bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between visceral fat amount and brain cortical thinning in the community‐dwelling elderly population
Authors: Noh Young , Cho Jaelim , Seo Seongho , Kim Woo‐Ram , Park Kee Hyung , Kim Changsoo
Published: December 2020

Background

Despite emerging evidence suggesting that visceral fat may play a major role in the neurotoxic effect of obesity, no study has investigated the association between visceral fat amount and cortical thickness in the elderly. We examined the association of abdominal fat amount with cortical thickness and subcortical structures in the elderly.

Method

Community‐dwelling individuals (≥60 years of age) without known neurological diseases (n=316) were included. Areas of subcutaneous fat and visceral fat were estimated from computed tomography scan. Regional cortical thicknesses and subcortical volumes were obtained by analyzing brain 3T magnetic resonance imaging. A generalized additive model was built to explore non‐linearity between abdominal fat amount and cortical thickness. A generalized linear model was used to explore the brain imaging markers associated with an increase in abdominal fat amount (quintiles used for cortical thickness).

Result

There were inverted U‐shape relationships of visceral fat amount with global (p=0.02), frontal (p=0.02), temporal (p=0.02), and parietal thicknesses (p<0.001). The quintile 5 (the highest) group had significantly thinner cortices compared with the quintile 3 group in the global (β=‐0.04, p=0.004), parietal (β=‐0.04, p=0.01), temporal lobes (β=‐0.05, p=0.002), cingulate (β=‐0.06, p=0.01), and insula (β=‐0.06, p=0.02). The higher amount of visceral fat was significantly associated with the smaller volume of the pallium (β=‐0.66, p=0.01) and putamen (β=‐1.36, p=0.03). Most of the associations between subcutaneous fat amount and the brain imaging markers were not significant.

Conclusion

We found an inverted U shaped relationship between visceral fat amount and cortical thickness in elderly individuals. Future studies are needed to elucidate causal relationships and explore other factors which may be confounders.
Stroke memory rehabilitation (SMaRT) programme for mild ischemic stroke: Preliminary findings
Authors: Ong Angeline , Wong Fennie , Ng Sheng Chun , Leong Man Qing , Chua Esther Vanessa , Kandiah Nagaendran
Published: December 2020

Background

There are 6000‐7000 stroke survivors yearly in Singapore with about 40% being at risk for post‐stroke cognitive impairment (PSCI). Stroke Memory Rehabilitation (SMaRT) programme was designed to reduce the incidence of PSCI, facilitate transition back to the community, improve the mood and quality of life of patients with mild ischemic strokes. We report the preliminary outcomes of the program.

Method

Participants who attended the programme from April 2018 to Dec 2019 were included in this study. Each patient attended 8 two‐hour sessions over 8 weeks, focusing on cognitive processes (episodic memory, executive function and visuospatial function); healthy lifestyle habits, relaxation techniques and goal setting. All patients were administered neuropsychological assessments and questionnaires pre‐programme, 8 weeks and 6 months post‐programme. Paired sample t‐tests were applied to evaluate the changes in scores over the four time points on each outcome measure, subject to Bonferroni correction for family‐wise errors.

Result

156 participants (mean age=63.53 years, SD=9.63; mean education=9.95 years SD=4.18, 65.4 % male). Significant improvements in all outcome measures were observed from pre‐programme to all other time points. Cognitive scores significantly improved from pre to post‐programme and pre to 6 months post‐programme on the Montreal Cognitive Assessment (24.52 to 25.36; p<.001 and 25.05 to 25.98; p<.001 respectively); Visual Cognitive Assessment Test (VCAT) Score (22.67 to 24.14; p<.001 and 22.63 to 24.92; p<.001). Scores for Trail Making Test‐A only significantly shortened from pre‐ to 6 months post‐programme (52.00 to 45.52; p<.001). Depression levels significantly reduced on the Geriatric Depression Scale (4.01 to 3.29; p=.001 and 3.46 to 2.33; p<.001). Activities of daily living measured on the NEADL significantly improved (52.24 to 55.15; p<.001 and 52.48 to 56.27; p<.001). Quality of life (DemQOL) also significantly improved (88.77 to 91.88; p=.006 and 91.83 to 95.52; p<.001).

Conclusion

Preliminary findings demonstrate encouraging improvement in global cognition, executive function, quality of life, depression and activities of daily living from pre‐programme to 8 weeks and 6 months post‐programme. A multi‐approach structured cognitive rehabilitation programme for stroke survivors may thus be useful in preventing post‐stroke dementia.
Greater than the sum: Federated analyses in Alzheimer’s disease using the Human Brain Project Medical Informatics Platform (MIP)
Authors: Sokolov Arseny A. , Phenix Thierry , Chaptinel Jérôme , Leroy Melanie , Kherif Ferath , Redolfi Alberto , Pasquier Florence , Démonet Jean‐François , Ryvlin Philippe
Published: December 2020

Background

The abundance of patient data collected during clinical routine is rarely harnessed towards progress in neuroscience. However, multimodal real‐life data may provide significant insights into pathophysiology, disease progression and prognosis, in particular in the field of Alzheimer’s disease. The aim of the Medical Informatics Platform (MIP) within the Human Brain Project is to create an intuitive interface that allows remote computational analyses of clinical data stored in the respective medical centers.

Method

The concept of federated analyses refers to the statistical processing of physically separate and non‐aggregated data sets in a single user interface. The MIP interface provides advanced statistical approaches, remote data access and local user regulations. Authorized MIP users are able to test their hypotheses using a flexible portfolio of data sets, modalities and data processing tools.

Result

At the present stage, three memory clinics have contributed to the MIP: the Leenaards Memory Centre at the University Hospital Lausanne, Switzerland; the University Hospital Lille Memory Centre, France; and the IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli di Brescia, Italy. The data sets contain demographic, neuropsychological and volumetric MRI data from 5154 individuals with subjective and mild cognitive impairment or dementia. The data include clinically probable Alzheimer's etiology according to CSF biomarkers. Proof‐of‐concept and validation analyses will be presented. Reference data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which can be downloaded by MIP users in accordance with ADNI rules, can be compared with the clinical data in the MIP.

Conclusion

Federated analyses such as afforded by the MIP within the Human Brain Project do not only allow novel scientific insights due to a substantial increase in sample size and cross‐validation, but also ensure a high level of data protection. The MIP has a considerable potential for discovery in clinical neuroscience.
Brain beta‐amyloid in twin pairs discordant for episodic memory performance
Authors: Lindgren Noora , Karjalainen Tomi , Ekblad Laura L. , Helin Semi , Karrasch Mira , Teuho Jarmo , Tuisku Jouni , Kaprio Jaakko , Rinne Juha O. , Vuoksimaa Eero
Published: December 2020

Background

β‐amyloid pathology (Aβ) and episodic memory (EM) impairment are biological and cognitive hallmarks of Alzheimer’s disease (AD). However, most studies on the Aβ–EM association have been conducted in unrelated individuals and cannot tell if this relationship is confounded by shared genetic and/or environmental effects. We investigated if cortical amyloid pathology‐EM relationship is evident within twin pairs: a design that controls for shared genetic (fully in monozygotic [MZ] and partly in dizygotic [DZ] pairs) and environmental effects.

Method

We studied 45 same‐sex (mean [SD] age = 72.9 [4.0] years; 18 women pairs) twin pairs. EM discordance was based on a mean of two verbal delayed free recall measures: Logical Memory and Word List Learning from CERAD‐NB. We also studied within‐pair differences in 3 continuous EM scores (verbal immediate free recall [VerIFR], verbal delayed free recall [VerDFR], and visual delayed free recall [VisDFR]) in relation to within‐pair differences in cortical amyloid pathology. Cortical amyloid pathology in AD signature regions was measured with carbon‐11‐labelled Pittsburgh compound B ([11C]PiB) and quantified as standardized uptake value ratio (SUVR) with cerebellar cortex as a reference region.

Result

A total of 42 pairs were discordant for EM (23DZ/19MZ). Twins with poorer EM had higher cortical [11C]PiB SUVR compared to their co‐twins (1.44 vs 1.36), but this difference was not statistically significant (mean intra‐pair difference of 6% / 0.08 SUVR units [95%CI: ‐0.05; 0.20], P=0.23). Using continuous scores within all pairs, co‐twins with higher SUVR had poorer EM scores (Ps< 0.006): VerIFR (r= ‐0.42), VerDFR (r= ‐0.41) and VisDFR (r= ‐0.46). In DZs, within‐pair differences in EM scores were significantly related to within‐pair differences in SUVR with correlations ranging from ‐0.42 to ‐0.51 (Ps< 0.05, N=24). In MZs, non‐significant within‐twin pair correlations ranged from ‐0.31 to ‐0.36, (Ps= 0.11 – 0.16, N=21).

Conclusion

By using case‐control twin design we showed that within twin pairs, a co‐twin with higher amyloid pathology had poorer episodic memory. Results suggest that amyloid‐EM relationship is evident when controlling for shared environmental and genetic effects, but studies with larger samples of MZ and DZ twins in different stages of AD continuum are warranted.
Associations between dietary spermidine intake, cognition and brain volumes
Authors: Tavares Juliana F , Landstra Elvire N , Brunner Julia , Boenniger Meta M , Lohner Valerie , Conrad Johanna , Nöthlings Ute , Breteler Monique MB
Published: December 2020

Background

Spermidine is the most abundant polyamine in the human body, but its intracellular concentrations decrease with ageing. Spermidine supplementation reportedly protected against age‐related changes in cognition and brain structures in fruit flies (Gupta et al, 2013), and increased memory performance in older human adults (Wirth et al, 2018). However, the effects of dietary spermidine intake on brain‐related outcomes are unclear. Therefore, we evaluated whether and how dietary spermidine is cross‐sectionally associated with cognitive function and brain structures in a population‐based sample.

Methods

We based our analyses on participants from the Rhineland study with complete nutritional and cognitive assessment (n=2906, age 54.8±13.5 years), and with complete nutritional assessment and T1‐MRI scans (n=2264, age 54.1±13.4 years). Habitual dietary spermidine intake was estimated through a validated food frequency questionnaire. Cognitive performance was measured using eight cognitive tests that assessed performance in multiple domains (processing speed, executive functions, working and episodic verbal memory). These domains were summarized using z‐score averaging, producing a global cognitive function score. Brain volumetric measures (total brain, white and grey matter, cortex and hippocampus) were obtained using Freesurfer (Fischl et al, 2002). We quantified the relation between spermidine intake and the outcomes with multivariate linear models adjusted for age, sex and education. For brain volumes, models were additionally adjusted for estimated total intracranial volume.

Results

The mean dietary intake of spermidine was 55.1±21.4 μmol/day. Higher spermidine intake (per SD increase) was associated with better global cognitive performance (ß=0.02, 95%CI=0.001 ‐ 0.03), and processing speed (ß=0.03, 95%CI=0.004 ‐ 0.05) and episodic verbal memory (ß=0.03, 95%CI=0.001 ‐ 0.06) domains. Conversely, dietary spermidine intake was not or inversely associated with brain volumetric measures (cortex: ß =‐0.91, 95%CI=‐1.82 – ‐0.02; left hippocampus: ß =‐0.01, 95%CI=‐0.03 – ‐0.002).

Conclusions

Our results confirmed a positive association between dietary spermidine intake and better global cognitive function. However, we also found higher dietary spermidine intake to be associated with smaller cortical and left hippocampal volume. These seemingly contradictory results underscore the need for further research to better understand the effects of spermidine in cognition and brain related outcomes as well as the biological mechanisms underlying these associations.
Plasma amyloid‐β oligomerization assay as a screening test for abnormal amyloid status
Authors: Mofrad Rosha Babapour , Scheltens Philip , An Seong Soo , Kang Sungmin , Kim SangYun , Van Berckel Bart N.M. , Visser Pieter Jelle , van Der Flier Wiesje , Teunissen Charlotte E.
Published: December 2020

Background

The dynamic process of amyloid‐β (Aβ) oligomerization is considered vital for the neurotoxic effects of Aβ in Alzheimer’s disease (AD). Measuring plasma Aβ oligomerization tendency (OAβ) in blood would provide a simple and low‐cost tool for AD diagnosis. Therefore, we assessed the performance of plasma OAβ as a marker for abnormal amyloid status. We additionally evaluated the effect of long‐term storage, as this may influence plasma OAβ levels.

Method

We included 414 subjects regardless of clinical diagnosis from the Amsterdam Dementia Cohort and European Medical Information Framework for AD project (table1). Amyloid status was determined by visual read on Positron Emission Tomography (PET). Plasma OAβ was measured using the Multimer Detection System (MDS). The effect of long‐term storage on plasma MDS‐OAβ was assessed using Generalized Linear Models (GLM) including storage period, amyloid status, and their 2‐way interaction. In case of a significant 2‐way interaction, the cohort was stratified based on the median storage‐period (4 years). Age and Apolipoprotein (APOE)e4 adjusted, plasma MDS‐OAβ levels were evaluated between normal and abnormal amyloid individuals using GLM. Associations between plasma MDS‐OAβ and Aβ‐PET status were assessed using logistic regression analyses and receiver operating characteristics analyses.

Result

We found a 2‐way interaction for amyloid status and storage period on plasma MDS‐OAβ levels. In samples stored ≤4 years, but not >4 years, plasma MDS‐OAβ was higher in abnormal Aβ‐PET individuals, and could identify abnormal amyloid status with an Area Under the Curve (AUC) of 74% (95%CI:67%‐81%). Combining APOEe4 and age with plasma MDS‐OAβ revealed an AUC of 81% (95%CI: 74%‐87%; figure 1), which performed better than age and APOEe4 genotype alone (AUC: 70%, 95% CI: 63‐78, p=0.01). Using the highest Youden cutoff (45, sensitivity=76%, specificity=69%) to identify 100 individuals with abnormal Aβ‐PET status reduced the number of PET scans by 118, and lowered PET costs from 1.490.000 to 900.000 USD (40%).

Conclusion

Plasma MDS‐OAβ together with APOEe4 and age, has the potential to identify brain amyloidosis. Additionally, plasma MDS‐OAβ as a screener could reduce the costs may reduce the number of PET scans needed to screen for amyloidosis, which is highly relevant for clinical trials.
Optimized regional analysis to detect longitudinal 18F‐RO‐948 tau PET change in early AD
Authors: Klein Gregory , Scott David , Leuzy Antoine , Smith Ruben , Jögi Jonas , Ohlsson Tomas , Stomrud Erik , Borroni Edilio , Hansson Oskar
Published: December 2020

Background

Analyses from the Swedish BioFINDER‐2 study have shown that tau burden change seen via 18F‐RO‐948 tau PET tracer replicates the post‐mortem spreading pattern of tau. The greatest longitudinal changes have thus far been seen in Braak regions I/II for amyloid positive (Aβ+) cognitively unimpaired (CU) subjects, and Braak regions III/IV and V/VI for Aβ+ subjects with mild cognitive impairment (MCI) and AD dementia, respectively. In the design of clinical trials, selecting a composite cortical region with the greatest longitudinal effect size (LES) is a key objective in keeping trial sample size practical. In this study, we employed a Lasso optimization method to determine a combination of brain subregions optimized for maximal effect size in the pre‐symptomatic and early AD populations.

Method

Study participants were scanned at baseline and a targeted first follow‐up scan at 12 months with 18F‐RO‐948 tau PET. Annualized change of tau burden for 116 subregions was computed using FreeSurfer v6.0 and an SUVR method with an inferior cerebellar grey reference region. Subjects were analysed separately based Aβ‐status (using CSF Aβ42/Aβ40) and baseline clinical diagnosis: CU, MCI and dementia due to AD. A Lasso optimization with 5‐fold cross validation was used to explore the optimum combination and weighting of ROIs to maximize LES.

Result

Longitudinal scans from 14 Aβ+ CU subjects and 18 Aβ+ MCI were included in this analysis. Maximum LES via Lasso for the Aβ+ CU group was 1.01, and 0.81 for the Aβ+ MCI group. Both sets of composite ROIs included three subregions, listed as follows with decreased Lasso weighting: (left‐entorhinal, right‐amygdala, right‐hippocampus) for Aβ+ CU and (left‐fusiform, left‐temporal pole, right‐superiorparietal) for the Aβ+ MCI group. Lasso LES was larger than LES found with Braak staging ROIs: 0.87 for the Aβ+ CU group using Braak I/II, and 0.62 for the Aβ+ MCI group using Braak III/IV.

Conclusion

A Lasso method determined composite target ROIs with greater effect size than ROIs selected using Braak staging models. Little overlap exists in region sets optimized for pre‐symptomatic and early AD populations, indicating that careful endpoint design is required to detect change in longitudinal studies.
Worse baseline lung function is associated with worse cognition among older black and white adults
Authors: Bobrow Kirsten , Rouch Laure , Hoang Tina D , Yaffe Kristine
Published: December 2020

Background

Prior studies indicate that lung function may be an important risk factor for cognitive impairment and decline, but the body of evidence has largely been restricted to cross‐sectional and single‐time point measurement studies in white populations.

Methods

We studied 1128 black and 1641 white participants, mean age 74 years (SD 3), without prevalent dementia at enrollment in the Health Aging and Body Composition (Health ABC) Study. Participants completed spirometry assessments including Forced Expiratory Volume in 1 second (FEV1) at baseline, years 5, 8, and 10. Digit Symbol Substitution Test (DSST) and Modified Mini‐Mental exam (3MS) were used to assess processing speed and global cognitive function at years 5, 8, 10, and 11. We evaluated the association of baseline and rate of change in lung function in relation to baseline and change in cognitive performance (stratified by race) with mixed linear regression models and adjusting for demographics, comorbid health conditions and health behaviors.

Results

Compared to white participants, black participants had less education, lower socioeconomic status, and were more likely to be current smokers. Baseline mean FEV1 was 2300 ml (SD 551) and 1949 ml (SD 640) in white and black participants. During follow‐up lung function decreased by 207 ml (95%CI 199, 215) and 139 ml (95%CI 130, 148) respectively. In multivariable adjusted analyses, higher baseline lung function was associated with better cognitive test scores. One standard deviation (SD) lower baseline FEV1 was associated with worse DSST scores (by 1.50 (95%CI 0.42,2.73) and 0.60 (95%CI ‐1.0, 2.16) points in whites and blacks respectively, p for interaction = 0.04.) In both black and white participants, there were small but not significant effects of decline in lung function on subsequent cognitive performance and decline.

Conclusion

While the magnitude of the association was stronger in whites, we found worse baseline lung function was associated with worse cognitive function up to 10 years later in both black and white participants. Declines in lung and cognitive function vary by population‐level factors. For interventions, it is important to determine if these associations are biological or socially patterned.
Approaches to overcome recruitment challenges in a rural setting in India: Strategies adopted in Srinivasapur Aging, Neuro Senescence and Cognition (SANSCOG) study
Authors: Chaudhary Kiran , Rao Girish N , Sivakumar Palanimuthu T , Sundarakumar Jonas , Rao Naren P , Ravindranath Vijayalakshmi , Investigators SANSCOG
Published: December 2020

Background

Recruitment and retention of participants is a rate limiting step in any clinical research study, more so in a rural setting. The SANSCOG study is a large‐scale, longitudinal, rural, cohort study, to gather long term data to identify risk and protective factors for normal and pathological aging, dementia and other related disorders.

Method

The study will recruit 10,000 participants, out of which 1500 have completed baseline visit. Our recruitment strategy centred around utilising expertise within existing health care set‐up in Srinivaspur, India. We targeted 6 primary health centres and their associated villages. We collaborated with public health officials and gathered census data to identify potential participants (age ≥ 45 years). We formed a field team, conversant with the language and knowledgeable about local culture. By working closely with link workers, who are part of government health system, to promote health and well‐being initiatives in villages (ASHA), we were able to build better connections with the community. In consultation with village leaders, we conducted awareness programs, informing participants about our study. We maintained periodic contact with participants through telephone or in‐person house visits and actively engaged the community through activities like general health awareness camps, street plays and sports events. Though we don’t offer any treatment, the clinical team provides brief feedback on participants blood test reports, ECG and MRI and makes appropriate referrals to the primary health system, if necessary.

Result

We approached 3891 participants from 19 villages, out of which 48% consented. We observed that despite being marginalized, this community’s willingness to contribute to the study, with the notion of potentially helping their future generations, was remarkable. From our experience, the most crucial approach was forming alliance with existing health system to build community connections. We assessed participants interest to continue in the study via telephone calls (n=700) or house visits (n=255); having found the later strategy to be more effective, our approach was modified for subsequent follow‐ups. A pilot follow‐up was completed for 142 participants.

Conclusion

The SANSCOG project provides unique insights on recruitment approaches that can be tailored and adopted for increasing study enrolment in rural cohorts in developing countries.
Dementia prediction in the general population: External validation of 12 prognostic models in the AGES‐Reykjavik Study
Authors: Vonk Jet M.J. , Geerlings Mirjam I. , Gudnason Vilmundur , Launer Lenore J. , Greving Jacoba P.
Published: December 2020

Background

Multivariable prognostic models in the general population predict individual risk of developing Alzheimer’s disease (AD) or all‐cause dementia, which can aid selection of high‐risk individuals for clinical trials and prevention. Development of new models flourished across the past decades. However, external validation for the majority of models is lacking. We aimed to evaluate external performance of previously published prediction models for AD or all‐cause dementia.

Method

Based on multiple systematic literature reviews, we identified 12 eligible models for external validation in the AGES‐Reykjavik Study, a prospective population‐based cohort study (n=5343 without dementia at baseline; 76.6±5.7 years). Models were developed to predict either AD or all‐cause dementia up to 5, 6, or 10 years of follow‐up, and were based on logistic, Cox, or competing risk regression. Predictive performance was assessed with C‐statistics (discrimination) and calibration plots (observed vs. predicted probabilities).

Result

During 45,021 and 40,917 person‐years of follow‐up, 1099 participants developed dementia and 492 participants developed AD, respectively. The mean observed risk of dementia was 5.1% [CI:4.5‐5.7] for 5 years, 10.1% [CI:9.2‐11.0] for 6 years, and 22.8% [CI:21.5‐24.1] for 10 years; the risk for AD was 2.0% [CI:1.6‐2.4], 5.6% [CI:4.9‐6.3], and 12.1% [11.0‐13.2], respectively. Table 1 presents the validated models and their C‐statistics. Models ranged from 2‐11 predictors; all models with a cognitive test obtained C‐statistics ≥0.75, all models without ≤0.73. Information to perform calibration was provided for 5 models, and all but one showed overestimation of predicted risk (Figure 1).

Conclusion

The majority of models showed acceptable discrimination (C‐statistic >0.70), but poor calibration with systematic overestimation. These models may be acceptable for exclusion of dementia or AD (if the predicted risk is low, the observed risk is even lower), but lack the ability to accurately identify individuals at higher risk. The one model that calibrated well was developed with logistic regression, a technique that ignores observation times and censoring, which can introduce bias into the prediction process. Updating existing models or development and external validation of new models aimed at identifying high‐risk individuals using Cox regression or competing risk regression is therefore warranted.
Predicting conversion from mild cognitive impairment to Alzheimer's disease using cortical diffusivity analysis
Authors: Torso Mario , Hardingham Ian , Jenkinson Mark , Chance Steven A ,   National Alzheimer’s Coordinating Center (NACC)
Published: December 2020

Background

Alzheimer's Disease (AD) is characterized pathologically by important neural architecture changes. Diffusion Tensor Imaging (DTI) has provided promising results for the investigation of microstructural changes of white matter, but its use in cortical grey matter is still limited. In the present study, we investigated the performance of our novel cortical diffusivity measurements [McKavanagh et al. 2019] for classifying patients with AD, healthy elderly subjects (HS), patients with mild cognitive impairment (MCI) who progress to probable‐AD (MCI‐converter, MCI‐C), and those with MCI who do not progress to probable‐AD (MCI‐stable, MCI‐S). The aim here was to test the classification power of our novel cortical diffusion measurements and to test their correspondence with the standard hallmarks of AD pathology measured in CSF (total‐tau, phosphorylated‐tau and amyloid beta).

Method

DTI and T1 structural scans and CSF data of 454 subjects (respectively 310 HS, 48 MCI‐S, 45 MCI‐C and 51 AD) from the National‐Alzheimer’s‐Coordinating‐Center (NACC) were used. Three novel whole brain cortical diffusivity measures (AngleR, PerpPD, and ParlPD) [McKavanagh et al. 2019], and three standard measures (mean diffusivity [MD], cortical grey matter volume, and bilateral hippocampal volume) were calculated for each subject. Receiver Operating Characteristics (ROC) curve analysis and the Area Under the Curve (AUC) were used to assess the group discrimination capability of our method.

Result

The results showed that the new DTI derived measures can detect altered quality of cortical grey matter in AD patients, distinguishing between these and HS with an AUC of 97.5, and between MCI‐C and MCI‐S with an AUC of 87.8%. All the cortical diffusivity measures were significantly correlated with CSF values (total‐tau, phosphorylated‐tau and amyloid beta).

Conclusion

Our findings support using cortical diffusivity measurements as a surrogate of cortical microstructure quality for identification of the early stages of AD. These changes were consistent with CSF signature in which B amyloid was sensitive in the early stages and tau was elevated in the late stages (MCI‐C and AD). Further development may aid early diagnosis, patient cohort selection, and quantification of the microstructural changes in response to therapies in clinical trials.
Neuronal activity topography (NAT) analysis of EEG can predict neurocognitive deterioration earlier than FDG‐PET
Authors: Ishii Kenji , Tanaka Mieko , Watanabe Yuri , Sano Akiko , Kobayashi Yohei , Ishibashi Kenji , Wagatsuma Kei , Asada Takashi , Kosugi Yukio
Published: December 2020

Background

We recently reported that FDG‐PET can predict neurocognitive deterioration three years earlier than cognition in our aging cohort. This study examined whether EEG detects the deterioration as early as FDG‐PET.

Method

Two groups of subjects’ data‐set with normal PET/cognition were selected from our cognitively normal (CN) elderly cohort who participated in the same‐day EEG and FDG‐PET annually. The NLC group (n = 41, age = 75.2±4.7y, MMSE = 29.3±1.1) consists of those whose PET findings remain normal for more than three successive years. NL2 group (n = 22, age = 75.1±4.9y, MMSE = 29.0±1.5) consists of those whose PET findings deteriorate within three years. Each PET image was classified into five ranks (A/A‐/B/B‐/C) by visual and statistical analysis and A/A‐ were regarded as normal. The results of neuropsychological tests (MMSE, HDS‐R, MoCA) and Neuronal Activity Topography (NAT) analysis indices derived from five minutes EEG record at rest with eyes closed were compared between the two groups.

Result

The average value of the two groups is significantly different in (1) the index sNAT value based on the power spectrum of the EEG, (2) the index vNAT value based on the power ratio of the sNAT values of adjacent frequency subbands, and (3) the mean power frequency of the occipital region (sNATNLC = ‐0.077±0.071, sNATNL2 = ‐0.022±0.103, p = 0.03* ; vNATNLC = ‐0.080±0.076, vNATNL2 = ‐0.038±0.059, p = 0.03* ; MPFNLC = 9.29±0.48Hz, MPFNL2 = 8.97±0.55Hz, p = 0.02*). In the NL2 group, a significant negative correlation was found between vNAT value and MMSE, and MoCA (CORvNAT‐MMSE = ‐0.43, p = 0.05* ; CORvNAT‐MoCA = ‐0.59, p < 0.01**. Above findings suggest that the signs of cognitive deterioration in near future is detectable using NAT analysis.

Conclusion

In cognitively normal subjects whose PET findings start to deteriorate in the next following years, signs of deterioration are already detectable with NAT analysis of EEG. This suggests that the alteration of neuro‐electrical activity may precede the decline of cerebral glucose metabolism. Further study with larger groups is necessary.
Studies on the pragmatic performance and validity of a plasma amyloid β measurement system by immunoprecipitation‐mass spectrometry
Authors: Kaneko Naoki , Yoda Ritsuko , Korenaga Akihito , Ohashi Yuko , Honda Mamoru , Hioki Yusaku , Sekiya Sadanori , Iwamoto Shinichi , Tsujino Kazushige , Tanaka Koichi
Published: December 2020

Background

The measurement of plasma amyloid β recently attracts much attention as a biomarker of Alzheimer’s disease. We developed a highly sensitive method for simultaneous detection of a plurality of amyloid β peptides in human plasma by using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS). In this study, we examined the effects of interfering substances in human plasma to reinforce the performance and practicability of this approach.

Method

Anticoagulants, Alzheimer's disease drugs, peptides having the epitope with high homology to 6E10 anti‐amyloid β antibody, and a drug having a similar mass to the amyloid β peptide were added to human plasma. The doped plasmas were then analyzed by IP‐MALDI‐MS. Plasma with PBS added was used as a control.

Result

Two biomarker values (Aβ1‐40/Aβ1‐42 and APP669‐711/Aβ1‐42) in the interfering substances doped plasma were compared to those of control plasma. The results showed that the addition of any of those drugs had only a slight effect on the measured values, and the difference between the plasma biomarkers to which the compound was added was ± 10% or less relative to the control.

Conclusion

The analysis of plasma amyloid β biomarkers by IP‐MALDI‐MS is a unique method for the simultaneous detection of multiple amyloid β peptides requiring only one kind of antibody. Addition of twelve kinds of contaminants to the human plasma have limited effects on the analytical performance of the system.
Impact of APOE‐ε4 on cerebral amyloid deposition in participants with abnormal soluble amyloid levels
Authors: Cacciaglia Raffaele , Molinuevo Jose Luis , Salvadó Gemma , Suárez‐Calvet Marc , Shekari Mahnaz , Operto Greg , Fauria Karine , Minguillón Carolina , Farrar Gill , Buckley Chris J , Blennow Kaj , Zetterberg Henrik , Eichenlaub Udo , Kollmorgen Gwendlyn , Gispert Juan Domingo ,   ALFA study
Published: December 2020

Background

Amyloid pathology can be detected using cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) imaging, even though they measure two distinct beta‐amyloid (Aβ) pools. While CSF Aβ concentrations reflect the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques in the brain tissue. Many studies have shown the concordance between the two measures in individuals along the Alzheimer’s continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for Alzheimer’s disease (AD), affects the pattern of cerebral Aβ load as a function of CSF Aβ levels.

Method

The first consecutive 276 cognitively unimpaired (CDR = 0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ40 and Aβ42 concentrations were determined with the Roche NeuroToolKit (Roche Diagnostics) and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxel‐wise regression was performed to predict FTM uptake, with the following independent variables: age, sex, APOE‐ε4, and CSF Aβ42/40 ratio. Statistical threshold was set to p < 0.001 with a cluster extent correction of 100 voxels.

Result

As expected, CSF Aβ42/40 ratio was negatively associated with cerebral FTM uptake (Figure 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM‐binding across the whole sample (Figure 2b‐2c). Importantly, we found a significant interaction between CSF Aβ42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Figure 3).

Conclusion

Compared to non‐carriers, APOE‐ε4 carriers showed higher cerebral Ab load for any given level of CSF Aβ42/40 in areas that are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the Alzheimer’s continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.
Blood pressure at the age of 70 as a predictor of incident dementia: A 15‐year longitudinal study
Authors: Wetterberg Hanna , Najar Jenna , Rydén Lina , Kern Silke , Zettergren Anna , Skoog Ingmar
Published: December 2020

Background

We have previously reported that blood pressure (BP) at age 70 predicted incident dementia in a birth cohort born 1901‐02. It is known that BP in older adults has decreased in high‐income countries during the last decades. The aim of this paper was to explore whether BP at age 70 still predicted incident dementia in a cohort born three decades later.

Method

A population‐based sample of 70‐year‐olds born 1930 was followed for 15 years as part of the Gothenburg H70 Birth Cohort studies. Dementia was diagnosed by geriatric psychiatrists according to the DSM‐III‐R criteria at all examinations. All individuals with prevalent dementia at baseline were excluded in this study. Among drop‐outs, the Swedish National inpatient register was used to detect dementia. Systolic (SBP) and diastolic blood pressure (DBP) were measured at baseline and all follow‐ups. To compare the mean blood pressure levels between the groups, Students t‐tests were used.

Result

At baseline, 588 participants were free from dementia and 107 individuals developed dementia during the study period. Of these, 18 developed dementia between age 71‐75, 27 between 76‐80, and 62 between 81‐85. Those who developed dementia between age 76‐80 had higher mean SBP (165 [sd +21.9] versus 155 [sd +22.1], p=0.016), and DBP (90 [sd +10.7] versus 86 [sd +10.7] p=0.045) at age 70, compared to those who remained dementia‐free. There were no differences in SBP or DBP at age 70 among those who developed dementia between age 71‐75 or between age 81‐85.

Conclusion

Our results suggest that high blood pressure at the age of 70 predicts dementia incidence between age 76‐80 years, despite that mean BP was considerably lower in the later born cohort.
DNA methylation differences associated with peripheral biomarkers in the EMIF‐AD cohort
Authors: Smith Rebecca G. , Bos Isabelle , Vos Stephanie J.B. , Verhey Frans R.J. , Scheltens Philip , Engelborghs Sebastiaan , Frisoni Giovanni B. , Blin Olivier , Richardson Jill , Bordet Régis , Tsolaki Magda , Popp Julius , Martinez‐Lage Pablo , Lleó Alberto , Johannsen Peter , Freund Yvonne , Frölich Lutz , Vandenberghe Rik , Lovestone Simon , Streffer Johannes , Andreasson Ulf , Blennow Kaj , Visser Pieter Jelle , Zetterberg Henrik , Bertram Lars , Lunnon Katie
Published: December 2020

Background

Alzheimer’s disease is associated with increases in amyloid β and hyperphosphorylated tau which is thought to occur decades before the onset of clinical symptoms, leading to cell loss and inhibition. Finding biomarkers to detect these changes before neuronal loss and therefore permanent damage has occurred is integral. Current biomarkers using cerebrospinal fluid (CSF) measures and positron‐emission tomography (PET) imaging are invasive or expensive to perform. In this study we use the European Medical Information Framework Alzheimer’s disease (EMIF‐AD) cohort to looks for blood related epigenetic (DNA methylation) changes which relate to CSF and existing peripheral biomarkers.

Method

Whole blood samples from EMIF‐AD were accessed for DNA methylation on Illumina EPIC arrays. We assessed DNA methylation levels in 886 individuals with > 10 central and local biomarker measures, including amyloid, tau, neurogranin and YKL‐40. We also performed regional analysis to look for regions of significant DNA methylation change and identified specific pathways that show methylomic changes in association with specific biomarkers.

Result

We identified epigenome‐wide significant probes associated with many of our biomarker measures including most notably central amyloid β‐42, amyloid β‐40/42 ratio, neurogranin and YKL‐40 CSF levels as well as with local phosphorylated tau and total tau measurements. We also are able to use collections of CpG sites to create classifiers that predict high levels of CSF biomarkers.

Conclusion

In the future, identified sites and collections of sites could be used as a proxy for other biomarker measures due to the less invasive and less expensive nature of blood collection DNA methylation analysis. We are currently undertaking further analysis of this cohort using imaging and clinical measures.
Associations between physical activity and markers of brain pathology in autosomal dominant Alzheimer’s disease: A preliminary report
Authors: Guzman‐Velez Edmarie , Vila‐Castelar Clara , Pardilla‐Delgado Enmanuelle , Fox‐Fuller Joshua T , Bocanegra Yamile , Baena Ana , Ramirez‐Gomez Liliana A , Lopera Francisco , Taylor J Andrew , Quiroz Yakeel T
Published: December 2020

Background

Physical activity is a promising lifestyle factor that could protect against memory decline in preclinical Alzheimer’s disease (AD). Greater physical activity has been shown to attenuate the relationship between amyloid‐b and cognitive decline and neurodegeneration in individuals at risk for dementia. Yet, little is known about the relation of physical activity with tau pathology, a strong predictor of cognitive decline. Autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to study preclinical AD since carriers of ADAD mutations are destined to develop dementia at early age, have a well‐characterized disease trajectory, and do not present age‐related comorbidities. We examined physical activity levels in young mutation carriers and non‐carriers from a Colombian kindred with ADAD, and explored the associations among physical activity, brain pathology (amyloid and tau), hippocampus volume, and memory performance.

Methods

Ten Presenilin‐1 E280A cognitively unimpaired mutation carriers and 23 matched non‐carriers (ages: μ=37.46, σ:6.01) traveled from Colombia to Boston for 11C Pittsburgh compound B‐PET (amyloid), Flortaucipir‐PET (tau), MRI and cognitive testing. All completed the 7‐day Physical Activity Recall questionnaire, which provides a measure of metabolic equivalents (METS) based on an estimate of the energy expenditure for common physical activities. Group differences were tested using the Mann Whitney U test. Linear regressions were used to examine associations between METS, imaging markers, and memory.

Results

Compared to non‐carriers, mutation carriers had greater cortical amyloid (non‐carriers: μ=1.05, σ=0.03, carriers: μ=1.26, σ=0.20, p<.001), and performed worse on the CERAD word list recall test (non‐carriers: μ=7.96, σ=1.24, carriers: μ=5.83, σ=2.75, p=.012). Groups did not differ in age, sex, education or METS (non‐carriers: μ=248.89, σ:27.53; carriers: μ=249., σ:20.81). Further, METS were not significantly associated with pathology levels, age, hippocampus volume or memory. However, those carriers (n=4) with the highest entorhinal and inferior temporal tau burden also had the lowest METS.

Conclusion

Preliminary findings of this ongoing study suggest that physical activity levels may not be associated with markers of neurodegeneration or memory performance in early preclinical ADAD. Future studies with larger samples and longitudinal follow‐up are needed to better understand the role of physical activity in the risk and progression of AD.
Trans‐ethnic meta‐analysis of interactions between genetics and early life socioeconomic status on memory performance and decline in older Americans
Authors: Faul Jessica D. , Kho Minjung A. , Zhao Wei , Rumfelt Kalee E. , Mitchell Colter , Smith Jennifer A.
Published: December 2020

Background

Later life cognitive function is influenced both by genetics as well as early‐ and later‐life socioeconomic context, and these factors may also interact with each other. Previous research has demonstrated interactions between adult socioeconomic status and several gene regions that influence memory performance and decline in older adulthood, but few studies have examined whether genetics also interacts with childhood socioeconomic factors.

Methods

We used growth curve modeling to estimate episodic memory performance at age 65 (trajectory intercept) and decline thereafter (trajectory slope) in European ancestry (EA, N = 10,468) and African ancestry (AA, N = 2,252) participants from the Health and Retirement Study. Early‐life socioeconomic context included measures of parental education and financial strain. We selected 39 gene regions previously associated with cognitive performance, dementia, and related traits from GWAS. We tested whether all variants (1000 Genomes imputed data) and/or rare exomic variants (exome chip data) in these gene regions interacted with childhood socioeconomic context to influence memory using gene‐based tests (Interaction Sequence Kernel Association Test (iSKAT) or iSKAT Optimal Unified Test (iSKAT‐O)). For iSKAT analyses, we conducted a trans‐ethnic meta‐analysis.

Results

Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions (p < 0.05) with at least one childhood socioeconomic measure on memory performance and/or decline; however, all but one (father’s education by SLC24A4 gene region in AA) were not significant after multiple testing correction (FDR <0.1). In trans‐ethnic meta‐analysis, two gene regions interacted with childhood socioeconomic context (FDR <0.05). Both interactions were robust to adjustment for respondent’s own educational attainment and APOE ε4. For both interactions (mother’s education by MS4A4A on memory performance (meta‐analysis p = 0.0005), and father’s education by SLC24A4 on memory decline (meta‐analysis p = 0.0009)) in both EA and AA, the genetic effect was stronger in participants with low parental education.

Conclusions

Examination of common and rare variants in genes discovered through GWAS shows that childhood socioeconomic context may interact with a few key gene regions to jointly impact memory function and decline in later life. Genetic effects may be more salient for those with lower childhood socioeconomic status.
Regional distribution of tau pathology in cognitively unimpaired, genetically identical twins
Authors: Coomans Emma M. , Tomassen Jori , Wolters Emma E. , Golla Sandeep S.V. , den Hollander Marijke , Verfaillie Sander C.J. , Collij Lyduine , Windhorst Albert D. , Boellaard Ronald , Barkhof Frederik , Ossenkoppele Rik , de Geus Eco J.C. , Scheltens Philip , Visser Pieter Jelle , Van Berckel Bart N.M. , den Braber Anouk ,   the AMYPAD consortium
Published: December 2020

Background

Limited information is available on the genetic and environmental contributions to early AD pathology. Within a sample of cognitively unimpaired genetically identical older twins we aimed to assess 1) effects of amyloid‐ß pathology on [18F]flortaucipir (tau) binding and 2) spatial similarities in tau patterns within twin pairs.

Method

To date, ten twin pairs (i.e. twenty twins) from the on‐going EMIF‐AD PreclinAD study underwent dynamic (0‐30min and 80‐100min) [18F]flortaucipir PET. Two twin pairs were concordant amyloid‐ß positive, four twin pairs concordant amyloid‐ß negative and four twin pairs amyloid‐ß discordant (i.e. one twin positive and co‐twin negative) based on [18F]flutemetamol visual read. [18F]flortaucipir binding potential (BPND) images were generated using receptor parametric mapping (reference region: cerebellar gray matter). First, we compared [18F]flortaucipir BPND in an early (entorhinal), intermediate (limbic) and late (neocortical) stage tau pathology region between amyloid‐ß positive and negative twins using generalized estimated equation correcting for twin dependency. Next, we examined spatial tau pattern similarities within twin pairs by correlating (Spearman) [18F]flortaucipir BPND across 46 ROIs from the Hammers template between each twin and their co‐twin for each true twin pair. Correlations were also performed for all non‐twin “random” pairs. Correlation coefficients within true twin pairs were compared to the correlation coefficients within random pairs, correcting for age and twin amyloid‐ß status.

Results

Amyloid‐ß positive twins showed higher [18F]flortaucipir BPND in entorhinal (p=0.01) and limbic (p=0.04) regions(Table‐1). Fig‐1 shows representative [18F]flortaucipir images of an amyloid‐ß concordant positive, concordant negative and discordant pair, with regional similarities observed in amyloid‐ß concordant pairs as well as dissimilarities in amyloid‐ß discordant pairs (Fig‐1;Fig‐2). Between‐twin correlations across regional [18F]flortaucipir BPND, to assess spatial tau pattern similarities, were higher for true twin pairs (r=0.71±0.17) compared to random pairs (r=0.45±0.23) (p=0.002)(Table‐2).

Conclusion

In line with previous studies, amyloid‐ß positive cognitively unimpaired twins showed higher tau deposition in early and intermediate tau stage regions. Furthermore, we observed higher spatial tau pattern similarities within true twin pairs compared to random pairs, suggesting a moderate genetic contribution to mechanisms underlying tau spread. With the upcoming larger sample we aim to further assess genetic and environmental contributions to early AD pathology.