bluuebunny/crossref_metadata_2025 huggingface dataset:
Spanish translation and adaptation of a family quality‐of‐life survey for families of people with a neurodegenerative disease
Authors: Vicario‐Molina Isabel , Ortega Eva González ,   NEUROQUALYFAM Group
Published: December 2020

Background

One of the main objectives of NEUROQUALYFAM Project is to assess the quality of life and the needs of support of families of people with a neurodegerative disease (ND) in Spain. For this purpose, The Family Quality of Life Survey‐Adapted for Main Caregivers of Persons with Dementia (FQoLS; DiZazzo‐Miller & Samuel, 2011) has been translated and adapted to the Spanish context.

Method

The “International Test Commission guidelines for test translation and adaptation” were taken into account, thus considering the following phases: 1) Two initial and independent translations of FQoLS; 2) Review and synthesis of the translations; 3) Focus groups with families of people with a ND, as well as with health, social and third sector professionals, in order to assess the relevance, clarity and appropriateness of items; 4) Synthesis and agreement by a committee of experts; 5) Backtranslation and comparison with the original items; 6) Pilot study of the consensual version with a sample of families with an individual with a ND.

Result

After the translation and adaptation process, the comprehension and appropriateness of items and response options in the preliminary version were verified. The application of the final version of the instrument and the assessment of its psychometric properties will be conducted in a subsequent phase of the study.

Conclusion

Preliminary results indicate that the instrument has been successfully translated and adapted to the Spanish context. Moreover, this questionnaire seems to be a useful tool for assessing the quality of life of families of patients with ND as well as for designing intervention strategies aimed to optimize support resources and improve families’ health and wellbeing outcomes.

Reference

DiZazzo‐Miller, R., Samuel, P.S. (2011). Family Quality of Life Survey: Main Caregivers of Persons with Dementia. Detroit, MI, USA: Wayne State University.
Age disparities in depression and subjective cognitive decline among a U.S. population‐based sample
Authors: Brown Monique J
Published: December 2020

Background

Subjective cognitive decline (SCD), a risk factor for Alzheimer’s disease (AD), has been theorized as one of the first signs of preclinical AD. Depression has been shown to be a risk factor for SCD among older populations. However, studies examining the age disparities in this association among US population‐based samples are lacking. Therefore, the aim of this study was to examine the potential age disparities in the association between depression and SCD.

Methods

Data for this cross‐sectional study were obtained from the 2018 Behavioral Risk Factor Surveillance System Survey, a nationally representative sample of the US non‐institutionalized population. Individuals answering questions on depression and SCD were included (n=2,742). SCD was operationalized by the question: “During the past 12 months, have you experienced confusion or memory loss that is happening more often or is getting worse?” Multivariable logistic regression models adjusting for gender, race/ethnicity, income, and education were used to determine the associations between depression and SCD by age group (middle aged, aged 45‐59 (n=1,076); “young old”, aged 60‐69 (n=880); “middle old”, aged 70‐79 (n=585); and older, aged 80 and older (n=201).

Result

After adjusting for gender, race/ethnicity, income, and education, those who were aged 45‐59 and reported depression were six times as likely (adjusted OR: 5.89; 95% CI: 3.55 – 9.79) to have SCD. Among individuals aged 60‐69, those who reported depression were four times as likely (adjusted OR: 3.52; 95% CI: 2.06 – 6.01) to have SCD within the past year. Among individuals aged 70‐79, those who reported depression were three times as likely (adjusted OR: 3.11; 95% CI: 1.64 – 5.89) to have SCD within the past year. Among individuals aged 80 and older, those who reported depression were twice as likely (adjusted OR: 2.45; 95% CI: 0.89 – 6.78) to have SCD within the past year.

Conclusion

Depression was associated with SCD among all age groups. However, as age decreased, the strength of the association increased. These findings suggest that SCD interventions addressing depression may be warranted for middle‐aged and older adults. Future research should assess potential pathways between depression and SCD among middle‐aged and older populations.
The ‘fold line’ shaped relationship between age, years of schooling and the Mini‐Mental State Examination scores in the aged 40 years or above: A cross‐sectional study in a rural area of Xi’an, China
Authors: Shang Suhang , Wang Jingyi , Zhang Binyan , Wang Jin , Jiang Yu , Chen Chen , Dang Liangjun , Qu Qiumin
Published: December 2020

Background

MMSE is commonly used to assess cognitive function.

Method

Participants were recruited from a village. The relationship between age, years of schooling (YOF) and MMSE scores was analyzed by multivariate linear regression and stratified analysis.

Result

1799 subjects were enrolled in the study, 1613 subjects aged 40‐69 years, and 186 subjects aged ≥70 years. 222 subjects were illiterate, 568 subjects received 1‐6 YOF, and 1009 subjects received ≥ 7 YOF. After the confounding factors were corrected, MMSE score decreased by 0.093 points (β=‐0.093, P<0.001) for every 1 year of age increasing in the subjects aged 40‐69 years, while that was 0.302 points (β=‐0. 302, P=0.001) in the subjects aged ≥70 years; and increased by 0.863 points (β=0.863, P<0.001) for each additional YOF in the subjects with 0‐6 YOF, while that was 0.179 points (β=0.179, P<0.001) in the subjects with ≥7 YOF. MMSE score expectation equation was established in four subgroups: (1) aged 40‐69 years and 0‐6 YOF: MMSE = 21.282 + 0.198 × gender (female: 0; male: 1) + 0.004 × age (value 40‐69) + 0.787 × YOF (value 0‐6); (2) aged 40‐69 years and ≥ 7 YOF: MMSE = 29.720 + 0.100 × gender (female: 0; male: 1) ‐ 0.078 × age (value 40‐69) + 0.195 × YOF (value 7‐15) (3) aged ≥ 70 years and 0‐6 YOF: MMSE = 39.227 + 1.461 × gender (female: 0; male: 1) ‐ 0.294 × age (value 70‐85) + 0.889 × YOF (value 0‐6); (4) aged≥ 70 years and ≥ 7 YOF: MMSE = 48.000 + 1.651 × gender (female: 0; male: 1) ‐ 0.308 × age (value 70‐85) ‐0.048 × YOF (values 7‐15).

Conclusion

In the population aged 40 or above in rural areas of Xi'an, China, with the increase of age, the rate of decline of MMSE score is higher in people aged ≥70 years than that in those aged 40‐69 years; as the increasing of years of schooling, the growth rate of MMSE scores is higher in people with 0‐6 years of schooling than that in people with ≥7 years of schooling.
Heterogeneity of Alzheimer’s disease: Insight from a novel mouse model of amyloid and tau lesions based on the inoculation of human brain preparations
Authors: Lam Suzanne , Boluda Susana , Herard Anne‐Sophie , Petit Fanny , Duyckaerts Charles , Delatour Benoit , Haïk Stéphane , Dhenain Marc
Published: December 2020

Background

A major challenge in clinical research is to better understand the heterogeneity of AD. Indeed, AD is heterogeneous regarding its origin, neuropathology and clinical expressions. While classical sporadic forms of AD (clAD) evolve over approximately 10 years, the “rapidly progressive form of AD” (rAD) is a non‐genetic aggressive form associated with a rapid clinical decline that evolves over approximately 2 years (Schmidt et al., Arch Neurol. 2011). Several studies have shown that the experimental inoculation of brain samples with Aβ‐ and/or tau pathology into transgenic (tg) mouse models overexpressing mutant human APP or tau promotes either Aβ or tau aggregation in the brain of the recipient animal (Gary et al., Acta Neuropathol Com. 2019). The phenotype of the inoculated brains is moreover reproduced in the recipient host (Watts et al., PNAS. 2014). The aim of this work was to study the impact of the inoculations of rAD versus clAD‐human brain preparations in tg mice mouse models of β‐amyloidosis to explore the mechanisms associated to AD heterogeneity.

Method

Brain samples were characterized pathologically and biochemically. The rAD, clAD, and ctrl (non‐Alzheimer) samples were inoculated in the CA1 region of 2‐month‐old APP/PS1dE9 mice (n = 15‐20/group). At 8 months post‐inoculation, an object recognition task (V‐maze) was conducted to assess memory performance. Aβ deposits (4G8 antibody), tau inclusions (AT8 antibody) and synaptic density were then quantified by immunohistochemistry in the hippocampus.

Result

Mice inoculated with either rAD or clAD brain preparations developed a similar increase of Aβ plaques and tau deposits as compared to ctrl‐inoculated mice. However, only the aggressive form of AD (rAD) led to significant cognitive alterations (Figure 1) and synaptic loss (Figure 2) after 8 months.

Conclusion

APP/PS1dE9 mice inoculated with AD brain preparations are new models to study both amyloid and tau lesions occurrence. Our results suggest that, independently from the amyloid plaque load or the severity of tau intraneuronal pathology, synaptic health variability may contribute to the heterogeneity of AD‐like phenotype. Acknowledgment: We thank France‐Alzheimer and the NeuroCEB/CNR‐prion brain banks.
An integrated epigenetic‐genetic study of neuropathology in the Brains for Dementia Research cohort
Authors: Hannon Eilis , Shireby Gemma , Brookes Keeley J. , Neilson Grant , Dahir Aisha , Walker Emma , Lunnon Katie , Love Seth , Thomas Alan J. , Morgan Kevin , Francis Paul T. , Mill Jonathan
Published: December 2020

Background

In addition to the APOE locus, there has been considerable success in identifying genetic variants associated with an increased risk of developing Alzheimer’s disease (AD). However, there remains considerable uncertainty about the causal genes involved in AD neuropathology and the way in which these loci are functionally regulated by AD risk variants. As the majority of genetic variants are hypothesised to act via disruptions to gene regulation, there is increasing interest in the role of the epigenome, which encompasses a diverse number of chemical modifications to DNA and nucleosomal histone proteins that directly influence gene expression.

Methods

We have profiled DNA methylation in 1,284 brain samples from up to two regions (prefrontal cortex and occipital cortex) from 656 individuals in the Brains for Dementia Research (BDR) cohort. After stringent quality control, we performed epigenome‐wide association studies of four quantitative measures of neuropathology, Braak stage, Thal amyloid stage, Lewy Body stage and Cerad stage. Using matched genetic data available for these samples, performed a genome‐wide association study of methylomic variation to identify DNAm quantitative trait loci (mQTLs). These mQTL were then were integrated with results from AD GWAS, using summary data‐based Mendelian randomisation, to identify loci where DNA methylation is associated with AD. Finally, we generated polygenic risk scores for these samples and performed an epigenome‐wide study of genetic risk for AD.

Results

We identified multiple differentially methylated positions (DMPs) associated with neuropathology and AD polygenic risk score, replicating previous findings at known loci and implicating genes linked to known neuropathological pathways. Integrating our database of mQTLs with summary data from a recent AD GWAS, we report pleiotropic associations between AD and DNA methylation at several sites in the genome, including associations annotated to genes implicated in AD (e.g. SLC39A13, SPI1, MS4A6A, and BCL3).

Conclusions

We identified epigenetic differences associated with detailed measures of neuropathology providing insights on the molecular processes that underlie the disease progression. Furthermore, we characterised the complex relationship between genetic and epigenetic variation, identifying molecular consequences of high genetic risk for AD and prioritising candidate genes for functional follow up.
Alzheimer's polygenic risk score in general population reveals new biomarkers for early diagnosis
Authors: Karkar Slim , Philippe Cathy , Hager Alexa , Mangin Jean‐Francois , Frouin Vincent
Published: December 2020

Background

In aging population, Alzheimer's disease (AD) with its different stages (preclinical, prodromal, mild to severe) has a strong genetic component. For a given individual and using summary statistics available from powerful reference GWAS in Alzheimer’s disease (IGAP, Lambert, 2013), one can compute a Polygenic Risk Score (PRS) for AD, that is a cumulative genetic risk computed with one subject’s genome variants. Using individual's PRS and MRI images in an aging general population like UK Biobank, we could point at imaging markers (endophenotypes) associated with early stages of AD.

Method

16,549 subjects aged 47‐74 from UK Biobank were included in the analysis. Using anatomical T1 MRI images (3T), opening measurements in 123 sulci were extracted with BrainVisa/Morphologist pipeline. Individual's PRS were computed using PRSice and summary statistics from IGAP study and then have been tested for an association with sulcal opening measurements.

Result

We obtained 24 sulci for which opening measurements was either positively or negatively associated with PRS (p < 0.05 after FDR correction). 17 sulcal opening showed increased widening w.r.t PRS with a main focus around the precuneus region, with superior parietal and central sulci. 7 sulcal opening showed opposite effect w.r.t the PRS and are located mostly in the orbital and insula region. See Figure for details.

Conclusion

For neurological disease like AD that have a strong genetic background, the combination of genetics and imaging data in large, aging general population studies like UK Biobank, provides powerful tools to identify new possible early markers of neurodegeneration. Focus on early risk patterns as the ones presented here with a main result on parietal sulcal alterations might facilitate identification of individuals at risk for cognitive decline and possibly support diagnostic procedures for AD.
Predictors of antipsychotic usage among patients with dementias and mild cognitive impairment
Authors: Dhikav Vikas
Published: December 2020

Background

Antipsychotics are commonly used to control a variety of psychotic symptoms e.g. agitation, or aggression and wandering behaviors which are part of behavioral and psychological symptoms of dementia (BPSD) in various dementias and mild cognitive impairment (MCI). Despite their extensive usage in these patients, predictors of their usage are unknown.

Method

A total of 948 patients with memory/cognitive complaints from July 2012 to December 2015 were screened in the present study. Those who met the diagnosis of MCI [Clinical Dementia Rating (score=0.5)] or Diagnostic and Statistical Manual‐IV (DSM‐IV) for diagnosis of dementia were recruited for the present study if they had BPSD and were on antipsychotic drugs. Fazekas White Matter Lesion (WMLs) Score was used to study the WMLs leasion load. BEHAVE‐AD scale was used to rate the severity of cases.

Result

We found a total of 398 patients with dementias and [M:F=330:68] and 550 patients with MCI with the mean age 74±4.1 and duration of illnesses 3.1±1.2 years were studied. In the MCI group [348: 198], the mean age was 64±3.1 and duration of illnesses 2.1±1.2 years. Antipsychotics were most likely used by those with vascular dementia, mixed dementias, AD with white matter lesions, dementia with co morbidities; and those with advanced illness. Patients older than 85 years were more likely to be on antipsychotics. Adverse effects of antipsychotics in elderly with dementias were common.

Conclusion

Certain categories of patients in dementia/MCI groups are more likely to receive antipsychotics than other patients.
Isolation of bioactive components from Corallocarpus epigaeus tuber and inhibitory potential against various molecular forms of acetylcholinesterase
Authors: Loganathan Chitra , Sakayanathan Penislusshiyan , Thayumanavan Palvannan
Published: December 2020

Background

In human, acetylcholinesterase (AChE) is involved in cholinergic neurotransmission. AChE exhibits as different globular form such as G4 (tetramer), G2 (dimer) and G1 (monomer). For the most part of the adult brain G4 forms is present. Nevertheless, under dementia such as Alzheimer’s disease (AD) conditions, the ratio between G1 and G4 form is increased which is involved in disease progression. Inhibition of AChE is considered important therapeutic intervention to overcome the AD. Corallocarpus epigaeus comes under the family of Cucurbitacea has known for the biological properties such as anti‐snake venom, analgesic, anthelminthic properties and antidiabetic activity. Identifying natural compounds with AChE inhibition is considered important for AD treatment. In the present study, bioactive fraction extracted from tuber of C. epigaeus was investigated for its inhibition against different molecular forms of AChE in in vitro.

Method

Dried tuber powder of C. epigaeus was extracted using various solvents sequentially by increasing polarity in Soxhlet apparatus. Methanol extract was further purified by silica column chromatography. The partially purified fraction was studied for the inhibition against different molecular forms of AChE. Kinetic analysis was carried out to determine the type of inhibition and inhibitor constant. The active compounds in partially purified fraction were determined using gas chromatography mass spectrum analysis (GCMS).

Result

Partially purified fraction of methanolic extract of C. epigaeus tuber inhibited all the molecular forms (G1, G2 and G4) of AChE at microgram per milliliter concentration. Kinetic analysis revealed the mixed type non‐competitive mode of inhibition with low Ki value. GCMS analysis 4H‐pyran‐4‐one, 2,3‐dihydro‐3,5‐dihydroxy‐6‐methyl and alpha‐linolenic acid as major constituents in the extract.

Conclusion

The bioactive components in tuber of C. epigaeus inhibited AChE in in vitro. This is the first report on the inhibitory effect of C. epigaeus tuber extract against AChE. Further in vivo studies are necessary to understand the anti‐dementia effect of C. epigaeus.
CAIDE risk score for the prediction of dementia risk in Mexican elders: 10/66 Dementia Research Group, population‐based study in Mexico
Authors: Salinas‐Contreras Rosa Maria , Acosta‐Castillo Gilberto Isaac , Sosa‐Ortiz Ana Luisa
Published: December 2020

Background

CAIDE (Cardiovascular Risk Factors, Aging, and dementia) Dementia Risk Score was developed to identify subjects with risk for developing dementia; using cardiovascular risk factors for dementia. CAIDE has showed to have a good predictive value. Mexican elders have different risk factors for dementia; the use of this type of score could be a good alternative to detect subjects at risk and implementing prevention strategies.

Method

We include 1,111 subjects of >65 years of age, without cognitive impairment and who had the information complete to calculate CAIDE [age (< 47, 47‐53, >53 years old), gender, education (> 10 years, 7‐9 years, < 7 years), systolic blood pressure (<140 or >140mmHg), body mass index (<30 or >30 kg/m2), the auto‐report of dyslipidaemia (the original CAIDE use only hypercholesterolemia) and physical activity. Diagnosis of dementia after the follow‐up was according to 10/66 algorithms, we determinate the predictive properties of CAIDE score.

Result

Those with a CAIDE score of 6‐7 showed a sensitivity of 66.23%, specificity of 34.7% and the 37.63% of proper classification at three years of follow‐up; for those with score of 8‐9, had a sensitivity 24.68%, specificity of 73.69% and the 69.18%, and for those with a score 10‐11, shown a sensitivity of 5.19%, specificity of 93.5% and the 85.4% of proper classification.

Conclusion

CAIDE score show a good specificity and sensibility. CAIDE scores of 6‐7 showed the best sensitivity but the 8‐9 scores obtain the best specificity. But we should consider different things for example we population have > 65 years old, this conditioning all our sample to obtain 4 points, and we use self‐report for some measures. CAIDE does not include diabetes, which has demonstrated to be an important risk factor for dementia in our population.
Proteogenomic analysis of cerebrospinal fluid reveals causal role of proteins from the autophagy‐lysosome pathway in Parkinson’s disease
Authors: Yang Chengran , Farias Fabiana H.G. , Harari Oscar , Rhinn Herve , Cruchaga Carlos , Benitez Bruno A.
Published: December 2020

Background

Integrating genetic variants associated with protein levels (protein quantitative trait loci; pQTLs) with variants from genome‐wide association studies (GWAS) using Mendelian randomization approaches has uncovered a causal role of previously unsuspected proteins in several diseases. We have successfully applied a combination of targeted proteomic and genomic approaches to the cerebrospinal fluid (CSF) of Alzheimer Disease (AD) patients to identify multiple novel genetic associations. However, there are currently no proteogenomic studies in Parkinson’s Disease (PD).

Methods

We used the SOMAscan 1.3k Assay (∼1,305 SOMAmers) in ∼1015 samples from the ADRC‐WUSTL. SOMAscan data from the Parkinson's Progression Markers Initiative cohort and Sasayama D, et al 2017 were used as replication cohorts. After stringent QC steps were applied to SOMA data, each SOMAmer was log10 transformed and standardized to zero. We used linear additive genetic regression models adjusted for age, sex, genotyping array and the first two principal components using Plink 1.9. We used the R package MendelianRandomization to integrate our CSF pQTL variants with PD‐related SNPs from the 2019 METAPD GWAS.

Results

We found significant cis‐pQTLs for Cathepsin B (p = 3.6 × 10−27), Alpha‐L‐iduronidase (p = 3.4 × 10−41) and Galactin‐3 (p = 2.7 × 10−41). MR found significant causal associations of PD risk with pQTLs for IDUA (b = 1.2, p = 5.0 × 10−6), CSTB (b = ‐1.4, p = 2.7 × 10−4) and Galactin‐3 (b = ‐1, p = 4.0 × 10−2). Most importantly, we found an association with progranulin (PGRN) trans‐pQTLs (p = 2.5 × 10−9). This association was replicated in the PPMI cohort (p = 1.9 × 10−9), and MR confirmed the significant causal link of PGRN (b = 4.6, p = 1.0 × 10−4) with PD. The PGRN pQTL in CSF is located in the LRRK2 gene locus. This SNP is also associated with the CSF levels of proteins from two additional PD‐associated genes CTSB (p = 1.6 × 10−3) and glycoprotein nmb (GPNMB, p = 1.5 × 10−4).

Conclusion

Our proteogenomic approach identified LRRK2 as a genetic modifier of three additional PD‐associated proteins in CSF. MR analyses confirmed the causal link of proteins from the autophagy‐lysosome pathway with PD. Our data provide new biological insights into how LRRK2 modifies PD risk and novel markers for screening of LRRK2 kinase activity.
Identifying gene expression signatures in individuals with minimal cognitive impairment in the presence of advanced Alzheimer's disease pathology
Authors: Gaur Pallavi , De Jager Philip L. , Menon Vilas
Published: December 2020

Background

The pathological hallmarks of Alzheimer’s disease such as amyloid plaques and neurofibrillary tau tangles are usually associated with the primary clinical manifestation of cognitive decline. Recent studies implicate that a subset of “resistant” individuals have high burden of AD pathology, yet do not exhibit dementia (cognitive decline). Here, we compared the publicly available gene expression profiles of these resilient individuals and susceptible individuals (showing both AD pathology and cognitive decline) in dorsolateral prefrontal cortex (DLPFC) brain tissue obtained from individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP).

Method

We conducted bulk RNA‐Seq analysis on data from the DLPFC of 239 individuals with differing AD pathological findings and clinical consensus diagnosis. This data set is available through the Synapse portal (AMP‐AD consortium). The patients were subdivided into four groups of control, weakly resilient, strongly resilient, and susceptible, according to their degree of pathology (Braak stage) and clinical cognitive diagnosis. The control group included individuals with no cognitive impairment and initial braak stages; 0 and 1. The weakly and strongly resilient groups included individuals with no and mild cognitive impairment with advanced Braak stages respectively, while the susceptible group comprised individuals with AD‐dementia and advanced tauopathy (Braak stage>4). We used DESeq2 between these groups with a multiple factor approach that corrected for sex and age of death.

Result

Our findings provide insight into genes that may be attributable to weak or strong resilience in the presence of relatively advanced AD pathology. Some of these candidate genes, such as SERPINA5 and GIPR, have previously been associated AD pathology and other neurodegenerative diseases, but we also identified a set of less well‐characterized genes that may be involved in cognition specific contributions to AD resilience.

Conclusion

Our study recapitulates genes with known associations with AD pathology, and also identifies new candidate genes and pathways worth pursuing further as potential therapeutic targets to mitigate cognitive decline associated with AD. As ongoing proteomics and snRNA‐seq data is generated, these candidates may be further refined through an integrative approach, yielding new insights into pathways involved in AD pathology‐mediated decline and cognitive resilience.
Longitudinal assessment of cognitive decline in the Amish
Authors: Song Yeunjoo E. , Miskimen Kristy , Laux Renee A. , Fuzzell M. Denise , Fuzzell Sarada L. , Sewell Jane L. , Miller Sherri D. , Adams Larry D. , Caywood Laura J. , Prough Michael , Close Jason E. , Herington Sharlene D. , Slifer Susan H. , Ramos Jairo , Vance Jeffery M. , Cuccaro Michael L. , Ogrocki Paula` K. , Lerner Alan J. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L.
Published: December 2020

Background

The Modified Mini‐Mental State (3MS) is a widely used measure of global cognition. The Old Order Amish are both genetically and environmentally homogeneous, with similar years of formal education across the population. Here, we investigated the longitudinal course of cognitive function as measured by the distribution of 3MS in the Mid‐Western Amish.

Method

After extensive QC, the 919 subjects with both baseline 3MS and AD status were analyzed. The change from 1st to 2nd measurement was used as the main longitudinal trait of interest. Mean decline differences in 4 baseline age groups (<70, 70‐80, 80‐90, >=90) were assessed. The differences in the average longitudinal decline of 3MS between AD cases and controls was assessed using Kolmogorov‐Smirnov tests and ANCOVA adjusted for age at exam and sibship.

Result

The overall baseline mean 3MS score was 89.52 [42, 100] at the mean age of exam 75.52 [60, 99]. The overall annual rate of decline was ‐0.3 [‐5, 5] from 1st to 2nd measurement (n=242) and ‐0.6 [‐2.1, 1.3] from 2nd to 3rd measurement (n = 23). The annual rate of decline was ‐0.96 [‐4, 1.7] in AD cases (n=18), ‐0.01 [‐5, 5] in AD controls (n=180) and ‐1.08 [‐5, 0.7] in an ‘Unclear’ group (n = 44). The most rapid annual decline of the 3MS was in age 80 to 90 group and the decline rate was significant (p‐value=0.004) compared to the lowest age group (<70) overall and in AD cases. In the Unclear group, the rate of decline was greatest in age 70 to 80. However, in the control group, cognition improved, with a 1.29 [‐1, 5] annual increase in age 80 to 90. The age and sibship adjusted differences in decline were significant (p‐value<2e‐10) between AD cases vs. controls as well as between Unclear vs. controls.

Conclusion

We explored the changes of 3MS scores over time and demonstrated different patterns of decline by age and AD status in the Amish. Our study is the first in this homogeneous Amish population, providing a better understanding and insight into the cognitive decline examining the change in 3MS over time.
Association of depressive disorder with the cognitive performance of Mexican older adults with type 2 diabetes mellitus
Authors: Ortega‐Ramos Alicia , Salinas‐Contreras Rosa Maria , Acosta‐Castillo Gilberto Isaac , Sosa‐Ortiz Ana Luisa
Published: December 2020

Background

Type 2 diabetes mellitus (T2D) and depression have both become pandemics over the last years. Both of these conditions have also been associated with signs of systemic inflammation, decreased insulin sensitivity, and autonomic dysfunction, all identified as risk factors for cognitive impairment and dementia. Our aim in this study was to explore the effect of depressive symptoms in the cognitive performance of Mexican older adults diagnosed with with T2D.

Method

We analyzed differences in global cognition (using the COGSCORE instrument) of adults aged 65 and over, with T2D, with a three‐year follow up within the 10/66 Dementia Research Group protocols in Mexico. T2D was diagnosed with glucose levels at baseline equal or greater than 126 mg/dl, and/or with self‐report of diabetes. Depression diagnosis was based on the International Classification of Diseases glossary version 10 (ICD‐10).

Results

The total sample consisted of 441 older adults people with T2D. 65% were women. The majority (72%) were outside glycemic control levels, 45% were overweight and 27% were depressed. In termos of cognitive performance, there was no significant difference in subjects with diabetes and depressive symptoms (p>0.47). When comparing the cognitive performance, there were differences between 1) the ages of 75 and 79 (p<0.052) and 80 or more (p<0.013) with the group of 65‐69 years; and 2) between those with low or normal BMI compared to those with obesity (p>0.56). Variables such as depression, area of study, educational level, marital status, and mass index showed no statistical significance.

Conclusion

In this study, we found that in a Mexican population with T2D the presence of depression did not show a significant effect on cognitive performance, which is controversial with other studies. Interestingly, those who were underweight or had a normal BMI had a decrease in cognitive function, so we must pay attention to mental health but also complement it with nutrition and establish prioritary intervention measures that allow weight control, decrease chronic degenerative diseases, and that could consequently reduce cognitive impairment.
Recruitment strategies for the genetics of Alzheimer disease in the Puerto Rican population
Authors: Silva Concepcion , Mena Pedro Ramon , Tejada Sergio , Adams Larry D , Rodriguez Vanessa C , Celis Katrina , Prough Michael , Bussies Parker , Sierra‐Lopez Carolina B , Contreras Maricarmen , Manrique Patricia , Feliciano Nereida I , Chinea Angel , McCauley Jacob L , Acosta Heriberto , Vance Jeffery M , Cuccaro Michael L , Beecham Gary W , Pericak‐Vance Margaret A , Feliciano‐Astacio Briseida E
Published: December 2020

Background

With over 5.1 million individuals, the Puerto Rican population makes up over 1.5% of the US population and is the 2nd largest Hispanic/Latino population in the continental US. There are an estimated of 60,000 cases of AD on the island. The Puerto Rico Alzheimer's and Related Dementias Initiatives (PRADI) cohort will both leverage and complement existing AD Resources, the Alzheimer Disease Sequencing Project (ADSP) with the inclusion of a diverse and underrepresented population. At present, the cohort consists of a total of 935 total participants including individuals from 115 multiplex AD families. There are 418 cases of dementia, 217 mild cognitive impairment, and 300 unrelated and family‐based controls.

Method

We examined the most successful strategy to recruit cases and controls as well as multiplex families for both case/control and family‐based genetic studies. We began by engaging a wide range of stakeholders across the island. The core activities of our team include relationship building, partnership development and maintenance, and coalition building. For the community outreach, we utilize mass media like newspapers, radio interviews, and focal group presentations and engaged the following stakeholder groups: Alzheimer disease day care centers, elderly housing in San Juan, senior day care centers, non‐profit organizations, private neurology offices, and other community‐based organizations such as the Alzheimer’s Association.

Result

The percent of patients recruited through each stakeholder group were 45.76% (428/935) from community outreach, 34.33% (321/935) from private neurologist practices, 18.93% (177/935) from senior day care centers and 0.96% (9/935) from Alzheimer disease day care centers. The mean age and standard deviation of cases and controls were 78.22 years (±9.37) and 70.84 years (±7.92) respectively. Examining the data with respect to multiplex family structure, we found that 53.77% of the families (including the largest families) came from private physician referral.

Conclusion

Partnering with diverse stakeholders and building coalitions proved to be effective as an outreach method for recruitment. Private physicians remain an excellent source for the identification of multiplex AD families for family‐based genetics study. Outreach community‐based approaches are highly successful mechanisms to educate and engage participants in genetic research.
Use of lipid lowering drugs in cognitively impaired patients
Authors: Van Gils Aniek M , Wiersinga Julia HI , de Schraaf Sara AJ Van , Trappenburg Marijke C , Peters Mike JL , Meester Hanneke FM Rhodius‐ , Muller Majon
Published: December 2020

Background

Dementia and cardiovascular disease(CVD) are closely linked and share common risk factors. High cholesterol levels are a major risk factor for CVD and lipid‐lowering drugs(LLD) have proven to reduce this risk but are also associated with multiple side effects. Frail older patients, among them patients with cognitive impairment, are possibly less likely to experience benefit from LLD due to shorter life‐expectancies. However, there is a lack of consensus whether to continue or withdraw LLD treatment in this patient group. In this study, we examined LLD prescribing patterns for older patients(frail/non‐frail, with/without CVD) at different levels of cognitive impairment.

Method

We included data of 271 memory clinic patients with a diagnosis of dementia(n=146), mild cognitive impairment(MCI,n=80) and subjective cognitive decline(SCD,n=55) from the Amsterdam Ageing Cohort(AAC); mean age was 80(±5) yrs, 49% was female. Prevalence of LLD use was assessed for patients with and without CVD and stratified according to age(≤80,>80yrs), polypharmacy(<5,5‐8,>8 drugs) and physical frailty(gait speed<0.8,≥0.8m/s). LDL‐c levels were measured; patients with an LDL‐c level<2.5mmol/L were considered ‘on‐target’.

Result

In patients with CVD, LLD use in SCD, MCI and dementia patients was 45%, 61% and 69%; 78‐90% of these patients were on‐target. In patients without CVD, LLD use in SCD, MCI and dementia patients was 20%, 41% and 19%; 60‐71% of these patients were on‐target. No significant differences were found after stratification. Logistic regression analyses showed that, compared to SCD patients with CVD, dementia patients with CVD were more likely to use LLD; OR(95%CI) 3.2(1.0;9.8). Further, MCI patients without CVD were more likely to use LLD, compared to SCD patients without CVD; OR(95%CI) 8.6(2.1;35.1). These associations were independent of age, sex and multiple confounders.

Conclusion

Contrary to our expectations, patients with cognitive impairment(with/without CVD) used more LLD than patients with SCD. This relation was not explained by old age, polypharmacy, or physical frailty. Our study provides insight in the current prescribing patterns of LLD in older patients visiting a memory clinic. Future research should focus on the efficacy of LLD use in older patients with cognitive impairment, in order to make a more applicable guideline in whether and when to continue or withdraw LLD in cognitive impaired patients.
Cognitive and clinical outcome measures for Alzheimer's disease prevention trials in adults with Down syndrome
Authors: Strydom Andre , Baksh Asaad , Hithersay Rosalyn , Aschenbrenner Andrew J. , Jaeger Judith , Carter Ben , Wijeratne Peter A , Alexander Daniel C. , Hassenstab Jason ,   Horizon21 Consortium
Published: December 2020

Background

Adults with Down syndrome (DS) are at ultra‐high risk for developing Alzheimer’s disease (AD) due to APP gene triplication on chromosome 21. There is interest in conducting trials of treatment that can delay or prevent onset of disease in at‐risk individuals with DS. Reliable outcome measures are required to demonstrate clinical benefit of treatment in a population with premorbid cognitive impairments that affect their performance on cognitive outcome measures. We aimed to identify the most efficient clinical and cognitive outcomes for prevention trials of AD in DS.

Methods

Analysis of cognitive data based on different test batteries from several recent longitudinal cohort studies of AD in DS in Europe and the US (n >300 with 2 years of follow‐up data), using staging and E‐Max models and other statistical methods.

Results

The age range within which cognitive decline can be first reliably observed in DS adults who do not yet have dementia is around age 45; this varies by outcome measure, with memory, attention, orientation and some verbal tasks being the most feasible and reliable tests for prevention trials. We will report effect sizes for these outcome measures to inform trial design.

Conclusions

Trials of treatment to prevent or delay AD in DS individuals using cognitive measures as primary outcomes are feasible if targeted at individuals within age ranges where decline can be first observed, but effect sizes (and sample sizes) vary by outcome measures selected.
Differential association between tau pathology and longitudinal cortical atrophy in subtypes of Alzheimer’s disease
Authors: Mohanty Rosaleena , Ferreira Daniel , Westman Eric
Published: December 2020

Background

Tau neurofibrillary tangle pathology and cortical atrophy progress at different rates when investigated cross‐sectionally or retrospectively (LaPoint 2017). However, convergence of the two over time remains unclear, especially in the subtypes of AD, which could inform about the underlying neural mechanisms. Here, we studied the association between tau pathology with positron emission tomography (PET) and cortical atrophy with retrospective and prospective structural magnetic resonance imaging (sMRI) in Alzheimer’s disease (AD) dementia. We identified subtypes using both modalities to compare their temporal evolution.

Methods

We identified 383 participants from the ADNI database, which comprised of 30 Aβ+ AD dementia patients, 54 Aβ+ prodromal AD patients, 99 Aβ+ preclinical AD and 200 Aβ‐ healthy individuals (HC). All subjects had tau PET (AV‐1451) and concurrent sMRI (T1‐weighted). Additionally, retrospective and prospective sMRI were available. Preliminarily, we analyzed data from the AD dementia group. Tau PET and longitudinal sMRI were preprocessed to generate regional measures (Desikan 2006) of partial volume corrected standardized uptake value ratio (SUVR) (Greve 2016) and cortical volume, thickness respectively. AD subtypes were characterized by regional volumes and tau SUVR as in a previous study (Byun 2015). Four subtypes were identified: typical AD (TAD), limbic predominant (LP), hippocampal sparing (HS) and minimal atrophy (MA). We investigated the association between tau SUVR and longitudinal cortical thickness in AD dementia and the four subtypes.

Results

In the preliminary analysis, we observed a significant negative association between tau SUVR and longitudinal cortical thickness (baseline and prospectively) in the entorhinal cortex. Significant association between tau SUVR and cortical thickness was also observed in temporal and parietal areas prospectively. Additionally, subtypes identified based on tau PET and sMRI did not always coincide at baseline, but prospective tracking was indicative of potential convergence between the two (Figure 1).

Conclusion

The association of increased tau PET binding with prospective cortical thinning suggests that including prospective imaging is critical to track disease progression. Preliminary evidence suggests that the convergence between tau pathology and cortical atrophy could occur at different rates in different subtypes. Learning subtype‐specific trajectory would be valuable for the design of disease‐slowing/modifying clinical trials.
Early alterations of hippocampal gabaergic synaptic properties induced by Aβ42 oligomers
Authors: Hidisoglu Enis , Chiantia Giuseppe , Franchino Claudio , Marcantoni Andrea , Carbone Emilio
Published: December 2020

Background

Synaptic dysfunction is one of the earliest hallmarks of Alzheimer’s Disease (AD). It is well known that the oligomeric form of amyloid β protein (Aβ42) rather than fibrils or plaques is the cause of the synaptic abnormalities and cognitive impairments associated with AD. To date, there are no comprehensive electrophysiological studies that investigate the neuronal mechanism of Aβ42‐induced synaptic changes and there is an impressive lack of information on how Aβ42 affects the elementary parameters involving GABAergic synaptic function.

Method

To reveal the effects of Aβ42 on GABAergic synapses, we recorded miniature and evoked inhibitory postsynaptic currents (mIPSC and eIPSC, respectively) in c57bl6 mice embryo hippocampal neurons. mIPSC analysis and eIPSC related analysis such as paired‐pulse ratio, cumulative eIPSC amplitude and multiple probability fluctation analysis were performed to evaluate elementary parameters associated with synaptic transmission, such as unitary conductance of GABAAreceptors, number of release sites, release probability, and size of readily releasable pool.

Result

We found Aβ42 increased the frequency and amplitude of miniature currents as well as the amplitude of eIPSCs. When we focused on paired pulse ratio (PPR) we found that it was not changed by Aβ42, suggesting that GABA release probability was not affected by this oligomer. On the other hand, a more detailed study of the presynaptic effects induced by Aβ42 by mean of multiple probability fluctuation analysis (MPFA) and cumulative amplitude analysis has shown an increase in the size of the readily releasable pool (RRP) and number of release sites (N) without any changes of the release probability (p).

Conclusion

Our results clarify the early effects induced by Aβ42 on GABAergic synapses by focusing on their pre‐ and postsynaptic site and contribute to address the development of new therapies for the treatment of AD. This project was supported by the European Molecular Biology Organization (EMBO). Project ID: EMBO‐7835.
Review and analysis of the Spanish regulations on health and social care of people with neurodegenerative diseases and their families
Authors: Valverde Eva María Picado , Ortega Eva González ,   NEUROQUALYFAM Group
Published: December 2020

Background

Neurodegenerative diseases (ND) constitute a problem of great magnitude, seriousness and complexity that require actions in the diverse areas of the Health and Social System (Ministerio de Sanidad, Servicios Sociales e Igualdad, 2016). These actions must cover the basic needs of patients and their families, while improving their care and quality of life. Given this situation, the aim of this study is to carry out a detailed review of the current national and regional regulations regarding health and social care of people with ND and their families.

Method

After a systematic review of 102 regulatory measures in Spain and in the Autonomous Community of Castile and Leon, those failing to consider the family of the person with ND were discarded. Finally, 35 instructions related to ND in terms of health and social services were analyzed and classified according to their scope (9 state regulations, 16 autonomous community regulations and 10 approved strategies).

Result

The analyses showed that: (1) only 34% of the regulatory instructions include contents that are directly or indirectly related to the quality of life of the families of these patients; (2) analyzed instructions do not specify how to coordinate resources and services in the health and social welfare sector for the care of people with ND and their families.

Conclusion

This study shows the lack of regulations in our region and country that specifically focus on the families of people with ND, as these relatives are not deemed to be direct beneficiaries. Likewise, there is a lack of specificity regarding the coordination of the services and resources for patients and their families. Reference: Ministerio de Sanidad, Servicios Sociales e Igualdad. (2016). Estrategia en Enfermedades Neurodegenerativas del Sistema Nacional de Salud. Madrid: Ministerio de Sanidad, Servicios Sociales e Igualdad.
Domiciliary Alzheimer visiting in Down syndrome pilot project: Preliminary results
Authors: Valldeneu Sílvia , Barroeta Isabel , Altuna Miren , Videla Laura , Benejam Bessy , Estellés Teresa , Fernandez Susana , Lleó Alberto , Blesa Rafael , Fortea Juan , Carmona‐Iragui Maria
Published: December 2020

Introduction

People with Down syndrome (DS) are at ultra‐high risk of developing Alzheimer’s disease (AD). A comprehensive health care approach is needed to enable an early diagnosis and an individualized follow up. The Alzheimer‐Down Unit developed a health plan which is offered to every adult with Down syndrome in Catalonia and which includes annual neurological and neuropsychological assessments together with clinical support and social counseling when needed. Within this plan, the “Domiciliary Alzheimer Visiting in Down syndrome” (DAVIS) pilot project adds domiciliary visits to bring closer this plan to those candidates who are not able to come to our site. In the present study, we analyze the preliminary results of this project.

Methods

Pilot observational cross‐sectional study. We contacted occupational centers /residences which included users with Down syndrome and we organized the visit of a neurologist and a neuropsychologist from our team. Candidates and their caregivers were informed about the health plan and those who accepted to participate were assessed. According to their cognitive status, they were classified into 3 groups: without cognitive impairment (aDS), prodromal AD (pDS) or AD dementia (dDS). Subsequently, a physically present or telephonic follow‐up visit, together with the option of collaborating with Primary Care, was offered. Participation in biomarkers research projects was also proposed.

Results

Between October 2018 and December 2019 we assessed 92 participants (mean age 42.5, 48.9% males) classified as aDS (77.1%), pDS (4.4%) or dDS (18.5%). The 67.4% and the 28.3% of the participants were recruited to continue with the physically present or telephonic follow‐up, respectively. A 10.9% of the participants agreed to collaborate on research projects.

Conclusions

The DAVIS pilot project facilitates the dissemination of our comprehensive health plan for adults with DS in Catalonia. Its clinical application allows the diagnosis of new cases of AD and brings closer research to the adult population with DS. The DAVIS pilot project emphasizes the need of social and health care improvements for adults with DS; however, an extended DAVIS project will generate solid data to influence on health policy and, potentially, to improve the people with DS and their caregivers quality of life.