bluuebunny/crossref_metadata_2025 huggingface dataset:
Process evaluation of the FindMyApps program trial: A tablet computer‐based intervention for self‐management and meaningful activities for people with dementia
Authors: Beentjes Kim Maria , Kerkhof Yvonne JF , Neal David Peter , Ettema Teake P , Koppelle Mylène Anouk , Meiland Franka , Graff Maud , Dröes Rose‐Marie
Published: December 2020

Background

It has been demonstrated that people with dementia’s wellbeing can improve by using touchscreen technology. The FindMyApps program is a training and web‐based selection‐tool to help people with dementia and their caregivers find suitable apps that can improve their self‐management and engagement in meaningful activities. As part of an exploratory RCT into FindMyApps a process evaluation was conducted according to the MRC Framework for process evaluation. Contextual, implementation and mechanisms of impact factors which may influence trial outcomes were evaluated.

Method

A mixed methods design was used, in which quantitative and qualitative data were collected by semi‐structured interviews (SSI) with stakeholders The SSI comprised closed and open questions, designed specifically for this study. Twenty people with mild dementia (MMSE >17; GDS 3‐4) or Mild Cognitive Impairment (MCI) and twenty informal caregivers in both experimental and control groups, as well as 3 other stakeholders (researchers, technical helpdesk person) involved in the implementation of the intervention, were interviewed. Participants were recruited in the Netherlands. Exclusion criteria: moderate to severe dementia or severe sight problems. All participant dyads were provided a tablet computer for the three months intervention period. In the experimental group, people with dementia and caregivers were trained to use the tablet and FindMyApps after which the caregivers guided the persons with dementia to learn to use FindMyApps and find, and use, suitable apps for self‐management and meaningful activities. In the control group, dyads only received general instruction in tablet use and a list of websites where to find potentially useful apps.

Result

Regarding contextual factors, it was found that some technical problems might have influenced the intervention. Regarding implementation, participants noted that the training in the use of FindMyApps was of variable quality. Regarding mechanisms of impact it was found that dyads usually used the apps they found through FindMyApps regularly and enjoyed them, but they did not use FindMyApps itself regularly.

Conclusion

FindMyApps was experienced as a useful tool by most people with dementia/MCI and informal caregivers. Several adaptations to the trial protocol are recommended, to ensure robust outcomes in a definitive trial into its effectiveness.
ABCA7 mutations are major contributors to Alzheimer’s disease in Belgian patients
Authors: Bossaerts Liene , Hens Elisabeth , Van den Bossche Tobi , De Roeck Arne , Engelborghs Sebastiaan , Peeters Karin , De Deyn Peter Paul , Sleegers Kristel , Van Broeckhoven Christine
Published: December 2020

Background

ABCA7 was initially associated with Alzheimer’s disease (AD) in genome‐wide association studies. Recent genetic studies suggest a role for rare premature termination codon (PTC) mutations in ABCA7. While we observed loss of ABCA7 protein for PTC mutations, there was a high variability between mutations due to transcript rescue. Apart from PTC mutations there are missense mutations with unknown effect on ABCA7 protein. Segregation patterns and pathogenicity of ABCA7 mutations are still poorly understood. We aimed at investigating the genetic contribution of ABCA7 in Belgian AD and control cohorts.

Method

Targeted resequencing of ABCA7 coding region or whole exome sequencing were used in Belgian AD patient (n = 1478) and control (n = 757) cohorts. Genetic variants were validated by Sanger sequencing. Haplotype analysis was done using STRs flanking ABCA7. Clinicopathological characteristics of carriers were retrospectively reviewed. Mean onset age was 69.3 ± 7.3 years for AD patients and 73.9 ± 8.0 years for controls.

Result

In 69 patient carriers we identified 15 different ABCA7 PTC mutations (69/1478, 4.67%) and 15 PTC in controls (OR = 2.46 (95% CI [1.40–4.33], p = 0.001). The AD PTC carriers had a mean onset age of 69.5 ± 9.7 years (range 48‐90). Also 114 missense mutations were observed in patients (114/1478, 7.71%) and 35 in controls (OR = 1.72 (95% CI [1.17‐2.55], p = 0.006)). The p.G1820S mutation was carried by a familial AD patient aged 65 years and was absent in controls. Genetic screening of family members showed an autosomal dominant inheritance pattern with co‐segregation of p.G1820S on a shared haplotype of at least 2.63 Mb. p.G1820S is located in the second nucleotide binding domain of ABCA7. Whole exome sequencing of family members excluded co‐segregation of variants in other genes associated with AD.

Conclusion

Mutations in ABCA7 are relatively frequent in the Belgian population and particularly in familial AD. Continued identification and characterization of ABCA7 mutations is needed in case clinical genetic testing of ABCA7 is considered. ABCA7 patients might represent an important subtype of AD and new knowledge about their clinical and genetic profile might contribute to diagnosis, risk prediction and development of targeted therapeutics.
Does cerebral hemodynamic compromise contribute to cerebral cortical microinfarcts: A proof of concept study in patients with internal carotid artery occlusion
Authors: van den Brink Hilde , Ferro Doeschka A , de Bresser Jeroen , Bron Esther E , Onkenhout Laurien P , Kappelle Jaap , Biessels Geert Jan ,   the Heart Brain Connection Consortium
Published: December 2020

Background

Cerebral cortical microinfarcts (CMI) are small ischemic lesions that are associated with cognitive impairment and are often detected in patients with dementia, also in patients with a clinical diagnosis of Alzheimer’s disease (AD). CMI probably have multiple etiologies. Cerebral hypoperfusion has also been proposed as a causal factor. We studied CMI in patients with internal carotid artery (ICA) occlusion, as a model for cerebral hemodynamic compromise, addressing CMI presence and spatial distribution, also in relation to the condition of the remaining arterial supply.

Methods

We included 95 patients with a complete ICA occlusion (age 66.2±8.3, 22% female) and a reference group of 125 participants (age 65.5±7.4, 47% female) from the Heart‐Brain Study. Participants underwent an extensive evaluation including clinical and neuropsychological assessment, and 3T brain MR, on which CMI were rated according to standardized criteria.

Results

CMI were more common in patients with an ICA occlusion (54%, median 2, range 1‐33) than in the reference group (6%, median 0; range 1‐7) (OR 14.3; 95% CI 6.2‐33.1; p<.001). Among patients with a unilateral ICA occlusion, CMI were more common ipsilateral to the occlusion than in the contralateral hemisphere (median 2 and 0 respectively; p<.001). In patients with CMI the number of (other) occluded or stenosed cervical arteries was higher (p=.038), and cerebral blood flow tended to be lower (B ‐6.2 ml/min/100ml; 95% CI ‐12.4‐0.02; p=.05) than in patients without CMI.

Conclusion

CMI are very common in patients with an ICA occlusion, preferably in the hemisphere of the occluded ICA and CMI burden was related to the severity of cervical arterial compromise. Supporting the etiological role of hemodynamics in the occurrence of CMI. Given the common occurrence of CMI in patients with AD and known effects of AD on cerebral perfusion, further studies on the interplay between AD pathologies, cerebral perfusion and CMIs in relation to clinical outcomes, in particular cognitive decline, are warranted.
Diffusion structural network metrics as a predictor for Alzheimer’s disease diagnosis in Down syndrome using support vector machine classification
Authors: Brown Stephanie SG , Mak Elijah , Grigorova Monika , Beresford‐Webb Jessica , Walpert Madeleine Jane , Jones Elizabeth , Hong Young T , Fryer Tim D , Coles Jonathan P , Aigbirhio Franklin I , Handen Benjamin L , Christian Brad T , Klunk William E , Menon David K , Nestor Peter J , Holland Anthony J , Zaman Shahid
Published: December 2020

Background

Alzheimer’s Disease (AD) is known to pathologically develop in Downs Syndrome in almost one hundred percent of cases, although at present structural changes to the brain are minimally utilized for diagnoses of neurodegeneration due to limited understanding of which white matter alterations are directly relevant to clinical presentation. By novel application of machine learning to metrics of the structural connectome in Downs Syndrome, this project aims to identify specific white matter networks that significantly impact classification of cases into AD positive or negative.

Method

A pilot sample of 21 healthy Down’s syndrome participants and 4 Down’s syndrome participants with a diagnostic consensus of either mild cognitive impairment (MCI) or dementia underwent diffusion‐weighted and T1‐weighted MRI scanning at 3T. These data form part of a consortium, which will be utilised to increase sample size for future iterations of this analysis. Whole brain structural connectomes were produced for each participant, utilizing fibre orientation distributions and spherical deconvolution informed filtering of the tractograms. For accurate localisation of nodes to brain regions, the T1‐weighted scan was pre‐processed, segmented, parcellated and co‐registered to diffusion space. Networks were created by examining connection density between T1‐delineated structural nodes. Connection density matrices were used to train and test a support vector machine (SVM) classifier.

Results

Preliminary results show widespread reduction in network structural connectivity in the Down’s syndrome participants diagnosed with dementia or mild cognitive impairment (Fig. 1). The parietal, occipital and to a lesser extent the temporal areas of the network exhibit the most marked decreases in connection density, and no edges of the network displayed increased connection density in dementia or MCI patients compared to healthy Downs syndrome. Multivariate analyses indicate that although SVM classification of the networks has a >80% accuracy, false‐negative classifications were common due to the low number of Down’s syndrome dementia participants.

Conclusions

This pilot application of SVM to diffusion‐derived brain networks in Down’s syndrome demonstrates utility and feasibility as a diagnostic classifier. We expect that increased sample size should yield a more robust trained model.
Can OMICS data help us to understand the mechanisms of APOE?
Authors: Sáez María Eugenia , Moreno‐Grau Sonia , Madrid Laura , Ramirez Alfredo , Ried Janina S. , González‐Pérez Antonio , Ruiz Agustín ,   GR@ACE/DEGESCO Consortium, CHARGE Consortium, GERAD Consortium
Published: December 2020

Background

While being the most prominent genetic risk factor for Alzheimer’s disease (AD), the effects of APOE variants on the biology and development of AD are still poorly understood. The IMI ADAPTED consortium strives to illuminate the mechanisms underlying the effects of APOE following a holistic approach. In this presentation we describe how the integration of a systematic APOE‐stratified re‐analysis of publicly available GWAS, transcriptomics and proteomics for AD led to new insights in APOE mediated effects in AD.

Method

We re‐analysed AD relevant data including 39,186 human genomes, 2,338 transcriptomes, and 2,365 proteomes along with snRNAseq brain data from diverse AD cohorts. Data were obtained from diverse public repositories and AD research consortia (AddNeuroMed,ADGC,ADNI,AMP‐AD,CHARGE,GERAD,GR@ACE,Mount Sinai,NIA‐GENADA,MAYO,ROSMAP and TGEN). Genes showing differences between cases and controls stratified by APOE genotype were identified as well as those showing differences between the APOE genotype carriers. Results of the different OMICS were integrated using the robust rank aggregation (RRA) method to identify effects which are consistent across multiple layers of OMICS data followed by pathway analysis.

Results

The stratified GWAS analysis identified genome‐wide significant loci for AD in the APOE ε3 and APOE ε4 genotype strata. After integration with plasma and brain expression profiles, the pathway analysis found enrichment for several processes related to the immune system and glia function among other relevant pathways, of which those differing between APOE strata are of particular interest.

Conclusion

The systematic APOE genotype‐stratified analysis of human GWAS, transcriptomics, and proteomics data revealed promising candidate genes and pathways that help to elucidate the mechanisms by which APOE affects the AD risk. OMICS data in APOE relevant cell models will refine these findings. Disclosure: This project has received funding from the Innovative Medicines Initiative 2 JU under grant agreement No 115975. This Joint Undertaking receives support from the EU’s Horizon2020 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.
Modelling AD‐relevant pathophysiology in neurons, astrocytes and microglia from two complete sets of isogenic iPSC lines generated by the ADAPTED project
Authors: Socorro Alfredo Cabrera , Schmid Benjamin , Clausen Christian , Holst Bjørn , Peitz Michael , Grezella Clara , Brustle Oliver , Bahnassawy Lamiaa , Bennett Keiryn , Ried Janina S. , Sáez María Eugenia , Ramaswamy Gayathri , Ruiz Agustin , Bakker Margot H.M. , Vicario Carlos , Lourenco Teresa Silva , Reinhardt Peter
Published: December 2020

Background

Apolipoprotein E (APOE) genotype is the main genetic risk factor for Alzheimer’s disease (AD). APOE ε2 haplotype is protective, APOE ε3 is neutral, and APOE Ɛ4 is associated with the highest risk to develop the disease. APOE highly is conserved in vertebrates, but homology between human and mouse sequence is low (73.4% for peptide and 78.7% for the genetic sequences). To better understand the contribution of each APOE allele to the pathophysiology of AD it is necessary to generate preclinical models that recapitulate the molecular and biochemical properties of this complex gene. Within ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) project we have generated and characterized human iPSC‐derived brain cells to fill this important gap.

Method

All ADAPTED isogenic iPSC‐lines were differentiated into clinically relevant cell types (neurons, astrocytes and microglia) that were characterized using unbiased methodologies (transcriptomics, metabolomics and proteomics) and functional assays such as neuronal activity, cytokine release and phagocytosis. We performed all possible comparisons across genotypes, and mostly focused on results that were replicated across the two sets.

Result

We prioritized the study of iPSC‐derived glial cells based on expression levels of apoE and their critical role in brain function and AD pathophysiology. Our strategy led to the identification of APOE allele‐specific molecular signatures and pathways that partially replicates clinical findings (e.g. inflammatory response and metabolic properties). Functional assays revealed genotype differences that were also replicated in different genetic backgrounds.

Conclusion

Systematic comparison of relevant cells types stratified by APOE genotypes revealed key signatures and mechanisms that have been associated to AD. Data generated from iPSC‐derived cells proves this model as a reliable tool to further study the human biology of APOE, providing one step further in our understanding of AD and the potential identification of more effective therapies. iPSC lines generated within ADAPTED are globally available to the scientific community via EBiSC repository.
Characterization of transcriptional and proteomics changes in brain cells derived from isogenic hiPSCs reveals cell type–and genotype‐specific mechanisms modified by APOE
Authors: Ried Janina S. , Curado Marco Rocha , Sáez María Eugenia , Bahnassawy Lamiaa , Lee Heyne , Reinhardt Peter , Mohler Eric G. , Madrid Laura , Socorro Alfredo Cabrera , Grezella Clara , Nicolas Armel , Rao Francesco , Ramaswamy Gayathri , Bakker Margot H.M.
Published: December 2020

Background

While being the most prominent genetic risk factor for AD, the effects of APOE variants on biology and the development of AD is still poorly understood. The IMI ADAPTED consortium strives to illuminate the mechanisms underlying the effect of APOE with several approaches. Complementing the reanalysis of the publicly available human data, hiPSC lines with different APOE genotypes (ε3/ε3, ε4/ε4, ε3/ε4, ε2/ε2), differentiated into distinct brain cell types provide a tool to study cell‐type level effects of the APOE genotype. Further, OMICS data of human APOE modified mouse model (ε2/ε2, ε3/ε3, ε4/ε4) allowed cross species comparison and model validation.

Method

For multiple brain cell types differentiated from the APOE modified isogenic hiPSC (neurons, astrocytes, microglia and macrophages) and mice transcriptomics and proteomics data were generated. Differential gene expression (DGE) and protein expression (DPE) was calculated, followed by gene set enrichment. Clustering approaches were used to identify shared and differing gene signatures across genotypes. We further applied upstream regulator and network analysis on the individual cell‐type results and integrated these results across cell types. The results were compared with DGE and DPE results from the humanized APOE mouse model. Finally, the identified genes and mechanisms were combined with the results of the integrated analysis of data from postmortem human brain samples of AD cases and controls.

Results

The observed transcriptional changes confirmed and extended the phenotypic observations and refined the insight of genes identified in the integrated analysis of APOE genotype stratified human OMICS data. Several genes/proteins and pathways were consistently identified on transcriptome and proteome level. Further, shared patterns of expressions of genes across genotypes and potential mechanisms involved in this were detected.

Conclusions

In depth transcriptomics and proteomics analysis of APOE modified hiPSCs‐derived cells enabled to study cell type and genotype specific effects and contributed with this to the understanding of mechanisms affected by different APOE genotypes. The findings in hiPSC we be compared with human blood and CSF OMICS analysis to be potentially used as biomarker for AD and AD progression.
Medical cannabis and cognitive performance in middle‐aged and old adults treated for chronic pain: A cross‐sectional analysis
Authors: Sznitman Sharon , Vulfsons Simon , Meiri David (Dedi) , Weinstein Galit
Published: December 2020

Background

Medical cannabis (MC) policies are currently undergoing rapid changes, with increasingly more jurisdictions around the world legalizing MC for various indications, including chronic pain. These developments make it increasingly likely that the general population, and in particular older populations, will consume cannabis regularly. Indeed, MC treatment is particularly prevalent among older individuals. A major concern related to cannabis use, and particularly in aging populations, is potential effects on brain health. Yet, there is a dearth of studies examining cognitive effects of cannabis in older adults.

Method

We recruited 63 MC and 62 non‐MC chronic pain patients over the age of 50 years with chronic neuropathic pain of organic origin from the Rambam Pain Medicine clinic in Haifa, Israel. Cognitive performance was assessed after abstinence of 8h in the MC users through CogState, a computerized battery designed to assess psychomotor reaction time, attention, working memory and learning. Linear regression models were used to test differences in cognitive performance between the two groups. Models adjusted for age, sex, education, cardiovascular disease and depression. Among MC users, the associations of dosage, cannabinoid concentrations, length and frequency of use and hours since last use with cognition were also examined.

Result

Mean age was 63±6 and 60±5 years in the non‐MC and MC patients respectively. MC patients were more likely to have cardiovascular disease (3% vs. 11%, respectively, p=0.025) and depression (7% vs. 21%, respectively, p=0.003). Sex, education levels, alcohol and cigarette use patterns and pain levels were similar. After adjustment, there were no significant difference between MC and non‐MC patients in any of the cognitive performance measures. Furthermore, years of MC use, frequency of use, hours since last use, number of strains used, THC/CBD concentration or dose were not related to cognitive performance on the different tests.

Conclusion

These results suggest that use of whole plant MC cannabis does not have a widespread impact on cognition in older patients. Considering the accumulating evidence showing efficacy of cannabis use for multiple health conditions, the lack of adverse effects on the brain can eliminate concerns and contribute to a better risk‐benefit assessment of MC treatment.
Prevalence and severity of neuropsychiatric symptoms in the prodromal stages of dementia with Lewy bodies and Alzheimer’s disease
Authors: Wyman‐Chick Kathryn A. , Erickson Lauren O. , Rosenbloom Michael H. , Weintraub Daniel , Barclay Terry R. , Barrett Matthew J.
Published: December 2020

Background

There has been minimal investigation into the prodromal features dementia with Lewy bodies (DLB) and how they may differ from prodromal features of Alzheimer’s disease (AD).

Method

The data analyzed for this investigation were collected as part of a large, prospective longitudinal study conducted by the National Alzheimer’s Coordinating Center (NACC database is funded by NIA/NIH Grant U01 AG016976). We identified 110 non‐demented participants who converted to DLB at a subsequent visit. Participants were age and sex matched to 220 non‐demented participants who later converted to AD. We examined between group differences in the prevalence of symptoms on the Neuropsychiatric Inventory Questionnaire (NPI‐Q) at time of dementia diagnosis and in the 1‐3 years preceding conversion to dementia using Chi‐Square or Fisher Exact Test analyses.

Results

For the DLB and AD groups, 82% were male and the average age at the time of dementia diagnosis was 75.4 years (SD=7.9). There was no significant difference in education between the two groups. The DLB group was significantly less culturally diverse than the AD group (See Table 1). Nighttime behaviors and hallucinations were significantly more common in the DLB group compared to the AD group at all time points during the prodromal phase and at the time of dementia diagnosis. There was no significant difference in the informant’s report of motor symptoms in the prodromal phases between the two groups (See Table 2).

Conclusion

The DLB group demonstrated a significantly higher prevalence of nighttime behaviors and hallucinations than the AD group in both the prodromal phase and at the time of dementia diagnosis. These findings support the occurrence of core clinical features of DLB during the prodromal phase of the disease [1]; however, there was no significant difference in the informant’s report of motor symptoms within the prodromal phases, which warrants a comparison utilizing more objective motor data. Reference: 1. McKeith IG, Boeve BF, Dickson DW, et al.; Dementia with Lewy Bodies Consortium. Diagnosis and management of Dementia with Lewy Bodies: Fourth consensus report of the DLB Consortium. Neurol. 2017;89:1‐13.
Economic status and mortality in Alzheimer's disease patients in Japan: LIFE Study
Authors: Ono Rei , Maeda Megumi , Fukuda Haruhisa
Published: December 2020

Background

Alzheimer's disease (AD) is an urgent global health priority, with a projected 75 million cases by 2030 and 131 million cases by 2050 worldwide. Low economic status in patients may affect prognoses by limiting the opportunities to receive appropriate care. However, the association between economic status and mortality among AD patients in Japan is unclear. This study sought to examine the influence of economic status on mortality in individuals with AD in Japan.

Method

Claims data from April 2014 to March 2019 were obtained from the Longevity Improvement & Fair Evidence Study (LIFE Study) database, which contains municipality‐level information. The study subjects were individuals residing in one rural city who received new diagnoses of AD in October 2014 or later. To analyze economic status, we examined the utilization of a program designed to reduce the maximum healthcare expenditures for low‐income individuals. Subjects who were enrolled in this program upon receiving a new AD diagnosis were designated low‐income individuals. All subjects were tracked for a maximum of 54 months following AD diagnosis, and the number of months before a mortality event was assessed. The hazard ratio (HR) for mortality in low‐income individuals was estimated using a Cox proportional hazards model that adjusted for sex, age, Charlson comorbidity index, healthcare expenditures in the 6 months before AD diagnosis, and anti‐dementia drug use.

Result

We identified 1,571 newly diagnosed AD patients from the LIFE Study database. The mean age was 83.6 years, 68.1% were women, and 17.5% were low‐income individuals. With a mean follow‐up period of 24.8 months, the mortality rate was 21.3% (334 subjects). The survival rates were 88.7% and 75.0% after 12 and 36 months of follow‐up, respectively. The HR (95% confidence interval) for mortality was 2.18 (1.69‐2.80) for low‐income individuals and 2.15 (1.71‐2.72) for men.

Conclusion

Low‐income status was associated with substantially poorer prognoses in new AD cases. These findings indicate a need for a thorough examination of the medical and nursing care services utilized by low‐income individuals with AD, and for an exploration of improvement strategies.
Characterization of subjective cognitive concerns (SCC) in a racially/ethnically diverse community‐based elderly cohort: Results from the Einstein Aging Study (EAS)
Authors: Katz Mindy J. , Wang Cuiling , Mogle Jacqueline , Rabin Laura
Published: December 2020

Background

SCC may play an important role in identification of pre‐clinical dementia, especially among individuals who experienced disparities. A small number of studies examined the differential prediction of objective cognitive decline between blacks and whites using SCC, yielding mixed results. It is important to identify any differential patterns of SCC endorsement among racially diverse groups to enhance the ability to capture current and future cognitive status.

Method

Using data from the EAS, a longitudinal community residing cohort aged 70+, an SCC composite was derived using 22 self‐reported items. Cognitive status was diagnosed by consensus conference (dementia, MCI, cognitively normal). Objective cognition was measured using 3 factor scores (memory, executive function, global/verbal) derived from a principal component analysis of our neuropsychological battery. Multiple linear regression models were used to evaluate racial differences in SCC at baseline for those who were cognitively normal, as well as to determine whether there was a differential association between SCC and objective cognition among racial groups. Cox models were applied to determine if there was racial heterogeneity for the effect of SCC on incident MCI, adjusting for demographics, estimated premorbid intelligence, medical co‐morbidities, and depressive symptoms.

Result

1720 participants of non‐Hispanic white or black race were cognitively normal at baseline and included in these analyses. There was no significant difference between blacks and whites on the SCC composite; however, there was a significant interaction between race and SCC on 2 of 3 objective cognition factors. Having more SCC at baseline was associated with worse objective cognitive performance in the memory and global/verbal domains in white and black participants, but the association was significantly weaker among blacks. While SCC was associated with greater risk of incident MCI (<0.0001), there was no significant interaction between race and SCC on incident MCI.

Conclusion

Despite having weaker, though still significant, associations with memory and global/verbal tasks in blacks compared to whites, SCC consistently predicted incident MCI across the two races. Future work should expand upon these results through replication in other diverse samples, inclusion of informant report data, and investigation of differential change in SCC over time and in relation to clinical conversion.
Soluble TNF mediates high‐fat and high‐carbohydrate diet–induced inflammation, alterations in peripheral blood and brain immunophenotype, and gut microbiome in a mouse model of amyloid pathology
Authors: Herrick Mary K. , MacPherson Kathryn P. , Eidson Lori N. , de Sousa Rodrigues Maria Elizabeth , Sniffen Lindsey J. , Wallings Rebecca , Kelly Sean D. , Hamilton Adam M. , Oliver Danielle , Yang Yuan , Chang Jianjun , Keating Cody E. , Coomes Alexandra , Sampson Timothy R. , Jobin Christian , Norris Christopher M. , Barnum Christopher , Tansey Malu Gamez
Published: December 2020

Background

Sporadic Alzheimer’s disease (AD) is a product of complex gene‐environment (GxE) interactions. Central‐peripheral immune cell crosstalk and traffic across the blood‐brain barrier (BBB) have been implicated in AD pathophysiology by recent studies that demonstrate a T‐cell signature in AD brain, gut dysbiosis in AD patients, and a significant epidemiological association between metabolic syndrome, obesity, and type‐2 diabetes with increased incidence of AD. Soluble tumor necrosis factor (sTNF), a known regulator of BBB and gut‐epithelial barrier permeability in chronic systemic inflammatory diseases that is increased in AD patient blood, was investigated as a regulator of immune cell traffic and AD‐like pathology in a mouse model of amyloid pathology subjected to an obesogenic diet.

Method

To investigate the effects of chronic peripheral inflammation on neuroinflammation and AD‐associated pathology, 2‐month old female 5xFAD (Tg) or non‐Tg mice were fed a high‐fat high‐carbohydrate diet (HFHC) or a balanced control diet (CD) for 8 weeks. After 4 weeks of diet, BBB‐permeant XPro®1595 was given subcutaneously every third day to selectively inhibit sTNF signaling. Neuroimmunological, histological, biochemical, genomic, and transcriptomic analyses were used to analyze effects on blood and brain immune populations, BBB permeability, inflammatory gene and protein expression, and gut microbiome.

Result

HFHC‐fed Tg mice showed decreased T cell numbers in the blood and increased Ly6C+ T cells in the brain as compared to Tg mice fed CD or non‐Tg HFHC‐fed mice. Tg mice fed HFHC diet displayed increased hippocampal TNF and ZO‐1 mRNA, modestly increased Aβ burden, and marked increases of Iba1+ cells. Analysis of gut microbiota revealed significant beta diversity genotype‐ and diet‐dependent differences between Tg and non‐Tg mice, synergy in GxE interactions, and the ability of XPro®1595 to reverse many of these features.

Conclusion

Together, these data suggest that an obesogenic diet enhances BBB permeability, disrupts innate and adaptive immune cell populations in the blood, promotes gut dysbiosis, and enhanced traffic of immune cells to the CNS through sTNF‐dependent mechanisms. Clinical trials in patients with MCI/early AD are underway to investigate the ability of a weekly dose of XPro1595 to reduce underlying inflammation without immunosuppression via selective targeting of sTNF.
Application of machine learning to predict amyloid, metabolic, and structural neuroimaging biomarkers in the progression of autosomal dominant Alzheimer disease
Authors: Luckett Patrick H. , McCullough Austin A. , McDade Eric , Benzinger Tammie L.S. , Morris John C. , Bateman Randall J. , Ances Beau M.
Published: December 2020

Background

Models of disease progression in autosomal dominant Alzheimer disease (ADAD) using multimodal neuroimaging, deep learning, and feature extraction algorithms were designed.

Method

Longitudinal structural magnetic resonance imaging (MRI), amyloid positron emission tomography (PET) and fluorodeoxyglucose (FDG) PET were acquired in 131 mutation carriers (MC) and 74 non‐carriers (NC) from the Dominantly Inherited Alzheimer Network observational study; the groups were matched for age, education and sex. Imaging data were evaluated with regard to expected years to symptom onset (EYO), apolipoprotein e4 (APOE e4) status, age, and gender. A deep feedforward neural network was trained to predict disease progression with respect to the given neuroimaging modality. Relief feature selection algorithms identified brain ROIs that were the strongest predictors of mutation status. Model simulations identified amyloid, metabolism, and atrophy trajectories, and ROC analysis identified cutoff values.

Result

The Relief algorithm identified the caudate, anterior cingulate, and precuneus as the strongest predictors amongst all modalities (Figure 1). The model yielded accurate results for predicting future PiB (R2 = 0.95, root mean squared error [RMSE] = 0.2), FDG (R2 = 0.93, RMSE = 0.1), and brain atrophy (R2 = 0.95) in MCs compared to NCs (Figure 2). Simulations revealed a sigmoidal trajectory for PiB, a biphasic response for FDG, and a gradual decrease in brain volume (Figure 3). Cutoff values were identified for PiB (caudate = 1.3, total cortical mean = 1.2), FDG (caudate = 1.4, total cortical mean = 1.6), and Volumes (caudate = 3.3k, total cortical mean = 575k) (Figure 4).

Conclusion

To provide targeted care for individuals with ADAD, novel methods are needed to model disease trajectories. Our model is accurate and capable of reliably forecasting future changes in amyloid deposition, glucose metabolism, and brain volume. The data‐driven approach represents an opportunity to discover novel mechanisms and disease trajectories in ADAD.
Impact of APOE4 and future family history on early adulthood cardiovascular risk: Results from a 30‐year cohort study
Authors: Koychev Ivan , Vaci Nemanja , Moonen Justine E , Yaffe Kristine , Nasrallah Ilya M , Sidney Stephen , Jindra Christoph , Gallacher John , Launer Lenore J
Published: December 2020

Background

Selected cardiovascular factors, APOE ε4 allele carriership and family history of dementia (FHD) are robust risk factors for late‐onset dementia. While it is recognised that cardiovascular factors exert their influence from mid‐age, it is unclear whether APOE ε4 carriership and a future FHD impact the process. Here we test the hypothesis that genetic and familial susceptibility for dementia are associated with an unfavourable cardiovascular risk profile starting from early adulthood.

Method

We used data from the CARDIA study which followed‐up 5116 individuals aged 18‐30 starting in 1984. Data from 2,497 30‐year visit attendees (mean age 55) was used to assess the associations of APOE ε4 carriership and future FHD with baseline and 30‐year measures of cardiovascular risk factors (LDL, HDL, glucose, blood pressure, BMI) suggested to be associated with late‐life cognitive impairment.

Result

APOE ε4 carriers, compared to non‐carriers, had higher LDL and lower HDL levels in early adulthood. Future FHoD was associated with worse late‐life but not baseline lipid profile. Compared to those with neither or one, persons having both FHD and APOE ε4 had the lowest baseline mean HDL and highest mean LDL (52 and 117 mg/dL for APOE ε4+/FHD+ versus 54 and 107 mg/dL for APOE‐/FHD‐ respectively). Interestingly, APOE ε4+/FHoD+ was associated with lower systolic and diastolic blood pressure relative to the APOE ε4‐/FHD‐ group in early adulthood but not year 30. Neither family history nor APOE ε4 were associated with early or late‐life levels of blood glucose or, BMI.

Conclusion

Our results indicate that APOE ε4 allele carriership associates with an unfavourable lipid profile (low HDL, high LDL) starting from early adulthood continuing into later life. Of the two factors, APOE ε4 allele carriership was more strongly associated with lipid levels, but family history of dementia does add some additional explanatory value to the association. Recent GWAS have identified cholesterol metabolism as a component of risk for dementia, and these results indicate that APOE ε4 allele effects peripherally measured lipids, starting at the latest in early adulthood. The relation between these levels and brain structure and function needs further evaluation.
Neuropathological diagnoses of subjects autopsied in the phase 3 clinicopathological study of flortaucipir F18 PET imaging
Authors: Beach Thomas G. , Montine Thomas J. , Serrano Geidy E. , Sue Lucia I. , Intorcia Anthony J. , Fleisher Adam S. , Pontecorvo Michael J. , Devous Michael D. , Lu Ming , Mintun Mark A. ,   A16 Study Investigators
Published: December 2020

Background

Avid Radiopharmaceuticals conducted a prospective case‐control clinicopathological study of flortaucipir F18 PET Imaging (AV‐1451‐A16) from October 2015 through June 2018. This presentation is an initial report of the detailed neuropathological findings of the 67 primary study subjects.

Method

Sixty‐seven valid study autopsies were performed. The cerebral patterns of flortaucipir PET images were visually assessed and compared to the patterns of immunohistochemical tau pathology. The study met pre‐specified success criteria, with imaging predicting an NIA‐AA B3 level of tau pathology (Braak V/VI) and a high level of Alzheimer’s disease neuropathologic change.

Result

There were 35 females and 32 males, mean age 82.6 (SD 9.4). Fifty‐three cases met intermediate or high ADNC levels, consistent with AD as a cause of cognitive impairment. Of these, many had additional major neuropathological findings (not mutually exclusive), meeting neuropathological diagnostic criteria for dementia with Lewy bodies (DLB; n=7), Parkinson’s disease (PD; n=1), progressive supranuclear palsy (PSP; n=5), hippocampal sclerosis (HS; n=5), vascular dementia (n=3) and corticobasal degeneration (CBD; n=1), while others had lesser findings of TDP‐43 proteinopathy restricted to the mesial temporal lobe (n=19), Lewy body pathology not meeting criteria for DLB or PD (n=18), age‐related tau astrogliopathy (ARTAG; n=15) or remote cerebral infarcts (n=10). Cases with less than intermediate ADNC (n=14) met neuropathological diagnostic criteria (not mutually exclusive) for PD (n=2), HS (n=2), DLB (n=1), PSP (n=1), CBD (n=1) and others had additional neuropathological findings of TDP‐43 proteinopathy restricted to the mesial temporal lobe (n=2), Lewy body pathology not meeting criteria for DLB or PD (n=4), ARTAG (n=3) or remote cerebral infarcts (n=2).

Conclusion

This high proportion of mixed neuropathology is typical of what has been published for other elderly autopsied subjects. Correlations of flortaucipir F18 PET imaging with these varied neuropathological types will be undertaken.
Standing activity as assessed by seismic accelerometers and cognitive function in community‐dwelling older adults: The MIND trial
Authors: Halloway Shannon , Dhana Klodian , Desai Pankaja , Barnes Lisa L , Aggarwal Neelum T , Evers Jordi , Sacks Frank , Carey Vincent , Morris Martha Clare
Published: December 2020

Background

Few older adults are able to achieve recommended levels of moderate‐vigorous physical activity despite known cognitive benefits. Alternatively, small movements, such as increasing movement while standing during usual tasks, can easily be integrated into daily routines by older adults. However, standing activity is best assessed with specific devices (i.e., seismic accelerometers). No existing study of older adults has examined the impact of device‐measured standing activity on cognition. Therefore, the purpose of this secondary analysis is to examine the association between standing activity (as measured by a seismic accelerometer) and cognition in cognitively healthy older adults.

Method

Participants were 98 cognitively healthy adult participants aged 65 years or older with family history of dementia from the ongoing MIND trial (NCT02817074), which tests the effects of a 3‐year diet intervention on cognitive decline. Exclusion criteria included diagnosis or symptoms of mild cognitive impairment or dementia. Linear regression analyses tested cross‐sectional associations between standing intensity and cognition. Standing activities were mean intensity of standing and static activities (sum of standing and shuffling) assessed by the MoveMonitor+ accelerometer/gyroscope. Cognition was composed of 4 cognitive domains constructed from 12 cognitive performance tests.

Result

Participants were on average 69.7 years old (SD=3.7), 69.4% women, and 73.5% had a college degree or higher. Both higher mean intensity of standing activity and static activity were significantly associated with higher levels of executive functioning and perceptual speed in models adjusted for age, gender, and education. Each log unit increase in standing activity intensity was associated with 0.77 units higher of executive function (p=.041), and 0.85 units higher of perceptual speed (p=.032). For static activities, significant log unit increases were 0.86 (p=.009) for executive function and 0.96 (p=.006) for perceptual speed. When we additionally adjusted for time spent in moderate‐vigorous physical activity and cognitive activity, the positive associations between higher intensity of standing and static activity and perceptual speed remained.

Conclusion

These findings suggest the importance of considering intensity of standing activity in cognition. The relationships should be further explored in longitudinal analyses and interventions that incorporate small changes to daily routines in addition to promoting moderate‐vigorous physical activity.
Insulin‐like growth factor 1 (IGF1) gene therapy modulates behavior, neurogenesis, and synaptic proteins in a rat model of sporadic Alzheimer's disease
Authors: Villar Maria Florencia Zappa , Hanotte Juliette López , Pardo Joaquín , Reggiani Paula Cecilia
Published: December 2020

Background

Sporadic Alzheimer’s disease (SAD) is the most prevalent neurodegenerative disorder worldwide and it is characterized by progressive memory loss and cognitive impairment. Brain activation of insulin signaling preserves memory in animal models and appears beneficial for patients. In contrast, the role of insulin‐like growth factor 1 (IGF1) remains controversial. Our aim was to determine the possible protective actions of IGF1 in a rat SAD model induced by intracerebroventricular injection of streptozotocin (icv‐STZ). To this end, we drove the expression of IGF1 using a recombinant adenoviral vector, RAd‐IGF1.

Method

We evaluated 3 animal groups: Sham, STZ and STZ+IGF1. STZ and STZ+IGF1 groups were injected with 3 mg/kg icv‐STZ and, 7 days later, the STZ+IGF1 group received the icv‐RAd‐IGF1. During the last two weeks until the end of the study (day 24 post icv‐STZ), we performed several behavioral tests. Additionally, we analyzed neuroblast cells, synaptic proteins and IGF1‐signaling pathway proteins in the hippocampus.

Result

IGF1 improved marble‐burying behavior, hippocampus‐dependent spatial memory, object recognition memory and decreased depression‐like behavior, all features affected by STZ. Also, brain IGF1 overexpression restored neurogenesis, enhanced SYT2, PSD95 and GAD65/67 levels, and modulated the IGF1 receptor signaling pathway in STZ animals.

Conclusion

Results indicate a protective role of IGF1 in our SAD model, as it was effective against behavior deficits and ameliorated hippocampal protein alterations induced by STZ. We conclude that IGF1 therapy has an interesting potential for SAD treatment.
Identification of multi‐issue protein quantitative trait loci (pQTLs) for Alzheimer disease
Authors: Yang Chengran , Farias Fabiana H.G. , Mihindukulasuriya Kathie A. , Davenport Richard , Wang Fengxian , Budde John P. , Rhinn Herve , Cruchaga Carlos , Harari Oscar
Published: December 2020

Background

Alzheimer disease (AD) is a neurodegenerative disease, affecting around 5.8 million people in the United States as of 2019. It has been widely studied, but there is still no effective treatment. Using large‐scale Genome‐wide association studies and whole genome/exome sequencing, researchers have identified common and rare variants associated disease risk that can be used to build prediction models. However, there are limited studies that use high‐throughput genomic approaches to identify novel biomarkers beyond genetic variations.

Method

We profiled 1,305 proteins using SOMAscan platform for 971 CSF, 636 plasma, and 458 parietal lobe from participants of the Knight‐ADRC. We aim to identify the genetic architecture that govern protein levels and how do these proteins modulate AD risk, age at onset, rate of progression, and additional neurodegenerative traits. To do so, we first identified protein quantitative trait loci (pQTLs) from CSF, plasma, and brain tissues. Next, we inferred causality between proteins with significant pQTLs and AD and neurodegenerative traits employing Mendelian Randomization (MR) approaches.

Result

We identified pQTLs in each tissue. We found 26, 17, and 206 novel pQTLs, in brain, plasma and CSF respectively. We also successfully replicated several reported pQTLs from CSF (e.g. rs2673908 associated with the protein Siglec‐9) and plasma (e.g. rs12740374 associated with the protein Granulins). To infer the causality between proteins and AD or other neurological diseases, we performed MR analysis by using pQTLs as instrumental variables. Overall, we processed MR framework using proteins with significant pQTLs within each tissue on seven neurological‐related traits. Known protein‐disease relationships were replicated. For example, plasma Siglec‐3 (CD33) increases the AD risk, consistent with a larger plasma‐proteome MR analyses by Zheng and colleagues in 2019. We also uncovered the novel proteins in pathways associated with AD risk and additional endophenotypes. In total, we found between 6 to 25 potential new biomarkers for AD progression, depending on the tissue we evaluated. Similarly, we identified 2 to 21 proteins associated with for AD age at onset.

Conclusion

Taken together, these findings prioritized the proteins for the functional validation study. Thus, the findings helped identify potential biomarkers for AD or other neurological traits.