bluuebunny/crossref_metadata_2025 huggingface dataset:
Practice variation in diagnosing dementia: A nationwide overview of diagnostic work‐ups in Dutch hospitals
Authors: Hafdi Melanie , Richard Edo , van Gool Willem A
Published: December 2020

Background

To date, there is no gold standard for diagnosing dementia and diagnostic strategies vary widely between specialists and hospitals. More insight into diagnostic practice variation can be used to improve quality of diagnostics. Aim: To determine variation in diagnostic strategies between Dutch hospitals.

Method

In the Netherlands, all health insurance claim data are centrally registered. Information on diagnostic ancillary services carried out from 2015 to 2018 was collected via national‐level insurance claims for patients that received a (new) diagnose‐coding for dementia in 2018. Hospitals were included in the analysis if they diagnosed >50 patients with dementia and were divided in academic medical centres (AMC), non‐academic training hospitals (TH) and general hospitals (GH).

Result

71 of 98 (72%) Dutch hospitals fulfilled the inclusion criterion, accounting for a total of 20.073 new dementia diagnoses in 2018. Nearly all patients underwent some form of ancillary diagnostic services (n=20.068) in the preceding 3‐4 years, however frequencies and diagnostic modalities differed widely between hospitals. The range of percentages between hospitals that performed MRI/CT‐imaging ranged from 37 to 99% (median 76.7%) of all patients that were diagnosed with dementia, neuropsychological assessment from 0‐89% (median 31.8%), cerebrospinal fluid examination from 0‐14% (median 2.4%), PET/SPECT‐imaging from 0‐16% (median 6.2%) and electroencephalography from 1‐20% (median 5.8%). The percentage of patients subjected to ancillary diagnostic investigations decreased sharply with increasing age (approximately 2 times for patients >90 years when compared to patients of 70‐80 years old). There were no distinct differences according to gender, or number of patients that were diagnosed, whereas PET/SPECT‐imaging was slightly more frequently used in academic centres (8% in AMCs versus 5% in GHs, p=0.003).

Conclusion

In the Netherlands, diagnostic ancillary methods used vary widely between hospitals both in frequency and modality. This variation may be driven by the flexibility in national guidelines due to limited evidence of diagnostic accuracy and added value of different diagnostic tests, varying doctor and patient preferences and differences in available diagnostic techniques per hospital. Future research could explore this heterogeneity further and help to identify a practice strategy that combines the most benefit with the least burden for patients.
Intensive measurement of cognition to support early detection of cognitive change in individuals at risk of dementia
Authors: Brewster Paul , Rush Jonathan , Ozen Lana , Jacobs Diane M , Kaye Jeffrey , Nygaard Haakon B , Feldman Howard H , Hofer Scott M ,   Canadian Thumbs Up Study Group
Published: December 2020

Background

Cognitive changes in nondemented older adults are best measured longitudinally and relative to individual baselines. Effect sizes of early changes in cognition are small with most traditional measures, and so there is a need for alternative measurement approaches that can improve statistical power to detect change. Remotely administered mobile assessments can address this need by permitting much more frequent repeated measurements, which then permits statistical delineation of early slopes of decline from performance variation associated with extraneous factors (e.g., mood, practice). MyCogHealth is an iOS/Android app for self‐administered cognitive assessments and customizable surveys. Inclusion of MyCogHealth in the Canadian Thumbs Up program (CTU) will permit evaluation of feasibility and utility of intensive measurement designs for capturing early cognitive changes in older adults identified to be at increased risk of dementia.

Method

The CTU Platform Trial Cohort will complete five intensive measurement “bursts” in three‐month intervals using MyCogHealth. Each burst involves brief self‐administered assessments completed twice daily across seven consecutive days. Each assessment includes the Symbol Match test (processing speed), Dot Memory (visual short‐term memory), a digital Trailmaking Test analogue, and surveys assessing state factors that can affect cognition. A pilot cohort (N=17; Mean age=74; Mean MoCA score=28) was followed for 12 months using this protocol to evaluate feasibility and psychometric integrity of the Symbol Match and Dot Memory tests in this design.

Result

In the pilot cohort Symbol Match correlated with Digit Span Forward and the Trailmaking Test (r=.51‐.66). Dot Memory correlated with Backward Digit Span (r=.49), Trailmaking Test (r=‐.59), object naming (r=.64), and visual episodic memory (r=.58). Retest reliability was .80 for Dot Memory and .87 for Symbol Search. Intraclass correlation was .77 for Symbol Search and .42 for Dot Memory. Participant retention was 100% and compliance with burst testing was 94%.

Conclusion

Preliminary results support the feasibility, validity, and reliability of self‐administered burst testing deployed longitudinally. Inclusion of MyCogHealth in CTU should be informative in capturing early slopes of decline in the study cohort. Such early detection of decline will inform more powerful, personalized trials where those at the highest predicted risk would be included and those at lower risk excluded.
The Brain Health Support Program: A web‐based interactive platform to increase dementia literacy and awareness regarding lifestyle factors in at‐risk individuals
Authors: Belleville Sylvie , Nygaard Haakon B , Bherer Louis , Camicioli Richard , Carrier Julie , Anderson Nicole D , Dang‐Vu Thien Thanh , Dwosh Emily , Ferland Guylaine , Harris Elaine , Laurin Danielle , Liu‐Ambrose Teresa , Madlensky Lisa , Miller Lesley , Montero‐Odasso Manuel , Phillips Natalie , Pichora‐Fuller M Kathleen , Robillard Julie , Smith Eric E , Speechley Mark R , Wittich Walter , Chertkow Howard , Feldman Howard H ,   CCNA
Published: December 2020

Background

Prior studies have reported that older adults can benefit from formal educational programs about dementia. Participating in an online educational program focusing on risk and protective factors could potentially increase participants’ dementia literacy, empowerment, and engagement in brain health promotion, which in turn could reduce their dementia risk. The goal is to develop a comprehensive, compelling, and evidence‐based online educational program on risk and protective factors for dementia.

Method

The Brain Health Support Program is being developed as part of the Canadian Consortium on Neurodegeneration in Aging CAN‐Thumbs‐Up initiative. The program is designed to improve dementia literacy, promote lifestyle changes in at‐risk individuals who are cognitively intact or have mild cognitive impairment, and evaluate its effectiveness.

Results

The content is based on the epidemiological literature on risk and protective factors for dementia. The format is determined from a review of web‐based educational programs for older adults and is co‐created with experts, stakeholders and citizen advisors. The program contains eight interactive modules with new content provided weekly over a 12‐month period. The modules contain general information and tips on modifiable risk factors including diet, physical activity, cognitively stimulating activity, sleep, vascular health, social and psychological factors, vision and hearing, as well as information on dementia, stigma, and stereotypes. Participants have access to an individualized risk profile to determine personal goals and are given feedback on lifestyle changes. Content is available in French and English. Changes in dementia literacy, self‐efficacy, attitudes toward dementia and modifiable risk factors will be collected from the platform.

Conclusion

Providing access to scientifically validated education through an interactive web‐based platform is expected to have a positive effect on participants’ attitude, engagement in brain health behaviours and dementia literacy. It might also increase readiness to change and maintain positive lifestyle changes. The content and format are co‐created with users and stakeholders, which should increase its relevance and facilitate future implementation.
Association between polygenic risk score of Alzheimer’s disease and CSF amyloid beta 42 in a cohort of 70‐year‐olds from the general population
Authors: Zettergren Anna , Najar Jenna , Kern Silke , Hardy John , Guerreiro Rita , Bras Jose , Zetterberg Henrik , Blennow Kaj , Skoog Ingmar
Published: December 2020

Background

Recently, it was reported that as much as 45% of cognitively normal 70‐year olds from the general population had pathological CSF levels of either amyloid beta or tau, and the APOE e4 allele was significantly more common among these individuals. However, very few studies have investigated the effect of non‐APOE polygenic risk score (PRS) for Alzheimer’s disease (AD) on CSF biomarkers in representative population‐based samples. The aim of the present study was thus to investigate the relation between AD‐PRS and CSF biomarkers for AD and neurodegeneration in a representative sample of 70‐year‐olds.

Method

A total of 303 individuals belonging to the Gothenburg H70 Birth Cohort Studies were included in the study. Genotyping was performed using the NeuroChip (Illumina) and imputation was done with the Sanger imputation service using the reference panel of Haplotype Reference Consortium data (HRC1.1). A PRS was calculated based on the allele counts of 23 AD risk‐variants multiplied with effect sizes (β‐coefficients) from IGAP. CSF levels of amyloid beta 42, total‐tau, phosphorylated tau, neurogranin and neurofilament light were measured with ELISA. Linear regression models, adjusted for sex and APOE e4 status, were used to analyze the association between AD‐PRS and CSF biomarkers.

Result

An association was found between the AD‐PRS and amyloid beta 42 (p = 0.003), showing a decreasing level of the biomarker with an increasing level of the PRS. No associations were found between the AD‐PRS and any of the other biomarkers. When only including cognitively healthy individuals (CDR = 0; n = 247), the association with amyloid beta 42 was still significant (p = 0.03). There was an interaction between the AD‐PRS and APOE e4 status (p = 0.04); the association between the PRS and amyloid beta 42 was present in e4 carriers only.

Conclusion

Our results show that genetic risk for AD beyond the APOE locus is associated with CSF‐amyloid beta 42, but not with any of the other investigated CSF‐biomarkers, among cognitively healthy 70‐year‐olds recruited from the general population. This finding is in line with the amyloid cascade hypothesis, showing that changed levels of CSF amyloid beta 42 is one of the earliest biomarkers related to AD.
Decreased salivary lactoferrin levels are specific to Alzheimer’s disease
Authors: Sánchez Marta González , Bartolome Fernando , Antequera Desiree , Martín Verónica Puertas , Gonzalez Pilar , Gomez‐Grande Adolfo , Velasco Sara Llamas , Martín Alejandro Octavio Herrero San , Martinez David Andres Perez , Galende Alberto Villarejo , Atienza Mercedes , Palomar Miriam , Cantero Jose Luis , Perry George , Orive Gorka , Ibañez Borja , Bueno Hector , Fuster Valentin , Carro Eva
Published: December 2020

Background

Efforts focused on developing new less invasive biomarkers for early Alzheimer’s disease (AD) diagnosis are substantial. Evidences of infectious pathogens in AD brains may suggest a deteriorated defensive system in AD pathology. Lactoferrin (Lf), one of the major antimicrobial peptides in saliva, is an important oral defensive system that may control pathogen dissemination. In previous results, we demonstrated reduced salivary Lf levels in AD patients.

Method

To assess the specificity and clinical utility of salivary Lf for AD diagnosis, we examine the relationship between salivary Lf and cerebral amyloid‐β (Aβ) load in two different cross‐sectional studies including patients with different neurodegenerative disorders. Participants underwent neurological and neuropsychological examination and saliva sampling, and amyloid‐ PET neuroimaging. Salivary Lf concentrations were measured using ELISA assay.

Result

Two prospective, cross‐sectional, multicenter studies were examined divided in two different cohorts. Study participants for cohort 1 were consecutively enrolled between 2014 and 2018 from the 12 de Octubre University Hospital Neurology Service in Madrid (Spain) and Pablo de Olavide University in Sevilla (Spain). Study participants for cohort 2 were consecutively enrolled between June 2017 and December 2018 as part of the Atherobrain ‐ Heart to Head (H2H) project. Salivary Lf levels were significantly lower in mild cognitive impairment (MCI) and AD patients compared to cognitively normal subjects and frontotemporal dementia (FTD) subjects. The diagnostic performance of salivary Lf in the cohort 1 had an under the curve [AUC] of 0·95 (0·911–0·992) for the differentiation of the MCI/AD group positive for amyloid – PET (PET+) versus healthy group, and 0·97 (0·924–1) versus the FTD group. In the cohort 2, salivary Lf had also an excellent diagnostic performance in the health control group versus prodromal AD comparison: AUC 0·94 (95% CI 0·876–0·989).

Conclusion

Salivary Lf has a very good diagnostic performance to detect AD, as reduced salivary Lf levels shown a clear association to amyloid‐positive biomarker profile. Our findings support the utility of salivary Lf as a non‐invasive and cost‐effective AD biomarker in clinical practice and clinical trials.
Dynamic PET imaging reduces sample sizes to detect longitudinal amyloid accumulation
Authors: Alves Isadora Lopes , Collij Lyduine , Heeman Fiona , Molinuevo Jose Luis , Schmidt Mark E , Lammertsma Adriaan A , Cash David M , Barkhof Frederik , Gispert Juan Domingo ,   the AMYPAD Consortium
Published: December 2020

Background

Detecting amyloid‐β plaque accumulation in individuals who are initially amyloid negative can help understand the earliest stages of Alzheimer’s disease (AD). This study aimed to determine sample sizes that would be needed to detect statistically significant longitudinal changes using semi‐ (standard uptake value ratios; SUVR) and quantitative (distribution volume ratios; DVR) PET measures at global and regional levels.

Method

[11C]PIB scans of 239 cognitively normal (CN) subjects (mean age 63.4 ± 9.3 years) in the OASIS‐3 data‐set, who underwent at least two PET scans, were included. Regional SUVR and DVR were extracted using a cortical composite as target, and cerebellar gray matter as reference region (PUP, https://github.com/ysu001/PUP). PET positivity was defined by Gaussian Mixture Modelling of the global SUVR (SUVR>1.16). Annual accumulation rates were calculated using linear regression, and sample sizes to detect a significant longitudinal change (alpha = 0.05; 1‐beta = 0.80) were determined with the sampsizepwr function in Matlab. The percentage of accumulators (rates of change >2SD of negative group) was also computed.

Result

As expected, rates of change were higher in subjects with positive PET at baseline, and APOE‐ε4 carriership increased accumulation rates in both negative and positive groups (Table 1). Using either metric, orbitofrontal and precuneus displayed the highest rates of change in the negative group. SUVR rendered higher accumulation rates than DVR, but also displayed higher variability. As a consequence, to detect 0.22% early accumulation (mean of negative group), global DVR required N = 584 compared with N = 917 for global SUVR (Figure 1). In addition, DVR classified 13% of subjects as accumulators compared with 9% for SUVR. Finally, precuneus and orbitofrontal regions classify more subjects as accumulators than global SUVR, i.e. 17 and 25%, respectively.

Conclusion

As compared to SUVR, DVR can reduce the sample size needed to detect longitudinal amyloid changes by approximately 40% in amyloid negative populations. Additional improvements in statistical power can be achieved by focusing on precuneus and orbitofrontal regions.
Differential diagnosis of dementia combining web‐based cognitive testing and MRI
Authors: Rhodius‐ Meester Hanneke F.M. , Koikkalainen Juha , Paajanen Teemu , Mahdiani Shadi , Barkhof Frederik , Herukka Sanna‐Kaisa , Hänninen Tuomo , Ngandu Tiia , Kivipelto Miia , van Gils Mark , Hasselbalch Steen Gregers , Mecocci Patrizia , Remes Anne , Soininen Hilkka , Scheltens Philip , van Der Flier Wiesje , Lötjönen Jyrki
Published: December 2020

Background

Differential diagnostics in dementia is challenging. To date, the basic assessment still includes imaging of the brain and cognitive testing with pen and paper. Web‐based cognitive tests however hold potential for standardized and low‐cost screening in clinical workup. How they perform when combined with imaging of the brain is unknown. We therefore evaluated the accuracy of a new web‐based cognitive battery (Muistikko [1]) detecting different types of dementia, when combined with brain MRI, and compared this to traditional cognitive testing and MRI.

Method

We included 229 subjects from two memory clinic cohorts (PredictND and VPH‐DARE), consisting of 188 controls, 29 patients with Alzheimer’s dementia (AD), 7 with frontotemporal dementia (FTD) and 5 with vascular dementia (VaD) (Table 1). All patients performed a traditional cognitive test battery (consisting of MMSE, RAVLT, TMT‐A and B, Animal Fluency), web‐based cognitive testing and had MRI of the brain. Although Muistikko is composed of seven subtasks, only global cognitive score (GCS) was used as defined in [1]. From MRI, multiple imaging biomarkers were defined [2]. Disease‐state index classifier was developed from the predictors [2]. Cross‐validation was used to calculate balanced accuracy (BACC; average of sensitivities for each diagnostic group). Given the class imbalance, we also calculated prevalence corrected accuracy (PACC).

Result

BACC was 66 % and PACC 64% when using the traditional cognitive test battery + MRI. Both BACC and PAC were 69 % when using the web‐based cognitive testing + MRI (Table 2). Of note, since we compare four diagnostic groups, BACC by guessing would be 25%.

Conclusion

This study shows that combining web‐based cognitive tests with MRI data results in high accuracy when separating different types of dementia. The results were comparable with the standard traditional work‐up. Web‐based cognitive testing is therefore a promising tool to support the clinician in the daily challenge of differential diagnostics, especially when combined with MRI data. References: [1] Paajanen, S. et al. Detecting cognitive disorders using Muistikko web‐based cognitive test battery. Alzheimer’s & Dementia 13(7):Supplement,P234‐P235,2017 [2] Bruun, M. et al. Evaluating combinations of diagnostic tests to discriminate different dementia types. Alzheimers Dement 2018 Aug17;10:509‐51.
Examining centiloid quantification against visual assessment using [18F]flutemetamol PET
Authors: Collij Lyduine , Salvadó Gemma , Alves Isadora Lopes , Reimand Juhan , Wink Alle Meije , Zwan Marissa D. , Niñerola‐Baizán Aida , Perissinotti Andrés , Scheltens Philip , Farrar Gill , Buckley Christopher , Molinuevo Jose Luis , Barkhof Frederik , Van Berckel Bart N.M. , Gispert Juan Domingo ,   the ALFA study,   the AMYPAD consortium
Published: December 2020

Background

Determining the presence of amyloid pathology in vivo is possible by visual read (VR) and quantification. VR is the method of reference for clinically assessing amyloid pathology, and guidelines are based on distinguishing positive scans from Alzheimer’s dementia patients from healthy controls negative scans. More quantitative approaches using cut‐off values also focused on identification of early amyloid pathology in preclinical populations. This study investigated whether a VR‐defined cut‐off would perform similarly to recently proposed Centiloid (CL) cut‐offs.

Methods

[18F]flutemetamol PET images of 352 cognitively unimpaired (CU) participants from the ALFA+ and 145 patients from the ADC cohort were included (Table 1). Scans were read by an experienced reader according to the product guidelines, collecting the number of positive regions (0‐5) and the final positive/negative classification. Tracer uptake was quantified with the standard CL pipeline. Using VR as the reference standard, previously proposed CL=12/30 cut‐offs were tested for sensitivity and specificity. In addition, a data‐driven cut‐off was determined using ROC analysis and the Youden Index.

Results

152 (30.6%) scans were read as positive. The CL=30 cut‐off resulted in 80.3% sensitivity and 100% specificity, while the CL=12 cut‐off greatly improved the sensitivity to 95.2% and kept a high specificity at 95.9%. Based on the ROC analysis, a CL=16 cut‐off was found, with both excellent sensitivity (93.9%) and specificity (98.2%) (AUC of .99, 95% CI: .989‐.998) (Figure 1). Mean CL values significantly increased with increasing number of visually positive regions (F=568.10, η
2=.85, p<.01, Figure 2, Table 2). Number of visually positive regions was related to age in the ALFA+ CU population (F=9.17, η
2=.12, p<.01).

Conclusion

Using VR as reference standard, we found a similar CL cut‐off to that proposed by previous work using independent amyloid biomarkers (post‐mortem and CSF). These results illustrate that CL can be as sensitive as VR to early amyloid pathology. Importantly, these results could (at least partially) be attributed the level of experience of the reader and the inclusion of mainly cognitively unimpaired subjects. In addition, our results suggests that it can be of value to visually capture the extent of amyloid burden in addition to negative/positive classifications.
Regular physical activity is associated with greater cortical inhibition in middle‐aged adults: Findings from Barcelona Brain Health Initiative
Authors: España‐Irla Goretti , Albu Sergiu , Morris Timothy P , Redondo‐Camós María , Delgado‐Gallén Selma , Cattaneo Gabriele , Tormos‐Muñoz Josep M , Bartrés‐Faz David , Pascual‐Leone Alvaro ,   Barcelona Brain Health Initiative Group
Published: December 2020

Background

Aging has been associated with changes in the mechanisms of brain plasticity, specifically with the reduction of motor cortex excitability and decreased effectiveness of mechanisms of cortical inhibition (Pascual‐Leone et al., 2011; Lissemore et al., 2018). Emerging evidence suggests that regular practice of physical activity, which can increase cardiorespiratory fitness (Sobol et al., 2016), may prevent age‐related decline in the mechanisms of brain plasticity (Gomes‐Osman et al., 2017). We therefore hypothesized that those who engage in more physical activity would have greater corticospinal excitability and more efficient cortical inhibition.

Methods

Seventy‐eight healthy adults (39 women), between 41 and 65 years old were included in the study. The amount of physical activity was assessed using a self‐reported 5‐point Likert scale where 1 equalled sedentary and 5 equalled engagement in aerobic physical activity >3 hours/week. The peak respiratory oxygen uptake (VO2 peak), aerobic threshold (VT1) and anaerobic threshold (VT2) were measured by cardiopulmonary exercise test with ventilatory gas analyses. Transcranial magnetic stimulation was used to assess resting motor threshold, motor evoked potential (MEP) amplitude and long‐interval intracortical inhibition (LICI), a measure of cortical inhibition.

Results

Spearman’s rank correlation revealed that greater engagement in regular physical activity was associated with higher VO2 peak (ρ=.470, p = .001), VT1 (ρ=.371, p = .001) and VT2 (ρ=.414, p = .001), and higher amplitude of resting MEP (ρ=.287, p = .018). Mann‐Whitney U tests revealed higher MEP amplitude (p =.003) and more efficient LICI (p =.018) in the group who exercised >3 hours/week compared to the sedentary group.

Conclusions

Regular physical activity in middle‐aged adults is related with better cardiorespiratory fitness, greater corticospinal excitability and more efficient cortical inhibitory mechanisms.
Hippocampal connectivity may predict cholinesterase inhibitors response in mild Alzheimer’s disease
Authors: Moraes Adriel Santos , Magalhaes Thamires Naela Cardoso , Lecce Natalie , Teixeira Camila Vieira de Ligo , de Campos Brunno , Rezende Thiago Junqueira Ribeiro , Talib Leda Leme , Forlenza Orestes Vicente , Cendes Fernando , Balthazar Marcio Luiz Figueredo
Published: December 2020

Background

Alzheimer's disease (AD) is a neurodegenerative disease that has been related to impairment of cholinergic system1. Changes in the cholinergic pathways observed in AD would result in severe deterioration of memory3. The aim of this study is to evaluate whether cerebrospinal fluid (CSF) biomarkers (Aβ42, p‐Tau and t‐Tau), hippocampal volumes (HV) and Default Mode Network (DMN) functional connectivity (FC) could predict response to the available treatment.

Method

We evaluated 38 mild AD patients who was using cholinesterase inhibitors (AChEI) at therapeutic doses for, at least, 24 weeks. All subjects underwent clinical evaluation, neuropsychological assessment, MRI at 3 Tesla (Achieva Intera Philips) and CSF biomarkers before or shortly after the onset of cholinesterase inhibitors. They were reevaluated after a minimum period of 24 weeks. CSF biomarkers were evaluated INNOTEST® kits (Fujirebio). Hipoccampal Volumes we assessed by Fressurfer software. DMN functional connectivity was evaluated by UF2C software. Patients were classified according to the MMSE (Mini Mental Status Examination) score before and after the stable use of cholinesterases inhibitors. Patients who remained stable or improved in the MMSE were classified as ‘Responders”; and the others as “Non‐responders”. We performed logistic regression to assess prediction of the proposed biomarkers (CSF, HV and DMN FC).

Result

Logistic regressions did not reveal any statistically significant results in relation to CSF or HV biomarkers. However, the complete model, containing predictors of DMN was significant (X
2 = 11,776, Nagelkerk R2 = 0,375, p = 0.008). Only right hippocampal connectivity predicted AChEI response (p= 0.017), showing that the higher the hippocampus FC, better the response to AChEI.

Conclusion

Right hippocampus FC could predict the response to AChEI in our model. However more controlled studies are needed for safer conclusion.
Plasmatic microRNA profile as biomarkers for the diagnosis of obstructive sleep apnea in Alzheimer’s disease patients
Authors: Carnes Anna , Piñol Gerard , Dakterzada Faride , Targa Adriano , Tahan Nuria , Moncusi Anna , Benitez Ivan David , Barbe Ferran
Published: December 2020

Background

To investigate the potential of microRNAs (miRNAs) as biomarkers for the diagnosis of obstructive sleep apnea (OSA) in Alzheimer’s disease patients

Method

In this prospective, single‐center study (NCT02814045), patients were diagnosed with Alzheimer’s disease according to the National Institute on Aging ‐ Alzheimer’s Association (NIA‐AA) recommendations. In addition, OSA was defined as an apnea‐hypopnea index (AHI) >15 events/h according to overnight polysomnography (PSG). Blood samples were collected at the following morning, and then a RT‐qPCR Taqman Low‐Density Arrays of 768 miRNAs was performed.

Result

The cohort included 29 patients, from which 12 patients were diagnosed as non‐OSA (41.38%) and 17 as OSA (58.62%). The median (SD) age of the individuals was 75.8 (5.99) years and the majority was composed of women (96.6%). We observed a set of 9 miRNAs that provided a discriminatory model of the OSA risk profile. From these, 7 miRNAs were significantly correlated with the AHI, suggesting a role not only as biomarkers for the presence of OSA but also for its severity.

Conclusion

Our preliminary results suggest that there are a set of miRNAs that could be important biomarkers for the diagnosis of OSA in Alzheimer’s disease patients and for the evaluation of OSA severity in those patients. These results should be further confirmed in a validation cohort.
Identification of APOE phenotypes in microglia and neurons derived from isogenic hips cells: A study of the IMI ADAPTED consortium
Authors: Bahnassawy Lamiaa , Buchheit Johanna , Curado Marco Rocha , Ried Janina S. , Sáez María Eugenia , Nicolas Armel , Rao Francesco , Kaplan Charlotte , Mohler Eric G. , Lee Heyne , Untucht Christopher , Korffmann Juergen , Lakics Viktor , Cik Miroslav , Grezella Clara , Brustle Oliver , Peitz Michael , Mañes Santos , Ramaswamy Gayathri , Socorro Alfredo Cabrera , Bakker Margot H.M. , Reinhardt Peter
Published: December 2020

Background

One of the most prominent genetic risk factors for Alzheimer’s Disease (AD) is the Apolipoprotein E (APOE) ε4 allele. Unlike the “neutral” ε3 variant, or the protective ε2variant, the ε4 variant is strongly associated with late‐onset AD, albeit by mechanisms that are not well‐understood.

Methods

To shed light on the biology of APOE in the development of AD, as part of the IMI (Innovative Medicines Initiative) consortium “ADAPTED”, we acquired two human induced pluripotent stem cell (hiPSC) lines, that were isogenically modified to carry the alleles ε2/ε2, ε3/ε3, ε3/ε4, ε4/ε4, as well as a knockout line. Neurons and the phagocytic cells of the CNS, the microglia were differentiated from all ten lines and subjected to thorough phenotyping, including RNA‐seq and proteomics analysis.

Results

Cortical neurons do not secrete apoE under normal conditions and treatment of these cells with microglia‐enriched factors and apoE increased their overall Abeta secretion, without significant differences between the various genotypes. Microglia, on the other hand, secrete large amounts of apoE in varying quantities depending on the APOE genotype. Additionally, microglia carrying the ε4/ε4 genotype have a significantly reduced phagocytic capacity compared to their ε3/ε3 counterparts. These observations were supported by whole transcriptome sequencing, which revealed major differences in inflammatory and phagocytic activity‐related gene expression between the different APOE genotypes.

Conclusions

This unique set of ten isogenic hiPSC lines enabled us to assess the cellular phenotypes in functional human neuronal cells. Microglia omics show changes in an array of AD‐relevant pathways, and being the main producers of apoE, these changes need to be understood in depth. Follow‐up experiments will validate candidate genes that might help design new therapies for APOE ε4 AD patients. Disclosure: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This study was sponsored by AbbVie Deutschland GmbH & Co. KG. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the abstract. Some authors are currently employed by AbbVie and may own AbbVie stock.
Dementia awareness in Southern Switzerland among older adults
Authors: Fadda Marta , Fiordelli Maddalena , Ibnidris Aliaa , Franscella Giovanni , Albanese Emiliano
Published: December 2020

Background

Public awareness of dementia is at the core of the WHO global action plan on the public health response to dementia. Evidence on dementia awareness in cognitively healthy older adults is limited. We measured dementia awareness, acceptance and understanding in a large sample of elders living in the Italian‐speaking part of Switzerland.

Method

Between September and December 2019, 1,364 older adults (65 years or more) living in Ticino were invited to participate in an online survey. We collaborated with a large local association of older adults (Associazione Ticinese Terza Età, ATTE) to recruit participants, and to translate and adapt the Dementia Knowledge Assessment Scale (DKAS), a 25 items Likert scale designed to measure knowledge of dementia from a biomedical perspective. The DKAS was previously validated, its score ranges between 0 and 50.

Result

628 men and women aged 65 to 97 (Mean: 73.3; Standard Deviation: 5.6) participated in the survey. Of these, 61.7% were women, 85.6% were highly educated (baccalaureate and above), and 75.4% retired. 42% of respondents believed that dementia is part of the normal ageing. DKAS scores varied markedly (Mean: 17.7; Standard Deviation: 6.9; range=1‐40), were higher for women (p<0.001), younger (p=0.031) and more educated (p=0.042) participants.

Conclusion

The misconception that dementia is an ineluctable part of ageing was common, and level of dementia awareness markedly varied and was generally low in a large sample of elderly people living in the Italian‐speaking Canton of Switzerland. Our results have important implications for future actions and campaigns to raise awareness about dementia and to assess its effects.
Association between microbiota dysbiosis and endothelial dysfunction in Alzheimer’s disease: An in vivo cross‐sectional study
Authors: Cattaneo Annamaria , Marizzoni Moira , Mirabelli Peppino , Mazzelli Monica , Luongo Delia , Salvatore Marco , Frisoni Giovanni B.
Published: December 2020

Background

Increasing evidence shows that the gut microbiota (GMB) may be involved in the pathogenesis of several brain disorders. Metagenomic data support an association between certain bacterial genera and Alzheimer’s Disease (AD), but the functional dynamics of the gut microbiota remains elusive. This study aimed at evaluating whether inflammatory mediators and bacterial products represent a potential pathogenic link between specific gut bacteria and amyloid pathology in AD.

Method

Seventy‐two older persons with cognitive performance from normal to dementia with brain amyloid status were recruited and stool and blood samples were collected. Bacterial composition of fecal samples was inferred using 16S sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology, https://qiime2.org/). Blood lipopolysaccharide (LPS), short chain fatty acids (SCFAs) acetate, propionate, valerate and butyrate by gas chromatography with flame ionization detector (GC‐FID) and circulating adhesion molecules by flow cytometry bead‐based immunoassay panel. We compared HC, amyloid negative (Amy‐) and positive (Amy+) patients with respect to GMB‐specific variables and endothelial biomarkers.

Result

Metagenomic differences were mainly related to the HC rather than Amy+ or Amy‐. Despite a similar GMB, Amy+ and Amy‐ reported differences in the levels of several blood GMB‐related products: Amy+ had increased valerate (p<.001 vs both HC and Amy‐) and LPS (p=.011 vs Amy‐; p=.031 vs HC) levels while Amy‐ decreased acetate (p<.001 vs Amy+; p=.003 vs HC) and increased butyrate (p<.001 vs Amy+; p=.002 vs HC) levels. Endothelial dysfunction, as indicated by the upregulation of adhesion molecules (NCAM, PECAM‐1, ICAM‐2, PSGL‐1), was observed in Amy+ only (p<.030 vs Amy‐; p<.010 vs HC). High levels of these adhesion molecules were associated with elevated levels of acetate and valerate and low levels of butyrate (0.26<|rho|<0.51, p<.024).

Conclusion

The mechanisms linking GMB dysbiosis and cognitive impairment in the presence or absence of brain amyloid deposition are different. Reduction of butyrate together with increased acetate, valerate and LPS levels may compromise the tissue‐blood barrier integrity, facilitating the AD pathological cascade. Microbiota functional dynamics, more than its composition, may be a potential biomarker of AD and provide new leads for treatments aimed at preventing or delaying neurodegeneration.
Quantifying the synaptic vesicle‐associated protein, VAMP2, to verify changes in cerebrospinal fluid in preclinical stages of Alzheimer’s disease
Authors: Goossens Julie , Dewit Nele , Belbin Olivia , Lleó Alberto , Vanmechelen Eugeen
Published: December 2020

Background

Synapse loss, a pathological hallmark of Alzheimer’s disease (AD), is quantified in the brain using synaptophysin in western blot and immunohistochemistry, while the in vivo imaging compound 11C‐UCB‐J targets synaptic vesicle glycoprotein 2A (SV2A). Both proteins are characteristic of synaptic vesicles (SVs) and are found in the majority of synapses. Since synaptophysin is not stable in CSF or serum, it is not a suitable marker to monitor synaptic integrity in fluids (Schlaf et al., 1998). Vesicle‐associated membrane protein 2 (VAMP2), another SV component critical for vesicular trafficking, was identified as potential fluid surrogate for synapse loss using relative quantification (Lleo et al., 2019). Here, we have developed a new digital immunoassay for VAMP2 and evaluated its CSF profile in 226 samples from the AD continuum. For comparison the more established post‐synaptic marker Neurogranin (Ng) was included, which is expressed in dendrites of excitatory glutaminergic neurons.

Method

The immunoassay (Simoa) for VAMP2 was established using a commercial rabbit mAb and a novel high‐affinity mouse mAb 15E4. CSF was measured in duplicate on the HD‐1 analyzer across cognitively normal controls (n=68), preclinical AD stage 1 (Amyloidosis +, n=31), preclinical AD stage 2 (Amyloidosis +, neurodegeneration +, n=8), prodromal AD (n=80) and AD dementia (n=39). Ng was quantified with ELISA (EUROIMMUN).

Result

The assay was able to quantify VAMP2 in all CSF samples with an average CV below 10%. Three quality control samples had an inter‐/intra‐assay variability below 10%. VAMP2 levels correlated strongly with Ng in all AD stages (r=0.78‐0.96, p<0.0001). VAMP2 (p<0.0001) and Ng (p<0.0001) were decreased by 40% in preclinical AD stage 1. They were both elevated in the prodromal (VAMP2 25%, p=0.0009; Ng 70%, p<0.0001) and dementia group (VAMP2 25%, p=0.014; Ng 50%, p<0.0001).

Conclusion

A novel immunoassay for VAMP2 is capable of detecting changes in different AD stages. CSF changes in VAMP2 and Ng precede clinical symptoms and CSF neurodegeneration markers in the AD continuum. In line with observations that CSF‐tau and CSF‐Aβ abnormality precede plaque and tangle load via PET imaging, future longitudinal studies relating synaptic fluid markers with synaptic PET ligands (i.e. 11C‐UCB‐J) could extend these findings.
Increased Aβ pathology associated with increasing fractional anisotropy in the nucleus basalis of Meynert: A postmortem MRI and histopathology study
Authors: Jonkman Laura E. , Lin Chen‐Pei , Frigerio Irene , Boon Baayla D.C. , Zhou Zihan , Steenwijk Martijn D. , Rozemuller Annemieke J.M. , Schoonheim Menno M. , Bouwman Femke , Van de Berg Wilma D.J.
Published: December 2020

Background

Cholinergic deficiency is an early and key feature of Alzheimer’s disease (AD). Post‐mortem studies have shown accumulation of pathology and cholinergic cell loss in the nucleus basalis of Meynert (NbM). In‐vivo MRI studies have shown decreased NbM volume and microstructural diffusion changes. We aim to connect the two and assess the direct within‐subject association between local Aβ and (p‐)tau burden with MRI volume and diffusion measures of the NbM, using a post‐mortem MRI‐pathology pipeline.

Method

Eleven clinical and pathological confirmed AD (6F, 66y±12) and 11 age‐matched non‐neurological donors (6F, 70y±7) underwent post‐mortem in‐situ 3T MRI. T1‐w for anatomical labelling and DTI for quantification of microstructural integrity by measuring fractional anisotropy (FA) and mean diffusivity (MD). Upon subsequent autopsy, the basal forebrain was selected for paraffin embedding and ChAT, Aβ, and (p‐)tau immunohistochemistry. The NbM was identified on MRI and histology based on strict anatomical boundaries. Study outcome measures were NbM MRI T1 volume, FA and MD, as well as ImageJ analyzed ChAT neuron count, Aβ and (p‐)tau area %‐load. Group comparisons were made using non‐parametric tests. MRI‐histology measures were correlated using Spearman’s rho.

Result

NbM MRI volume was smaller in AD cases than controls (189mm3 ± 36 vs 229mm3 ± 49, p=0.03), but no regional difference in FA or MD was found. Compared to controls, AD cases showed higher Aβ (p=0.015) and (p‐)tau (p=0.003) load in the NbM, but no significant difference in ChAT neurons. All cases taken together, correlations between MRI measures and histology showed a negative association between NbM volume and Aβ (rho=‐0.56, p=0.045) and NbM volume and (p‐)tau (rho=‐0.57, p=0.042). Furthermore, a positive association was found between NbM FA and Aβ load (rho=67, p=0.013).

Conclusion

Compared to controls, an increase in NbM pathology in AD is associated with a decrease in volume without a significant difference in ChAT cell count, leading to compaction of tissue and hence an increase in fractional anisotropy. Further inclusion of cases should shed light on more subtle associations between NbM pathology and MRI measures, such as microstructural changes in cortical projections.
Incidence of dementia and major subtypes in a population‐based cohort of older people in São Paulo
Authors: Lopes Marcos A , Nassar Silvia M , Litvoc Julio , Folquitto Jefferson C , Barcelos‐Ferreira Ricardo , Filho Geraldo Busatto
Published: December 2020

Background

Efforts have been done in order to assess changes over time in dementia occurrence around the world. In developing countries, the scarcity of incidence studies and follow‐up of prevalence studies make the perspective of trends much more imprecise and turn the focus to the primary epidemiological objectives. This study aimed to estimate the incidence of dementia in a community‐dwelling elderly population from São Paulo and its distribution in relation to socio‐demographic and clinical variables and habits.

Method

A two‐phase design was conducted to a representative cluster sample of individuals aged 60 years old and over from three different socioeconomic levels. The screening‐phase consisted of a tested combination of cognitive and functional tests, applied to the subjects and informants in the community. In the hospital phase, Cambridge Examination, imaging and blood exams were performed; the diagnosis of dementia and dementia subtypes was made according to DSM IV criteria. Incidence rates were calculated dividing the number the dementia cases by the amount of time between the prevalence and incidence studies. Incidence rates were expressed in persons‐year, multiplied by 1000, for dementia and subtypes of dementia. The risk of developing dementia was calculated using Cox regression.

Result

From 1370 electable subjects, 678 were accessed to evaluation. Forty‐two subjects were diagnosed with dementia. The incidence rate of dementia was 11.22 persons‐years (95%CI: 8.09 – 15.17). The most incident subtype of dementia was Alzheimer’s Disease: 8.90persons‐year (95%CI: 6.13 ‐ 12.51). Multivariate analysis observed that higher ages, presence of diabetes and presence of MCI amnestic increased the risk of developing dementia; age‐adjusted risk was higher in low frequency of playing games and reading books. The risk of developing Alzheimer’s Disease, exclusively, for women compared to men, was nearly three times higher.

Conclusion

The incidence rate was very close to the other Brazilian study and European, Western and Asian studies. The predominance of Alzheimer’s Disease corroborated the Western studies and probably had a contribution to the higher risk of MCI amnestic in developing dementia. The findings about intellectual habits and female sex should be seen cautiously considering their complexity and the limitations of the present study.
Internet‐based supportive interventions for family caregivers of people with dementia: A systematic review and meta‐analysis
Authors: Leng Minmin , Wang Zhiwen
Published: December 2020

Background

Family caregivers of people with dementia always experience high levels of psychological burden and physical strain, so effective and practical support is essential. Internet‐based interventions can provide convenient and efficient support and education to potentially reduce the physical and psychological burden associated with providing care. This review aimed to (1) assess the efficacy of internet‐based supportive interventions in ameliorating health outcomes for family caregivers of people with dementia, and (2) evaluate potential effects of internet‐based supportive interventions access by caregivers on their care recipients.

Method

An electronic literature search was conducted in the PubMed, Embase, Web of Science, CINAHL, Cochrane Library, and PsycINFO databases to identify relevant studies that were published up to November 2019. The two reviewers worked independently to identify randomized controlled trials (RCTs) that met the inclusion criteria and extracted data independently. The quality of the included RCTs was evaluated using the approach recommended by the Cochrane Handbook for systematic reviews of interventions. Standardized mean difference (SMD) with 95% CI was applied to calculate the pooled effect sizes.

Result

In total, fifteen RCTs met the eligibility criteria and were included in this systematic review. The meta‐analysis showed that internet‐based supportive interventions significantly ameliorated depressive symptoms (SMD = ‐0.20; 95% CI ‐0.31 to ‐0.10; p = 0.0002), perceived stress (SMD = ‐0.36; 95% CI ‐0.53 to ‐0.19; p < 0.0001), anxiety (SMD = ‐0.33; 95% CI ‐0.51 to ‐0.16; p = 0.0002), and self‐efficacy (SMD = 0.19; 95% CI 0.05 to 0.33; p = 0.007) in dementia caregivers. No significant improvements were found in caregiver burden or coping ability. Three studies assessed the unintended effects of internet‐based supportive interventions access by caregivers on their care recipients. The results showed that internet‐based supportive interventions had potential benefits on the quality of life and neuropsychiatric symptoms in care recipients.

Conclusion

Internet‐based supportive interventions were generally effective at ameliorating depressive symptoms, perceived stress, anxiety, and self‐efficacy in dementia caregivers, although negative results were found in some RCTs. Future researchers are encouraged to adopt personalized internet‐based supportive interventions to improve the health of family caregivers and their care recipients.