the knowledge, skills and attitudes of clinicians caring for patients with behavioral and psychological symptoms of dementia
Authors: Walaszek Art , Schroeder Molly , Albrecht Tammi , LeCaire Tamara , Carlsson Cynthia M
Published: December 2021

Introduction

: Approximately 90% of persons with dementia experience behavioral and psychological symptoms of dementia (BPSD) over the course of their illness. Primary care clinicians often provide care as specialty geriatric‐medicine or ‐psychiatry consultation may be difficult to obtain. Academic detailing (AD) is an evidence‐based educational approach for engaging and persuading healthcare professionals to make changes in their practice (Avorn 2017). We sought to enhance the knowledge, skills and attitudes of providers’ care of patients with BPSD using the AD model in primary care.

Methods

We implemented AD in an urban clinic serving a largely Black community and a rural clinic serving a large, White community. Each AD visit included didactic content, case discussion, and consultation regarding patients with BPSD. Eleven visits over 18 months are planned for each site. Outcome measures include a 10‐item multiple‐choice assessment of knowledge and an adaptation of the General Practitioners Attitude and Confidence Scale for Dementia (GPACS‐D) (Mason et al. 2019) at baseline before training, and 6 and 18 months, and Likert‐scale measurement of acceptability at 6 and 18 months, all self‐report.

Results

We present interim data. Five urban and 14 rural providers completed baseline assessments. Providers were mostly White (95%) and Non‐Hispanic (100%); 47% were female. Urban and rural providers had similar baseline BPSD knowledge (mean (SD) of correct answers, 5.4 (1.7) for rural, and 5.0 (2.6) for urban). The adapted GPACS‐D, where higher score indicates more confidence, showed less confidence (mean score 11.4 versus 16.6, p=0.01) in urban versus rural providers. The overall attitudes score indicate there may be more confidence in treating BPSD at baseline among the slightly older rural providers as compared to their urban colleagues. Thus far, eight of 22 planned AD visits have been completed; 6‐month assessments are forthcoming and will be presented.

Discussion

Academic detailing may be a feasible and effective way of increasing self‐reported knowledge and skills and improving self‐reported attitude of primary care providers responsible for the care of patients with BPSD. The pilot data collected in this study will inform the design of a larger study to measure the impact of AD on patient outcomes.
Analytical validation of plasma amyloid β measuring system by immunoprecipitation‐mass spectrometry
Authors: Yoda Ritsuko , Kaneko Naoki , Korenaga Akihito , Funatsu Shinji , Sakashita Nanami , Nishikaze Takashi , Ohashi Yuko , Honda Mamoru , Hioki Yusaku , Sekiya Sadanori , Ogata Koretsugu , Iwamoto Shinichi , Tsujino Kazushige , Tanaka Koichi
Published: December 2021

Background

With the increasing number of patients with Alzheimer's disease, construction of inspection system for blood biomarkers to replace or complement amyloid PET and CSF biomarkers has been required. Since our first report in 2014 (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014), we have been focusing on three amyloid peptides, Aβ1‐40, Aβ1‐42, and APP669‐711 in human plasma, and found that the combination of peptide ratios APP669‐711/Aβ1‐42 and Aβ1‐40/Aβ1‐42 became a biomarker for amyloid peptide accumulation in human brain (Nakamura et al., Nature 2018). Here we describe the analytical validation of plasma amyloid β measuring system by immunoprecipitation‐matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS).

Method

Commercially available human plasma and artificial plasma were immunoprecipitated with anti‐Aβ antibody (clone 6E10) covalently bound to the magnetic beads, then measured by MALDI‐TOF‐MS. The peak intensity of the Aβ‐related peptides was normalized by the internal standard peak, and biomarker values were calculated from those intensities. A method validation including experiments of calibration range, sensitivity, specificity, reproducibility, interfering substances, dilution linearity, recovery, and stability was performed.

Result

The system showed good linearity over the range from 15 to 150 pM for Aβ1‐40, and 3 to 15 pM for Aβ1‐42 and APP669‐711. The trueness was within 100 ± 25% at the lower limit of quantification and within 100 ± 20% at all other concentrations. The precision of the intra‐ and inter‐assay was 1% to 13% as a CV value. Recovery from spiked human plasma ranged from 83% to 101% at low, middle, and high concentrations. Stability testing has shown that the antibody beads are stable for up to 6 months in the refrigerator so far. The addition of the interfering substances, such as anticoagulants, Alzheimer's disease drugs, etc., had only a slight effect on the biomarker values showing 10% or less difference relative to the control. Further results will be reported in the presentation.

Conclusion

The results demonstrate that the plasma amyloid β measuring system by IP‐MALDI‐MS is an accurate, reliable, and robust assay that would be most suitable for screening subjects in clinical trials.
Economic burden of dementia studies in low‐ and middle‐ income countries (LMICs): A systematic review
Authors: Mattap Siti Maisarah , Mohan Devi , McGrattan Andrea , Allotey Pascale , Stephan Blossom CM , Reidpath Daniel , Siervo Mario , Robinson Louise , Chaiyakunapruk Nathorn
Published: December 2021

Background

More than two thirds of people with dementia are living in the low‐ and middle‐ income countries (LMICs). The growing dementia prevalence will result in significant economic burden in these countries. This systematic review aimed to summarise the evidence on the economic burden of dementia in LMICs.

Method

Seven databases (EconLit, EMBASE, PubMed, Cochrane Review (DARE), ERIC, PsycINFO and CINAHL) were searched from inception to September 2020 for original research articles reporting the economic burden or cost of illness for all‐cause dementia and/or its subtypes e.g., Alzheimer’s disease (AD), from any LMICs as defined by the World Bank. Two independent reviewers assessed studies for eligibility. Data on the location, study characteristics, cost estimation methods and estimated costs were extracted. The national level total, direct and indirect costs inflated to 2019, were expressed as a percentage of each country’s Gross Domestic Product (GDP) and were summarised using mean percentage of GDP. Study quality was assessed using the Larg and Moss method.

Result

The literature search identified 14092 articles, of which 22 studies met the eligibility criteria. The national cost of dementia was reported in 64% of the studies (from 120 countries). The remaining studies reported only patient level cost. Majority of the studies had low risk of bias. The average national dementia cost estimated as proportion of GDP was 0.42%. Informal care or indirect costs on average accounted for 62% of the total cost of dementia, while 38% was due to the direct cost.

Conclusion

Dementia is a major cause of economic burden in LMICs. Cost of informal care or indirect cost is the major contributor of this cost. The cost of dementia in LMIC has doubled since first reported in the World Alzheimer Report in 2015 (0.2% of GDP).

Acknowledgement: This research was funded by the National Institute for Health Research (NIHR) (16/137/62 ‐ Dementia Prevention and Enhanced Care (DePEC), Newcastle University, United Kingdom), using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care.
How do dementia risk differences between birth cohorts affect future incidence predictions: A microsimulation study
Authors: Brück Chiara C , Wolters Frank J , Ikram M. Arfan , de Kok Inge MCM
Published: December 2021

Background

In a recent coordinated analysis across population‐based cohorts, we have shown that the age‐specific dementia incidence has declined by 13% per decade since 1990. Here, we aim to incorporate these trends into the projection of the future dementia burden, using microsimulation models that can synthesise complex information, take time trends into account, and estimate long‐term and population wide intervention effects.

Method

Based on the Microsimulation Screening Analysis (MISCAN) model from cancer research, we developed a dementia microsimulation model. It synthesises data from the population‐based Rotterdam Study with published disease stage durations from several mostly clinical cohorts. We incorporate changes in demographics by defining unique birth and life tables for every 10‐year birth cohort between 1910 and 1980. Three trend scenarios in age‐specific dementia incidence were calibrated to fit the observed incidence data from the Rotterdam Study: 1) no risk differences between birth cohorts; 2) a linear decline of 13% in incidence rate per birth cohort; and 3) two nonlinear declines that result in the same cumulative decline and average incidence rate as the linear trend. Projections of the dementia incidence in the Netherlands until 2050 were calculated for every trend scenario.

Result

The model simulated 10 million individuals, representative of the Dutch population in the 1910 to 1980 birth cohorts. The model was able to fit the observed incidence data well. Figure 1 shows the incidence projections for the Dutch population implementing the aforementioned trend assumptions. Assuming no trend results in the highest incidence projections, the linear trend results in the lowest, and the nonlinear trends lie in between. By 2050, compared to no decline, the linear and nonlinear trends result in 40% and 25‐35% fewer incidence cases.

Conclusion

Assumptions about the trend in incidence play a crucial role for the projections of the future dementia incidence, and subsequently prevalence and mortality. We developed a model that is well capable of projecting trends on future incidence. An application to the Dutch population projects 25‐40% lower incidence than currently assumed. Modelling the effect of interventions and risk changes on a population level provides essential information for policy makers and researchers.
Menopause and later‐life cognition: Findings from the longest‐running population‐based birth cohort
Authors: Needham Louisa , Lu Kirsty , Nicholas Jennifer M , Schott Jonathan M , Richards Marcus , James Sarah‐Naomi
Published: December 2021

Background

Alzheimer’s Disease is more common in women than men. Menopause timing and type have been linked with cognition post‐menopause, but associations with dementia risk are unclear. Within the MRC National Survey of Health and Development (NSHD), childhood cognition predicts later‐life cognition and has largely explained menopause‐cognition associations post‐menopause. We now explore to what extent childhood cognition explains menopause‐cognition associations in later‐life and whether residual associations emerge.

Method

Prospective questionnaires at ages 43‐54 provided menopause age (years since birth until period cessation) and type (surgical/natural). Addenbrooke’s Cognitive Examination (ACE‐III) gave a measure of cognitive state at age 69 (maximum n=913). Cognitive domains were investigated using ACE‐III sub‐domains and cognitive tasks in a neuroimaging sub‐study (age 69‐71; maximum n=246) assessing memory, executive function, attention, visuospatial function, processing speed and non‐verbal reasoning. All cognitive outcomes were standardised. Multivariable regression analyses adjusted for relevant affective, early cognitive, sociodemographic, hormonal, health and genetic covariables, with multiple imputation of missing values using chained equations.

Results

Menopause associated with the following cognitive outcomes: total ACE‐III, ACE‐III verbal fluency, ACE‐III memory, ACE‐III visuospatial function, pre‐clinical Alzheimer’s cognitive composite, response inhibition, and intra‐individual variability in reaction times. Later menopause associated with better performance, while surgical menopause associated with worse performance. After accounting for childhood cognition, associations remained between menopause age and total ACE‐III (β=.012; 95% CI .001, .023), ACE‐III visuospatial function (β=.012; 95% CI .000, .023) and response inhibition (β=.034; 95% CI .008, .061), and between menopause type and response inhibition (β=‐.368; 95% CI ‐.665, ‐.070). With full adjustments, associations persisted between menopause age and ACE‐III memory (β=.011; 95% CI .000, .023). Intra‐individual variability in reaction times also remained associated with menopause age (β=‐.049; 95% CI ‐.079, ‐.019) and type (β=.413; 95% CI .076, .750).

Conclusion

In later‐life, associations emerge between menopause and cognitive domains implicated in dementia (memory, processing speed, attention). Later menopause associates with better performance and surgical menopause with worse. Associations are not fully explained by known predictors of later‐life cognition including childhood cognition and other lifetime covariables accounted for. Further exploration of the link between menopause and dementia risk in women is warranted.
Regional abdominal adiposity is associated with BMI‐related brain regions in middle‐aged adults at high risk of Alzheimer’s dementia
Authors: Golan Sapir , Boccara Ethel , Ravona‐Springer Ramit , Inbar Yael , Yore Iscka , Heymann Anthony , Beeri Michal Schnaider
Published: December 2021

Background

There is evidence for the involvement of midlife obesity in mild cognitive impairment (MCI), dementia, and Alzheimer’s dementia (AD) risk in late life. Obesity is primarily measured by body mass index (BMI), which poorly reflects body fat distribution. Regional abdominal adiposity has been related to inflammation and metabolic syndrome, both consistently linked to the neuropathology of AD and related disorders (ADRD). We examined the relationship between regional abdominal adiposity and regional brain volume, among middle‐aged adults enriched for AD risk due to parental history of AD.

Method

Participants were from the Israel Registry for Alzheimer’s Prevention (IRAP), which follows middle‐aged offspring of AD patients (N=390). At this time, 44 participants (Table 1) were scanned, via magnetic resonance imaging (MRI), for regional abdominal adiposity, including hepatic, pancreatic, and abdominal adipose tissues (AAT, visceral (VAT), and subcutaneous (SAT)). T1‐weighted volumetric brain MRI focused on three regions implicated in obesity and cognitive impairment: para‐hippocampus, amygdala, and inferior frontal gyrus (IFG). Following logarithmic normalization, linear regression was used to examine the association of regional abdominal fat with brain volume adjusting for age, sex, education, and intracranial volume. An additional adjustment for BMI was done to examine whether the associations are above and beyond global adiposity.

Result

Smaller amygdalar volume was associated with the percentage of VAT fat (r=‐0.324, p=0.044) and approached significance for pancreatic (r=‐0.283, p=0.08) and hepatic (r=‐0.307, p=0.057) fat. A smaller para‐hippocampal volume was associated with the percentage of pancreatic fat (r=‐0.317, p=0.05) and hepatic (r=‐0.447, p=0.004) fat, and approached significance for VAT fat (r=‐0.309, p=0.056). Fat percentage was not associated with IFG volume (Table 2; Figure 1).

Conclusion

Greater regional abdominal adiposity was associated with higher amygdalar and para‐hippocampal volumes, already in midlife, regardless of global body adiposity measured by BMI. Regional adiposity affects secreted factors relevant to brain function, suggesting an underlying mechanism. By AAIC 2021, we anticipate 100 IRAP participants will be assessed for regional abdominal adiposity, blood‐based related secreted factors, and brain MRI. These data may lead to the development of age‐specific interventions targeting specific adipose depots, which are expected to prevent or delay neuropathology, cognitive decline, and ultimately AD.
Cerebrospinal fluid and saliva lactoferrin as a diagnostic biomarker for Alzheimer’s disease in a mixed memory clinic population
Authors: Gleerup Helena Sophia , Jensen Camilla Steen , Høgh Peter , Hasselbalch Steen Gregers , Simonsen Anja Hviid
Published: December 2021

Background

The pathological changes in Alzheimer’s disease (AD) and other neurodegenerative disorders begin decades prior to their clinical expression. However, the clinical diagnosis of neurodegenerative dementias is not straightforward. Saliva is an easily obtained source of biomarkers, and previous studies have shown that biomarkers such as amyloid 1‐42 (Ab42), tau, lactoferrin and selected metabolites could be potential biomarkers for the diagnosis of AD and other neurodegenerative dementias. Lactoferrin is an iron‐binding, antimicrobial glycoprotein with a plethora of functions, including acting as an important immune modulator and by having a bacteriocidic effect, all factors which have been shown to be involved in the development and progression of AD. Two previous studies indicated that salivary lactoferrin could differentiate between neurodegenerative dementias. For the first time, lactoferrin levels were measured in the cerebrospinal fluid (CSF) in a consecutive cohort of patients from two memory clinics, and furthermore salivary lactoferrin was evaluated for its differentiation between AD and other neurodegenerative dementias.

Method

From two mixed, memory clinic cohorts, 222 CSF and saliva samples from 71 patients diagnosed with AD, 56 patients diagnosed with mild cognitive impairment (MCI), 75 patients diagnosed with non‐AD dementia and 20 subjects classified as healthy controls (HC), were analysed for lactoferrin. In addition, the association between lactoferrin in CSF and saliva and the concentrations of tau, phosphorylated tau (p‐tau) and amyloid 1‐42 (Ab42) in CSF were addressed.

Result

There was no correlation between CSF and saliva lactoferrin. Furthermore, no statistically significant differences were found in the levels of CSF or saliva lactoferrin between the diagnostic groups. In addition, no significant relationships were found between lactoferrin levels and tau, p‐tau and Ab42, respectively.

Conclusion

For the first time, CSF lactoferrin levels were assessed in mixed memory clinic cohorts. Although lactoferrin levels were quantifiable in CSF and saliva, neither CSF nor saliva lactoferrin could differentiate between neurodegenerative dementias in this study.
Fish intake and MRI burden of cerebrovascular disease in older adults
Authors: Thomas Aline , Crivello Fabrice , Mazoyer Bernard , Debette Stéphanie , Tzourio Christophe , Samieri Cécilia
Published: December 2021

Background

Cerebrovascular disease (CVD), a major contributor of cognitive aging, is characterized by subclinical damage visualized on brain MRI, including covert brain infarcts, white matter hyperintensities (WMH) and dilated perivascular spaces (dPVS). Few protective factors for brain vascular health, that may help prevent stroke and dementia, have been identified so far. Fish intake may prevent ischemic events and small vessel disease. When investigating factors with a pleiotropic effect such as fish, there is interest to capture pathophysiological burden globally, combining biomarkers into a single metric. Here, we investigated the association of fish intake with a global indicator of the MRI burden of CVD among older adults.

Method

This Three‐City Dijon study included 1,623 participants (≥65 years) without history of dementia, stroke or cardiovascular disease, who had completed a Food Frequency Questionnaire and underwent brain MRI with automated assessment of WMH, visual detection of covert infarcts, and grading of dPVS. A global indicator of CVD burden was estimated using a factorial analysis of mixed data; association of fish intake with the indicator was assessed by adjusted linear regression.

Result

The proportions of participants consuming fish less than once a week, once a week, 2 to 3 times and more than 4 times per week were 11%, 37%, 47% and 6%, respectively. The continuous CVD burden indicator, derived from the first dimension of the factorial analysis (32.4% of explained variance), was associated with a higher WMH load, more infarcts and higher dPVS severity. Higher fish intake was associated with a lower CVD burden indicator (P for trend <0.001). Compared to participants consuming fish less than once a week, the CVD indicator decreased by ‐0.19 units (95% CI, ‐0.37; ‐0.005) for those consuming fish 2‐3 times per week and by ‐0.31 units (‐0.59; ‐0.03) for ≥4 times per week. These effect estimates of eating fish at least twice a week were equivalent to having a 4 to 5 years younger brain in terms of vascular health (β = 0.05 units (0.03; 0.06) for each one year increase of age).

Conclusion

Fish consumption may promote brain vascular health before manifestation of overt brain disease.
Objective home sleep profiles differentiate Alzheimer disease from α‐synucleinopathies
Authors: Levendowski Daniel J. , Boeve Bradley F. , Neylan Thomas , Walsh Christine M. , Tsuang Debby W. , Salat David H. , Hamilton Joanne M. , Ruoff Leslie , Payne Sarah , Shprecher David , Lee‐Iannotti Joyce , Westbrook Philip R. , Berka Chris , Mazeika Gandis , St. Louis Erik K.
Published: December 2021

Background

Neurodegenerative disease (NDD) is associated with sleep disturbances, including decreased stage N3 and REM sleep and reduced spindle activity. Further, supine sleep position may impact NDD risk by altering glymphatic clearance. This study evaluated conventional and exploratory sleep metrics in the differentiation of subjects with normal cognition (NC) and patients with Alzheimer’s disease dementia (AD) and alpha‐synucleinopathies (α‐Syn).

Method

Home sleep data were acquired across multiple study sites using the self‐applied Sleep ProfilerTM, including 44 NC subjects (age=69+5.0), 22 patients diagnosed with AD (age=75+7.1) and 25 with α‐Syn (Parkinson’s disease=14, Parkinson’s disease with Dementia or Dementia with Lewy Bodies=11; age=69+6.9). Recordings were auto‐staged and technically reviewed, with 86% of the records having two‐night averages. Logistic regression and Mann‐Whitney U tests were used to characterize group differences based on age, conventional sleep metrics (i.e., sleep efficiency, sleep onset (SO), awakenings, percent of sleep time (%) in REM,N1, N2 and N3, and sleep spindles) and exploratory sleep measures [i.e., % supine, % Light N2 (L2=N2 epochs absent of spindles with K‐complexes and/or alpha or EMG (>40 Hz) intrusion), % NREM sleep with hypertonia (NRSH=>4 consecutive epochs with persistently elevated EMG power relative to delta and theta power) and % atypical N3 (AN3=epochs staged N3 with low theta and sigma power relative to delta, alpha, beta and EMG)].

Result

AD were older than both NC and α‐Syn patients (p<0.005). Both AD and α‐Syn had lower %REM and greater %supine than NC (p<0.005), and %NRSH was greater in α‐Syn than NC or AD (p<0.005). Based on logistic regression, AD was differentiated from NC based on age, %REM, %L2 (p<0.05) and %supine (p=0.06). α‐Syn was distinguished from NC using both conventional (%N3 and SO, p<0.05) and exploratory sleep metric (%AN3 and %NRSH, p<0.05; %supine, p=0.06). Age (p=0.05) and %NRSH (p<0.01) were the only metrics that differentiated α‐Syn from AD.

Conclusion

Objective home sleep profiles hold promise for differentiating NDD patients from NC. The sleep metrics that provided the greatest distinction between NDD and NC were %REM, %supine and NRSH, while only NRSH distinguished AD from α‐Syn patients. Further confirmatory studies are underway.