bluuebunny/crossref_metadata_2025 huggingface dataset:
Non‐linear relationship between plasma amyloid‐β 40 level and cognitive decline in a cognitively normal population
Authors: Gao Fan , Shang Suhang , Chen Chen , Dang Liangjun , Gao Ling , Wei Shan , Wang Jin , Huo Kang , Deng Meiying , Wang Jingyi , Qu Qiumin
Published: December 2020

Background

Recent studies have suggested that plasma β‐amyloid 42 is related to long‐term cognitive impairment and incident dementia. However, the relationship between plasma β‐amyloid 40 (Aβ40) level and cognitive decline is unclear. In this study, we aimed to characterize the relationship between cognitive decline and plasma Aβ40 in a cognitively normal population.

Method

This population‐based prospective cohort study included 1240 participants with normal cognition. The Mini‐Mental State Examination was used to assess cognitive function at baseline and two years later. Restricted cubic splines, multivariable logistic regression and multivariable linear regression models were used to evaluate the shape of the relationship between cognitive decline during the two‐year follow‐up period and plasma Aβ40.

Result

Participants with moderate Aβ40 levels had the highest risk of cognitive decline relative to individuals with low Aβ40 (odds ratio [OR]: 0.60, 95% confidence interval [CI]: 0.45‐0.81, p<0.001) or high Aβ40 (OR: 0.65, 95% CI: 0.49‐0.87, p=0.004) levels. The association between plasma Aβ40 and cognitive decline was not altered by sex, education level and APOE genotype (interaction p>0.05). However, this association was more evident among participants ≤65 years old than among those >65 years old (interaction p=0.021).

Conclusion

The relationship between plasma Aβ40 and cognitive decline was not linear, but an inverted‐U shape in a cognitively normal population. The underlying mechanism requires further elucidation.
Collaborating with Australian Indigenous communities: A protocol to address the high rates of dementia found in aboriginal and Torres Strait Islander people
Authors: Russell Sarah G , Quigley Rachel , Sagigi Betty , Miller Gavin , Strivens Edward
Published: December 2020

Background

In Australia, Indigenous people aged 45 and over have three to five times higher risk of dementia than the wider community. Research shows that up to a third of dementia cases may be delayed by modifying lifestyle risk factors. Specific risk and protective factors contributing to the increased dementia risk in Indigenous communities require clarification as the first step towards developing culturally appropriate interventions. The aim of this paper is to outline a study protocol investigating whether potential protective factors identified in the wider population as supporting cognitive function in later life confer protection to Indigenous populations.

Method

This project will use a Participatory Action Research approach to enable communities to identify and prioritise dementia risk reduction strategies/potential risk and protective factors. Using a Continuous Quality Improvement Framework, primary health care centres will address modifiable dementia risk factors identified to change practice and systems through the development of culturally appropriate interventions.

Results

Resulting interventions will identify and address barriers and enablers unique to Aboriginal and Torres Strait Islander communities.

Conclusion

The outcome will be a culturally appropriate framework that incorporates evidence‐based best‐practice guidelines for delivering community specific interventions for risk reduction and prevention of dementia.
Vascular risk factors and amyloid pathology: Additive or interactive associations?
Authors: Schott Jonathan M , Lane Christopher A , Barnes Jo , Keuss Sarah E , James Sarah‐Naomi , Lu Kirsty , Sudre Carole H , Cash David M , Parker Thomas D , Malone Ian B , Keshavan Ashvini , Murray‐Smith Heidi , Wong Andrew , Buchanan Sarah M , Gordon Elizabeth , Coath William , Barnes Anna , Dickson John , Modat Marc , Thomas David L , Chaturvedi Nishi , Hughes Alun , Crutch Sebastian J , Richards Marcus , Fox Nick C
Published: December 2020

Background

The two commonest contributors to late‐life cognitive impairment are Alzheimer’s (AD) and cerebrovascular disease; these two conditions almost invariably overlap. Understanding the determinants of the pathologies that underpin these conditions and how they interact to influence late‐life brain health is vital for rational risk prevention and for clinical trials.

Method

Data from the Insight 46 cohort will be presented, comprising individuals from the MRC 1946 British Birth Cohort all born in mainland Britain in one week in 1946. These individuals have been followed prospectively including serial measures of cognition from age 8, cardiovascular risk since the mid‐30s, and a range of cardiac and vascular outcomes in their 60s. At age 69‐71 they had detailed cognitive testing, 3T‐MRI including determination of white matter hyperintensity volume (WMHV) and 18F‐Florbetapir (β‐amyloid) PET. All individuals are being seen for a second visit, two‐years after the first.

Results

A total of 502 participants were assessed cross‐sectionally; data from up to 465 participants (51.0% male, mean age=70.7±0.7, 18.2% β‐amyloid positive) are available. Results of cross‐sectional analyses investigating the relationships between life course cardiovascular risk factors genetics, β‐amyloid and WMHV will be presented, alongside analyses of the associations of these pathologies with cross‐sectional cognitive function and MRI metrics. Investigations exploring mechanistic relationships e.g. between cardiac and vascular outcomes including pulse wave velocity and echocardiography, β‐amyloid and WMHV and cognition will be presented. Interim results of analyses exploring relationships between baseline β‐amyloid and WMHV and rates of cognitive decline and brain atrophy will be described in n=250 (47.6% female, age=72.5±0.33, 18.1% β‐amyloid positive) of the cohort. These results will be compared and contrasted with those from other cohort studies including the Atherosclerosis Risk in Communities (ARIC) study, and Mayo Clinic Study of Ageing.

Conclusion

Combining life course data, contemporaneous measurement of PET‐amyloid status, WMHV and cognition, vascular metrics and longitudinal measures of brain atrophy and cognitive change provides a powerful opportunity to explore how and when vascular and β‐amyloid pathology influence brain health in later‐life. Emerging evidence from several studies suggest that vascular risk influences the development of cognitive impairment and dementia principally via non‐amyloidogenic pathways.
Patterns of default mode network co‐activation in young APOE ε4‐carriers: An HCP replication study
Authors: Mentink Lara J. , Guimarães João P.O.F.T. , Sprooten Emma , Rikkert Marcel G.M. Olde , Haak Koen V. , Beckmann Christian F.
Published: December 2020

Background

Filippini et al. reported an increased default mode network (DMN) co‐activation during rest in young APOE ε4‐carriers [1]. This work has been of substantial importance, often used to illustrate the trajectory of DMN alterations in APOE ε4‐carriers from young adults and normal aging to mild cognitive impairment and AD. However, this study only assessed a small sample. Here, we aimed to replicate their finding in a substantially larger sample from the Human Connectome Project (HCP).

Method

We included participants from the HCP S1200 dataset. We followed the methods of [1] for structural MRI and resting‐state fMRI data, with the following deviations: instead of using voxel‐based morphometry to assess gray matter density, we assessed gray matter volume with FreeSurfer. To test for differences in DMN co‐activation and gray matter volume between APOE ε4‐carriers and non‐carriers, we used Permutation Analysis of Linear Models (PALM). PALM controls for biases induced by the family structure of the HCP sample. Results were family‐wise error rate corrected at p < 0.05.

Result

We included 167 APOE ε4‐carriers and 419 non‐carriers for the DMN analysis. In contrast to [1], we did not find significant differences in DMN co‐activation between carriers and non‐carriers. For the morphometric analyses, 243 carriers and 544 non‐carriers were included. No differences in brain volume were found between carriers and non‐carriers. For both analyses, including covariates (different combinations of age, sex, education level, head motion) did not alter the results.

Conclusion

We could not replicate the early findings of [1] in a large sample. Our results suggest that solely APOE ε4‐carriership does not influence brain function at a young age. Future work will focus on the use of polygenic risk scores to study whether any genetic predisposition for AD influences brain function in young adults. Still, genetic predisposition for AD might not have any measurable effect decades before clinical expression of AD. Therefore, repeating the analysis in a healthy, middle‐aged cohort could inform us whether the influence of genetic predisposition for AD increases over time. Altogether, our replication study is an important step forward in unravelling AD development. Resource: (1) Filippini et al., PNAS, 2009.
Quantifying dementia prevention potential in the FINGER randomized controlled trial using the LIBRA prevention index
Authors: Deckers Kay , Koehler Sebastian , Ngandu Tiia , Verhey Frans RJ , Kivipelto Miia , Solomon Alina
Published: December 2020

Background

Individuals in early dementia prevention trials may differ in how much they benefit from the interventions depending on their initial level of dementia risk. Using a composite risk score comprising health‐ and lifestyle factors (i.e., modifiable dementia risk) might be useful to better target future interventions and to monitor intervention effects during study execution. The present study examines whether the effects of a multi‐domain lifestyle intervention on cognition differ across baseline modifiable dementia risk, and to investigate the potential use of a modifiable dementia risk score as an outcome measure in intervention studies.

Method

The 2‐year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) randomized controlled trial recruited 1260 people aged 60‐77 and at‐risk of dementia from the general Finnish population. Participants were randomized 1:1 to a multi‐domain intervention group (diet, exercise, cognition, and vascular risk management) or control group (general health advice). Modifiable dementia risk was ascertained with the ‘LIfestyle for BRAin health’ (LIBRA) score. LIBRA consists of 12 risk and protective factors for cognitive decline and dementia, with higher scores indicating greater dementia risk (i.e. a more unhealthy lifestyle; range: –5.9 to +12.7). Primary outcome was change in cognition (baseline, 1‐ and 2‐year) measured with a comprehensive neuropsychological test battery (NTB) total score, and other outcomes include executive functioning, processing speed, memory and abbreviated memory.

Result

Higher LIBRA scores at baseline were associated with lower cognitive test scores and predicted more decline on the NTB total score and in the memory and abbreviated memory domain over the 2‐year study period, but treatment outcomes did not differ across LIBRA scores/tertiles. LIBRA scores declines both at one and two year follow‐up. There was more decline in the LIBRA score in the intervention group compared to the control group (B = ‐0.184, 95% CI ‐0.328 to ‐0.040; p = 0.012).

Conclusion

The FINGER intervention was evenly effective in those at low, medium or high lifestyle‐based risk. LIBRA may be useful as a surrogate/intermediate endpoint and surveillance tool to monitor intervention success during trial execution.
Association of early life BMI with dementia risk: Findings from a pooled cohort analysis
Authors: Hazzouri Adina Zeki Al , Vittinghoff Eric , Hoang Tina D , Golden Sherita H , Fitzpatrick Annette L , Zhang Adina , Yaffe Kristine
Published: December 2020

Background

The evidence about the timing and influence of some key cardiovascular risk factors, such as Body Mass Index (BMI), on the risk of Alzheimer disease and other dementias remains debatable. Studies have shown that high midlife BMI increases the risk of dementia, while high late life BMI may be protective; however, relatively little is known about the role of early life BMI on the risk of Alzheimer Disease and other dementias.

Method

We studied 5,104 older adults from two studies, the Cardiovascular Health Study (CHS, n=2,909) and the Health, Aging and Body Composition study (Health ABC, n=2,195) study. For CHS‐Health ABC older adults, we imputed early and midlife BMI, beginning at age 18, using linear mixed models applied to a pooled cohort which also included young and middle‐aged adults from CARDIA and MESA. BMI was then summarized by time‐weighted averages in early (ages 20‐49), mid (ages 50‐69), and late life (ages 70‐89). In CHS, dementia was adjudicated by an expert committee following a detailed neuropsychological test battery and neurological examination. In Health ABC, dementia diagnosis was determined based on hospitalization ICD codes, dementia‐related drugs and decline on the Modified Mini Mental State Examination. All analyses were sex stratified.

Result

CHS‐Health ABC participants had a mean age of 72.6 years (SD=4.2) at enrollment, 18% were black and 56% were women. For women, dementia risk increased with higher early life BMI: it was 1.8 times higher among those who were overweight (OR=1.8; 95% CI=1.31‐2.54) and 2.5 times higher among those who were obese (OR=2.45; 95% CI=1.47‐4.06), from pooled logistic regression models adjusted for midlife and late life BMI. For men, dementia risk increased with higher early life (Obese OR=2.47; 95% CI=1.46‐4.19) and mid life BMI (Overweight OR=1.51; 95% CI=1.11‐2.05 and Obese OR=2.00; 95% CI=1.16‐3.42), in models also adjusted for late life BMI. For both women and men, dementia risk decreased with higher late life BMI.

Conclusion

Our study is the first to report heightened dementia risk with higher early life BMI, for both women and men. Accounting for early life BMI, we found no effect for midlife BMI on dementia risk among women.
Novel homozygous nonsense mutation in SORL1 gene presenting as dementia and cerebral amyloid angiopathy
Authors: Palmero Víctor Antonio Blanco , Velasco Sara Llamas , Mora María Isabel Álvarez , Martínez David Andrés Pérez , Carro Eva , Martín Alejandro Octavio Herrero San , Sánchez Marta González , Martín Verónica Puertas , Bartolome Fernando , Muñoz Almudena López Rufián , Martínez Alba García , Galende Alberto Villarejo
Published: December 2020

Background

The SORL1 gene encodes a type‐I transmembrane protein termed sortilin‐related receptor (SorLA). SorLA regulates the intracellular transport and processing of the amyloid precursor protein in neurons, and therefore, it has been implicated in the pathogenesis of Alzheimer’s disease (AD). Several SORL1 mutations have been described as a risk factor for AD, especially rare missense and non‐coding variants. To date, there are no reports of nonsense SORL1 mutations in homozygosis. Also, the relationship between cerebral amyloid angiopathy (CAA) and SORL1 mutations is not well established.

Method

Case report.

Results

A 62‐year‐old man was referred to our department complaining of a 3‐year history of apathy, memory complaints and spatial difficulties. His family history was remarkable for early onset dementia in his father and behavioural problems in his mother starting at the age of 80. Neuropsychological testing showed moderate episodic memory impairment, mild ideomotor apraxia and mild dysexecutive symptoms. The MRI showed marked global atrophy, superficial siderosis and multiple cortico‐subcortical microhemorrhages, fulfilling Boston criteria for probable CAA. Genetic testing using whole exome revealed the variant c.364C>T (p.R122*) in SORL1 gene (NM_003105.5) in homozygosis. In addition, APOE genotype was 3/3.

Conclusion

we describe a novel SORL1 mutation associated with AD. This is the first human report of a SORL1 nonsense mutation in homozygosis. SORL1 could play a role in the development of CAA.
Transcriptome‐based analyses of EADB reveal new insights into Alzheimer's disease
Authors: Küçükali Fahri ,   EADB
Published: December 2020

Background

For the majority of Alzheimer’s disease (AD) genetic risk loci, the mechanism of action of variants or genes in AD pathophysiology remains unidentified. One way to approach this is to investigate the downstream effects of AD‐associated variants on molecular phenotypes such as expression and splicing. By integrating EADB and AD‐relevant brain expression and splicing data we performed the largest transcriptomic investigation of AD GWAS to date.

Method

We generated both eQTL and sQTL catalogues on six AD‐relevant brain regions by integrating whole‐genome sequencing (WGS) genotypes of a total of 1067 individuals with 1552 brain RNA‐Seq samples after quality control, available at AMP‐AD Knowledge Portal. We quantified expression and splicing using GTEx and Leafcutter pipelines, and used enhanced FastQTL to perform linear regression of WGS genotypes against normalized molecular phenotypes with adjustment for sex, genetic and transcriptomic principal components. We investigated the overlap between AD‐associated EADB GWAS variants and e/sQTL variants. We then generated expression and splicing weight panels using these catalogues and conducted expression and splicing TWAS for AD on summary statistics of the EADB GWAS including 100,000 Europeans. Long‐read nanopore sequencing was performed using 60 lymphoblastoid cell lines, 18 frontal cortex BA10 and 16 hippocampal cDNA samples on a MinION platform to further study complex splicing events.

Result

We identified 1225 genome‐wide significant variants that overlap with a significant eQTL (associated with 175 genes) and 525 genome‐wide significant variants that overlap with a significant sQTL (associated with 260 splice junctions) in at least one of the six catalogues created. Expression and splicing TWAS confirmed known AD‐associated genes and highlighted new genes in novel loci, including a gene on chromosome 10 located within one of the most significant novel loci of EADB GWAS, whose TWAS‐associated splice junctions (P = 7.24 × 10−10 and 7.33 × 10−10 in MayoRNASeq TCX and ROSMAP DLPFC TWAS) are hinting at novel cryptic exons, which we confirmed by Nanopore sequencing, within its functional domain.

Conclusion

Our results indicate that in addition to eQTLs, part of AD GWAS loci can be explained by sQTLs that are understudied in the field; and together these catalogues provide a valuable resource for understanding the genes involved in AD.
Better cardiovascular fitness is associated with better structural brain integrity in midlife: A population‐representative birth cohort study
Authors: d'Arbeloff Tracy , Cooke Megan , Knodt Annchen , Sison Maria , Ramrakha Sandhya , Keenan Ross , Poulton Richie , Hariri Ahmad R. , Caspi Avshalom , Moffitt Terrie E.
Published: December 2020

Background

Improving cardiovascular fitness has been promoted as a promising nonpharmacological strategy for buffering against age‐related cognitive decline and mitigating risk for Alzheimer’s disease and related dementia (ADRD). These beneficial effects may be related to the capacity for improved cardiovascular fitness to stave off age‐related brain atrophy. However, there is evidence that some neurological benefits associated with adult cardiovascular fitness may be better explained by early childhood factors—referred to as neuroselection—rather than any active neuroprotective effects of fitness on the brain.

Method

Data from 875 participants from the population‐representative Dunedin Study were utilized to investigate associations between cardiovascular fitness (VO2Max) at age 45, changes in cardiovascular fitness across adulthood, and structural brain integrity (cortical thickness, surface area, and subcortical grey matter volume) at age 45. Critically, the potential confounding effects of childhood IQ on any observed associations in midlife were evaluated in order to disentangle potential neuroselective from neuroprotective effects.

Result

Better VO2Max at age 45 was associated with thicker cortex in frontal and temporal lobes (βs:0.14 to 0.25, Figure 1b) and smaller hippocampal fissure volumes at age 45 (β=‐0.18). Higher rates of decline in VO2max were associated with lower total (β=‐0.11) and distributed regional (βs:‐0.11 to ‐0.19, Figure 2b) surface area at age 45. These associations were unaffected by the inclusion of childhood IQ in the analyses.

Conclusion

Better midlife cardiovascular fitness may offer neuroprotective effects on brain structure, which may in turn mitigate ADRD risk and buffer against cognitive decline.
Frailty, neuropathological burden and clinical severity: A cross‐sectional analysis of data from the National Alzheimer’s Coordinating Center
Authors: Ward David D , Wallace Lindsay MK , Rockwood Kenneth
Published: December 2020

Background

Within the National Alzheimer’s Coordinating Center (NACC) dataset, we quantified the associations of frailty and global neuropathological burden with clinical dementia severity, and explored whether frailty influences the expression of dementia at a given level of neuropathology.

Method

The sample included 2,621 individuals who had available clinical data and had undergone autopsy within 24 months of their last study visit. A 32‐item frailty index (FI) was calculated retrospectively using the deficit accumulation approach, and a measure of global neuropathological burden (NP) was calculated using a similar index approach from 12 markers of brain disease (e.g. neurofibrillary tangle Braak stage, density of neocortical neuritic plaques, severity of cerebral amyloid angiopathy, presence of microinfarcts). Linear models were used to model the change in the 18‐point Clinical Dementia Rating Scale sum of boxes score (CDR‐SB) per 10% increase in either the FI score or NP score, after adjusting for age, sex, education level, primary language, time from clinical assessment to autopsy, and APOE ε4 allelic status.

Result

The analytical sample was 80.8 years old (SD = 9.4 years, range = 60 – 100 years), on average. Each 10% increase in either measure was associated with a significantly higher CDR‐SB (FI: 2.41 points [95% CI = 2.27, 2.56]; NP: 0.87 points [95% CI = 0.73, 1.01]). A significant interaction indicated that the relationship between NP and CDR‐SB became weaker for each 10% increase in FI (P = .001). The largest increase in CDR‐SB due to a 10% increase in NP was observed among the least frail individuals (FI < 0.3; 1.15 points [95% CI = 0.91, 1.39]), with smaller and similar increases in CDR‐SB observed in both medium (FI ≥ 0.3; 0.77 points [95% CI = 0.47, 1.07]) and high frailty (FI ≥ 0.5, 0.73 points [95% CI = 0.39, 1.07]) groups.

Conclusion

An increasing degree of frailty and neuropathology are each independently associated with more severe impairment. Among the least frail individuals, neuropathological burden is closely related to clinical function, whereas clinical impairment may occur even at a low level of neuropathology in those who are more frail.
Longitudinal data in peripheral blood confirms PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicates its dynamic role in disease progression
Authors: Wang Qi , Chen Yinghua , Readhead Benjamin , Chen Kewei , Su Yi , Reiman Eric M. , Dudley Joel
Published: December 2020

Background

Genome wide genetic/epigenetic studies are revealing more risk loci associated with the Alzheimer’s disease (AD). One recent analysis of human epigenome‐wide association studies (EWAS) reports an association between variations in the gene PM20D1 and AD, showing hypermethylation in the brain tissues in patients with advanced‐stage AD.

Methods

We used whole genome DNA methylation data collected from peripheral blood mononuclear cells (PBMCs) in a cohort (n = 649) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among different diagnosis groups. We also leveraged the longitudinal data up to 4 years, sampled at approximately 1 year intervals to model the alterations in the methylation levels detected at the differentially methylated regions (DMRs) to delineate the methylation change course over aging and disease progression. The dynamic pattern of DNA methylation level with disease progression at the PM20D1 locus in brain tissues were also modeled from the data in The Religious Orders Study and Memory and Aging Project (ROSMAP) Study cohort (n = 740).

Results

When compared with controls, patients with mild cognitive impairment (MCI) consistently displayed promoter hypomethylation at reported methylation QTL gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in brain tissues in patients with advanced‐stage AD. By leveraging longitudinal DNA methylation data, linear mixed‐effects (LME) modeling for the unchanged diagnosis groups and U‐shape testing for those with changed diagnosis (converters) indicate that, we observe initial promoter hypomethylation of PM20D1 during MCI and early stage AD, which reverses to eventual promoter hypermethylation in the transition to late stage AD. We also confirm this observation in ROSMAP cohort as neuropathology deteriorates. Correlation of DNA methylation between blood and brain tissues at PM20D1 promoter region also demonstrates the pattern is consistent across tissues.

Conclusions

Our results confirm that PM20D1 is an mQTL for AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in‐depth study is thus warranted to fully decipher its role in the evolution of AD, and potentially explore its utility as a blood‐based biomarker for AD.
Towards a generalized deep learning framework for production scale segmentation of brain structures
Authors: McDougall Sean G , Delahanty Jeremy M , Sandoval Francisco , Knaack Alexander , Fletcher Evan , DeCarli Charles
Published: December 2020

Background

Whole brain segmentation from magnetic resonance imaging (MRI) remains a vital step in analysis workflows. We developed a deep learning framework that dramatically reduces the computational and human resources required for removal of non‐brain tissues. Segmentation of brain structures is currently resource intensive and remains a bottleneck in the analysis pipeline. Here we report on the capabilities of our previously developed deep learning framework to segment three specific brain structures of varying difficulty.

Method

We trained and tested a deep learning framework on three brain structures of varying difficulty: the Hippocampus, Cortical Grey Matter, and Lateral Ventricles. Training set size differed between segmentation task based on ground truth availability: Hippocampus (8,780 train, 878 test), Cortical Grey Matter (8,900 train, 890 test), Lateral Ventricle (8,700 train, 870 test). Data sets were derived from the following studies: ADNI, ADC, Khandle, Sol‐Inca and 90plus. At the core of our framework is a tunable multi‐stage convolutional neural network (CNN). The configuration used for these experiments is the same as our top performing configuration used for whole brain segmentation, a 5 stage 13 layer encoder followed by a 6 layer fusion decoder. All experiments were performed on an NVIDIA DGX Station with four Tesla V100 16GB GPUs. For both training and testing we used ground truth masks generated by atlas‐based segmentation techniques followed by human quality control. We used the F1 score, or dice similarity coefficient, between each prediction and ground truth mask to evaluate the quality.

Result

Sample predictions and their corresponding ground truth masks are shown in Figures 1‐3. F1 score distributions are shown in Figure 4 indicating performance in diverse imaging cohorts. General performance is high, but varies amongst ROIs. Outliers are most likely explained by low quality data.

Conclusion

Our preliminary results suggest our current deep learning framework can generalize relatively well without modification to its configuration, although performance for each ROI varies. Further modifications to the framework are needed to achieve production scale quality as well as increased quality control of ground truth masks to reduce the number of outliers and improve general performance.
The Spanish revised interview for deteriorations in daily living activities in dementia 2: Everyday functioning needs in people with dementia in Colombia and Chile
Authors: Giebel Clarissa , Gaviria Ana , Leon Tomas , Samaniego Lorena Moreno , Gabbay Mark , Franco Jose
Published: December 2020

Background

People with dementia (PwD) experience different levels of independence depending on the stage of dementia. Some PwD may struggle more with initiating activities than performing these, and vice versa. To capture this, the revised Interview for Deteriorations in Daily Living Activities in Dementia 2 (R‐IDDD2) has been developed and tested. The aim of this study was to adapt the R‐IDDD2 to Spanish populations to explore unmet everyday functioning needs in PwD living in Colombia and Chile.

Method

Back‐to‐back translation was used to translate the tool into Spanish, with the new tool (R‐IDDD2‐S) having been piloted in five PwD and family carers. Small changes were made to the wording as a result. The tool asks family carers (sometimes also PwD) about the PwD’s ability to initiate 17 daily activities, including making a hot drink, and the ability to perform 20 activities. Carers are also asked to rate the PwD’s ability to perform individual sub‐tasks, such as ‘paying with cash’ for finance management. A total of 100 family carers are expected to participate. The QoL‐AD measures the PwD’ quality of life. Data were analysed using frequency analysis and correlation analysis.

Result

To date, 17 carers (5 in Colombia, 12 in Chile) have completed the R‐IDDD2‐S. PwD were on average 75 years old (+/‐10), female (82.4%), and living at home (100%). PwD struggled mostly to initiate using the computer, maintaining an active social life, and doing housework. For the performance of daily activities, PwD experienced the most difficulties when performing tasks of medication and finance management as well as shopping and using public transport. Higher levels of overall initiative and performance difficulties were associated with lower levels of quality of life of the PwD (pInitiative = .004; pPerformance = .006).

Conclusion

In this ongoing study, the R‐IDDD2‐S highlights that PwD from Chile and Colombia seem to experience different needs when it comes to initiating and performing daily activities. By better understanding the various needs, and remaining abilities, PwD can be better supported in remaining as independent as possible in their own home for longer, and delay high cost dementia care services, such as care homes.
The ketogenic diet as a potential prevention or therapeutic strategy for AD
Authors: Craft Suzanne , Neth Bryan J , Mintz Akiva , Sai Kiran Solingapuram , Lockhart Samuel N , Cunnane Stephen , Whitlow Christopher T
Published: December 2020

Background

Diet is a powerful modulator of brain health. The ketogenic diet (KD), a very low carbohydrate diet, is remarkably effective in treating refractory epilepsy; 50‐70% of patients have >50% seizure reduction and 30% have >90% seizure reduction. Although the mechanisms underlying its effectiveness are not definitively known, reduction of neuronal hyperexcitability and neuroprotective effects of ketones have been demonstrated, as has reduction in AD pathology in rodent models. We tested the effect of a 6‐week Modified Mediterranean‐like KD (MMKD) compared with a low‐fat American Heart Association Diet (AHAD) on AD biomarkers and memory.

Method

The study used a randomized crossover design in which participants consumed either a MMKD (5‐10% of total daily calories obtained from carbohydrates) or the control AHAD (∼15% of calories obtained from fat per day) for 6 weeks, followed by a 6‐week washout period during which participants were instructed to resume their pre‐study diet, after which the second diet was consumed for 6 weeks. Diets were equicaloric with participants’ normal diet. Compliance was verified by measuring blood ketone levels. CSF collection, pseudocontinuous arterial spin label (pcASL) MRI, 11C‐AcAc/18F FDG Positron Emission Tomography (PET), and memory testing (Z score composite constructed from Story Recall and Free and Cued Selective Reminding Test) were performed at baseline and at the end of each intervention.

Result

A total of 20 participants completed both diets, with 3 participants discontinuing the study early. Mean compliance rates for completers were 90% for the MMKD and 95% for AHAD. The MMKD was associated with increased CSF Aβ42 and decreased tau. Cerebral perfusion increased after the MMKD in AD regions of interest, and whole‐brain ketone uptake increased on 11C‐AcAc PET. No changes in these outcomes were observed following the AHAD. Memory performance improved after both diets.

Conclusion

The MKKD intervention favorably influenced CSF AD biomarkers, cerebral perfusion, and memory. These results provide the basis for an ongoing Phase II study using a longer intervention in a larger sample of adults with MCI.
A strategic and cost efficient method for recruiting older adults at high risk for dementia
Authors: Ayers Emmeline , Blumen Helena M , Verghese Joe
Published: December 2020

Background

With no effective therapies to prevent, slow or stop the progression of Alzheimer’s Disease and related dementias, rates are expected to rapidly increase worldwide, increasing the necessity of research to examine interventions that alleviate symptoms and slow progression of cognitive decline. Strategic recruitment of individuals at high‐risk for developing cognitive impairment provides an opportunity to target study interventions for people who may show the greatest improvement in preventing and/or slowing progression of cognitive decline. The aim of the current study is to report a targeted and cost‐effective recruitment method to study “dementia‐at‐risk” older adults. We prospectively examined the association between “dementia‐at‐risk” status and incident dementia and pre‐dementia syndromes: Mild Cognitive Impairment (MCI) and Motoric Cognitive Risk (MCR) syndrome. MCR builds on operational definitions of MCI, substituting the cognitive criterion assessed by neuropsychological testing with slow gait. It is associated with increased risk for dementia and has only partial overlap with MCI.

Method

“Dementia‐at‐risk” was defined based on cut‐scores on either the Memory Impairment Screen (MIS) (scores >3≤6), a four‐item delayed free and cued recall test, and the AD8 (scores of ≥1), an eight‐item questionnaire that assesses memory, orientation, judgment, and function. Cox proportional hazard models adjusted for age, sex and education were used to examine the association between “dementia‐at‐risk” status and incident cognitive impairment in a sample of 446 cognitively healthy, community‐dwelling adults aged 65+ who completed telephone‐based versions of the MIS and AD8.

Result

Over a mean follow‐up of 1.5 years, participants developed incident MCR (n=22), MCI (n=34) and dementia (n=3). “Dementia‐at‐risk” status (n=120) was associated with risk of any incident cognitive impairment (MCR, MCI and dementia) (adjusted Hazard Ratio (aHR): 2.37, 95% Confidence Interval (CI): 1.38‐4.07) as well as with incident MCI alone (aHR: 3.54, 95%CI: 1.79‐7.02). No association was found with incident MCR alone.

Conclusion

Use of cut‐scores on either the telephone‐based MIS or AD8 to screen for “dementia‐at‐risk” participants provides a cost‐effective and strategic way to target older adults who may benefit the most from interventions that prevent or slow progression of cognitive decline. Expanded screening methods to identify a larger at‐risk population are needed.
The behavioral effects of virally induced human tau expression in the locus coeruleus of TgF344‐AD rats
Authors: Galloway Claire , McCann Ryan , Kelberman Michael , Chawla Shivaang , Weinshenker David
Published: December 2020

Background

Aberrant tau in the locus coeruleus (LC) is one of the first detectable neuropathological changes in Alzheimer’s disease (AD). Ubiquitous expression of mutant tau exacerbates pathological and cognitive impairments in rodent models of AD, but the consequences of wild‐type (WT) human tau expression in the LC is unknown. LC dysfunction has been linked to neuropsychiatric disorders and cognitive impairments that are relevant to AD, including sleep disorders, depression, anxiety, and memory loss. TgF344 AD rats are a transgenic rat model of AD that express APPSwe and PS1DE9 mutations and develop age‐dependent amyloid and tau pathology, neuroinflammation, cell death, and memory impairments that closely resemble humans with AD. We took advantage of this clinically‐relevant AD rat model to investigate the pathological and behavioral consequences of early human WT tau expression in the LC of TgF344 AD rats.

Method

At 2 months of age, TgF344 AD rats and WT littermates received bilateral LC infusions of human tau or mCherry control virus driven by the LC‐specific PRSx8 promotor. When rats were 6‐7 months of age, behavioral assays were administered to assess arousal (sleep latency), anxiety (open field, elevated plus maze, and novelty suppressed feeding), depression (forced swim task), and memory (Morris water maze and fear conditioning). Tau pathology in the LC was also evaluated by immunohistochemistry.

Result

Preliminary analyses suggest that the behavioral consequence of human tau expression in the LC may interact with genotype. Specifically, TgF344‐AD rats that received human tau virus infusions had reduced freezing during cued and contextual fear conditioning tests compared to TgF344 AD rats that received control virus. By contrast, freezing behavior in WT rats was not influenced by human tau infusions in the LC. Additional analyses to evaluate group differences in measures of arousal, anxiety, and depression tasks are still being analyzed. Rats that received human tau virus showed tau pathology in the LC that was reminiscent of that observed in early human AD.

Conclusion

Tau in the LC may contribute to early behavioral symptoms of AD that occur before widespread neuropathology and neurodegeneration occurs.
Three upstream ORFs in an alternative GRN 5′UTR influence downstream protein expression
Authors: Frydas Alexandros , Wauters Eline , Cacace Rita , van der Zee Julie , Van Broeckhoven Christine
Published: December 2020

Background

Frontotemporal dementia (FTD) is the second most common subtype of dementia regarding people under 65 years. It is caused by degeneration of the frontal and temporal lobes of the brain and leads to behavioral and language impairments. Upstream open reading frames (uORFs) play an important role in controlling protein expression. Variants in these elements have been linked with certain diseases. We are investigating the role of uORFs in progranulin (GRN)‐associated FTD.

Method

Patient sources are the Belgian FTD cohort (n = 366, age at onset (AAO): 63.3 ± 10.5y) and a cohort of GRN loss‐of‐function (LOF) mutation carriers (n = 112, 78 affected (AAO: 60 ± 7.1) and 34 unaffected). Targeted resequencing of uORF regions of GRN transcripts by amplicon target amplification assays (https://www.agilent.com). Reporter assays for characterization of GRN uORFs and identified variants.

Results

Sequencing of uORF regions within two different GRN 5′ untranslated regions (UTRs) revealed 2 genetic variants (rs76783532, rs75193026) located in GRN uORFs. Variant rs75193026 is found in an alternatively spliced 5′UTR of the canonical GRN transcript, which contains 3 uORFs. Reporter assays showed that this variant significantly increases the levels of the downstream protein (Kruskal‐Wallis test, p‐value = 0.0184). Abolishment of each GRN uORF in the alternative 5′UTR led to a substantial increase of the levels of the downstream protein (Kruskal‐Wallis test, p‐value <0.05). Combined mutations of all 3 uORFs initiation sites showed a 10‐fold increase in protein expression (Kruskal‐Wallis test, p‐value < 0.0001).

Conclusion

Differentially spliced GRN 5′UTR contains 3 uORFs that can potentially regulate expression of the downstream protein. The variant identified in the alternative 5′UTR appears to be functional based on the reporter assays, as it significantly increased protein expression. Estimation of mRNA changes in reporter assays will determine the impact of uORFs and the variant under study on transcriptional level. We are examining the possibility of uORF‐mediated translation by abolishing the canonical initiation codon of the downstream protein. We predict that our findings can contribute to novel mechanistic insights in GRN‐associated FTD.
Pathologic and cholinergic changes in the rostral prefrontal cortex of the oldest‐old
Authors: Maxwell Selena P. , Cash Meghan K. , Darvesh Sultan
Published: December 2020

Background

The oldest‐old are a continually expanding population of people 85 years of age and older. While the majority of this population expresses some degree of cognitive impairment typically associated with the aging brain, including executive dysfunction, a subset do not present with cognitive deficits. It is hypothesized that decreased cortical cellular and synaptic density, and neurotransmitter production in the aging frontal lobe contributes to executive dysfunction. The rostral prefrontal cortex (rPFC) is a region involved in executive function in part due to high cholinergic innervation. This study aims to characterize the neuropathologic and cholinergic changes in the rPFC in the oldest‐old.

Method

Male and female formalin‐fixed human rPFC of cognitively intact individuals over the age of 85 will be examined compared to sex‐ and age‐matched Alzheimer’s disease rPFC. Disease‐associated neuropathological load will be examined with immunohistochemical staining using specific antibodies for β‐amyloid (Aβ) species (total Aβ, Aβ1‐40, Aβ1‐42, protofibril and fibril oligomers), tau species (total tau, 3R, and 4R), α‐synuclein, and phosphorylated‐TDP‐43. The cholinergic system will be evaluated using histochemical staining for butyrylcholinesterase and acetylcholinesterase, and immunohistochemical staining with a specific antibody for choline acetyltransferase.

Result

Preliminary results indicate a high prevalence of abnormal intraneuronal Aβ aggregation in a subset of neurons of the middle laminar layers of several oldest‐old brains. One of these brains has concurrent abnormal tau aggregates in the white matter.

Conclusion

The results of this study will further our understanding of the mechanisms that allow a subset of the oldest‐old to maintain normal cognitive function despite age related changes to neural elements and the presence of disease‐associated pathology. Abnormal sequestering of disease associated proteins may indicate neuroprotective mechanisms which prevent loss of function in the rPFC.
Cognitive dysfunction is common in middle‐aged adults with type 2 diabetes in South Africa
Authors: Bobrow Kirsten , Kornblith Erica S , Gouse Hetta , Robbins Reuben N , Yaffe Kristine , Farmer Andrew J , Levitt Naomi
Published: December 2020

Background

Type 2 diabetes (T2DM) is a leading, potentially modifiable risk factor for cognitive impairment and dementia. However, very little is known about the burden of cognitive impairment in adults with T2DM in low‐ and middle‐income settings. We describe patterns of cognitive functioning and impairment in adults with T2DM in primary care in Cape Town, South Africa.

Methods

Participants were recruited from a final study visit of a randomized control trial study that assessed adherence support for T2DM (ISRCTN7076880) using brief‐messages. Participants completed a standardized neuropsychological test battery previously adapted for use in South Africa that assessed seven cognitive domains: learning (verbal and visual), delayed recall/memory (verbal and visual), working memory, processing speed, executive function, language, and fine motor skills. Linear regression was used to adjust individual raw test scores for age, sex and education. We used the standardized residuals from the models as a standard score and defined impairments as >1 standard deviation below the mean. Logistic regression models were fitted to explore associations between demographics, health behaviors, and glycaemic control and the number of domains impaired (≥2.)

Results

Eighty participants (75% women) with a mean age of 55 years (SD=11) and 9.2 (SD=3.4) years of education were enrolled. Mean HbA1c was 83 mmol/mol (SD=1.1) and duration of type 2 diabetes was 8 years (SD=6). Eight participants (11%) had co‐morbid HIV. Impairment was present across all cognitive domains. Proportion impaired varied by domain and test from 5% to 15%. One third of participants were impaired in only one domain, and one third in two or more. Male sex was significantly associated with impairment in two or more domains. Glycemic control, HIV‐status, self‐rated health, mood or premorbid functioning did not significantly predict impairment by type or number of domains impaired.

Conclusion

Cognitive impairment is common among middle‐aged adults with T2DM being managed in primary care in South Africa. Further research is required to clarify predictors, and by implication management of cognitive impairment in people with T2DM in low‐and middle‐income settings.
Low systolic blood pressure modifies the association of amyloid‐β with tau neuropathology
Authors: Oveisgharan Shahram , Capuano Ana W. , Kapasi Alifiya , Buchman Aron S. , Schneider Julie A. , Bennett David A. , Arvanitakis Zoe
Published: December 2020

Background

Few pathological studies have examined the association of the vascular risk factors with Alzheimer’s disease (AD) pathology. In this clinical‐pathologic study, we examined the association of vascular risk factors with the amyloid‐β and tau depositions, hallmarks of AD pathology.

Method

We leveraged post mortem data of 1580 participants from two longitudinal community‐based studies of older adults. Amyloid‐β and tau were quantified by postmortem examination. Vascular risk factors were summarized by calculating the Framingham risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid‐β and tau levels, and examined if the FRS modified the association of the amyloid‐β with tau.

Result

On average, participants were nearly 90 years old at the time of death and two thirds were women. The FRS was not associated wtih amyloid‐β (r = ‐0.01, p = 0.844), or tau levels (r = 0.02, p = 0.412). However, the FRS as a whole, and specifically the systolic blood pressure (SBP) component, modified the association of the amyloid‐β with the tau, such that the association was stronger at lower levels of FRS, and lower SBP specifically. Taking levels of SBP into account showed that the slope of tau accumulation per unit increase in the amyloid‐β was 40% steeper in participants who had a SBP < 120 mmhg, compared to those with a 130 ≤ SBP < 140 (estimate of slope difference = 0.197, S.E. = 0.087, p = 0.024).

Conclusion

Lower levels of SBP in late‐life is associated with a stronger association of amyloid‐β with tau neuropathology. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.