bluuebunny/crossref_metadata_2025 huggingface dataset:
Exome sequencing identifies three novel AD‐associated genes
Authors: Holstege Henne , Hulsman Marc , Charbonnier Camille , Grenier‐Boley Benjamin , Quenez Olivier , Ahmad Shahzad , Amin Najaf , van Rooij Jeroen G.J. , Grozeva Detelina , Norsworthy Penny , Hummerich Holger , Kawalia Amit , Mok Kin Y. , Shoai Maryam , Dols‐Icardo Oriol , van Der Flier Wiesje , Sims Rebecca , Amouyel Philippe , Hardy John , Clarimon Jordi , Mead Simon , van Swieten John C. , Ramirez Alfredo , van Duijn Cornelia M. , Williams Julie , Nicolas Gaël , Bellenguez Céline , Lambert Jean‐Charles ,   ADSP Consortium
Published: December 2020

Background

With the development of next‐generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimer’s Disease (AD), reaching odds ratios comparable with the main AD genetic risk factor, the APOE‐ε4 allele. Here, we set out to identify additional AD‐associated genes by a genome‐wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls, the largest AD‐WES dataset available worldwide.

Method

We integrated the data from 25,982 cases and controls from the European ADES consortium and ADSP consortium from the USA on a single server. We developed a unique bioinformatic pipeline that applies new techniques to homogenize and analyze these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of AD were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analyzed using a burden analysis, using both non‐synonymous and loss‐of‐function rare variants. Variant impact was prioritized using REVEL.

Result

In our discovery phase, we confirmed and further substantiated that carriership of protein‐damaging genetic variants in TREM2, SORL1 or ABCA7 is a major AD‐risk factor. High‐impact variants in these genes are mostly extremely rare and they are enriched in AD patients with early ages at onset. Furthermore, we identified three additional genes that were significantly associated with AD, in which we identified a similar relationship between very rare, high‐impact variants and an enrichment in AD patients with early ages at onset. We are currently replicating these associations and several additional suggestive findings in independent datasets. The final results will be presented.

Conclusion

Development of new homogenization methods has enabled the combined analysis of the largest AD‐WES dataset worldwide. With this, we were able to validate and expand on previous findings and to identify new genetic determinants of AD. Together, these genes pinpoint the most relevant pathways in the pathophysiological processes leading to AD.
Amyloid and tau PET in sporadic early‐onset Alzheimer’s disease: Preliminary results from LEADS
Authors: Rabinovici Gil D. , Iaccarino Leonardo , La Joie Renaud , Lesman‐Segev Orit H. , Soleimani‐Meigooni David N. , Provost Karine , Collins Jessica A. , Aisen Paul S. , Borowski Bret J , Eloyan Ani , Fagan Anne , Foroud Tatiana M. , Gatsonis Constantine , Jack Clifford R. , Kramer Joel H. , Saykin Andrew J. , Toga Arthur W. , Vemuri Prashanthi , Day Gregory S. , Graff‐Radford Neil R. , Honig Lawrence S. , Jones David T. , Masdeu Joseph C. , Mendez Mario F. , Onyike Chiadi U. , Rogalski Emily J. , Salloway Stephen P. , Wolk David A. , Wingo Thomas S. , Koeppe Robert A. , Dickerson Brad C. , Carrillo Maria C. , Apostolova Liana G.
Published: December 2020

Background

Previous studies have reported that age modifies the distribution and burden of tau (and, to a lesser extent, amyloid) pathology in sporadic Alzheimer’s disease (AD). Here we present preliminary baseline amyloid and tau PET results from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS), a multi‐site longitudinal study of sporadic early‐onset AD.

Method

135 patients meeting clinical criteria for MCI or probable AD and 50 cognitively normal controls (all age<65 at enrollment) were enrolled at 12 US centers between August 2018 and December 2019 (Table 1). 18F‐Florbetaben amyloid‐PET (FBB) was used to assign patients to EOAD (amyloid‐positive) or EOnonAD (amyloid‐negative) subgroups based on visual rating and semi‐quantification. 130 patients and all controls had 18F‐Flortaucipir tau‐PET (FTP). Regional Standardized Uptake Value Ratios (SUVR) for FBB (whole cerebellum reference) and FTP (inferior cerebellar gray reference) were extracted using co‐registered 3T‐MRI.

Result

98 patients (72.6%) were amyloid PET‐positive (EOAD) and 37 (27.4%) were amyloid PET‐negative (EOnonAD). Compared to EOAD, EOnonAD patients had higher MMSE, MOCA and CDR sum‐of‐boxes (CDR‐SB) and were more frequently male (Table 1). Patients with EOAD showed elevated FBB and FTP SUVR in temporoparietal and frontal cortex compared to CN and EOnonAD (Figures 1‐2). In EOAD, MMSE, MOCA and CDR‐SB were significantly correlated with FTP SUVR (Figure 3), while no significant correlations were found with FBB SUVR. EOnonAD patients showed variable FTP binding ranging from negative to mildly elevated binding in anterior temporal and frontal cortex and underlying white matter. Two EOnonAD cases showed intense FTP binding comparable to typical EOAD cases, despite visually and quantitatively negative FBB scans.

Conclusion

Patients with clinically mild, sporadic EOAD typically show an extensive distribution and burden of tau pathology in the setting of positive amyloid PET. Global clinical measures correlate with tau but not amyloid PET. Over 25% of patients meeting clinical criteria for early‐onset MCI/probable AD have negative amyloid PET, suggesting alternative etiologies for cognitive decline. These findings will inform future design of drug trials in this important and under‐studied population.
Examining early‐onset Alzheimer’s disease (EOAD) and late‐onset Alzheimer’s disease to understand the neuropathological substract of typical and atypical AD
Authors: Grinberg Lea Tenenholz , Petersen Cathrine , Nolan Amber L. , Resende Elisa de Paula França , Miller Zachary A. , Spina Salvatore , Miller Bruce L. , Rabinovici Gil D. , Seeley William W.
Published: December 2020

Background

Pathologically proven Alzheimer’s disease (AD) manifest clinically with a broad spectrum of cognitive presentations beyond the classic progressive amnestic‐predominant syndrome pointing to different patterns of selective vulnerability to AD pathology. As atypical clinical variants of AD tend to show a younger age of onset, EOAD cohorts present the best opportunity to understanding differences in the neuropathological substrate of typical vs. atypical AD presentation. Such studies may unveil mechanisms of selective neural vulnerability to AD and inform on novel modifiable pathogenic pathways. To reveal the features and mechanisms underlying the differences between typical and atypical AD, we investigated a sizeable clinicopathological series of sporadic EOAD. We hypothesized that a higher rate of comorbid pathology would explain an atypical AD clinical presentation.

Method

We used the UCSF/Neurodegenerative Disease Brain Bank (NDBB), which is a LEADS neuropathological hub. Neuropathological diagnosis follows internationally accepted research standards. We also employed quantitative neuropathological analysis in a subset for measuring p‐tau burden in neurons and astroglia. Definition of AD pathology required an ADNC ABC score ≥ A2B2C2. Sporadic EOAD cases manifested symptoms when < 65 years and lacked a AD‐associated autosomal dominant mutation.

Result

From 2009 to 2019, the NDBB performed 113 autopsies with a primary neuropathological diagnosis of EOAD. Of those, (41%) showed an atypical presentation (Figure 1). Typical and atypical EOAD were similar in age and disease duration, but atypical cases were more likely to be female and have less comorbid Lewy body disease (Table 1). In brain areas associated with the most affected cognitive domain, atypical cases demonstrated a higher proportion of neurofibrillary (Table 2), but not of amyloid plaques or age‐related tau astrogliosis.

Conclusion

Other than greater regional tau burden, no other frequent neurodegenerative changes underlie atypical presentation. LEADS will enable increasing the EOAD neuropathological cohorts to leverage investigation on the factors underlying an atypical AD presentation.
Study on the correlation of depression, cognitive function and living ability in Chongqing, China
Authors: Yang Wenkai , Lü Yang
Published: December 2020

Background

To examine the incidence of depression in elderly people over 60 in Chongqing and patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in the Memory Clinic of Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University.

Method

A total of 188 patients with MCI and 275 patients with AD who attended the Memory Clinic of Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, from January 2010 to December 2018. 317 community subjects without cognitive impairment were used as control in this study. The neuropsychological examination was conducted for all patients, and the demographics were recorded. In addition, depression and impairment of daily living were evaluated by the Geriatric Depression Scale (GDS‐30) and Activity of Daily Living (ADL) respectively.

Result

Depression was identified in 8.83% of subjects without cognitive impairment, 25.53% of patients with MCI, 25.09% of patients with AD. Compared with those without cognitive impairment, patients with cognitive impairment showed different symptoms in dysphoric mood, lack of vitality, worry, self‐evaluation of cognitive function, hopelessness and agitation (p<0.05). Furthermore, lack of vitality and self‐evaluation of cognitive function still remained statistically significant after adjustment for age, sex, and education level by logistic regression analysis [OR(95%CI(=1.312(1.164‐1.478) and 1.482(1.282‐1.714(,p<0.05].In addition, there was a close correlation between depression severity and cognitive function and living ability, that is, the low depression level (the low GDS score) indicates a good cognitive function (a high MMSE score) and living ability (a high ADL score).

Conclusion

Depressive symptoms show slight difference in patients with cognitive impairment or not. The health promotion for dementia‐related diseases in Chongqing still needs to be further promoted.
Usefulness of the self‐reported Dementia Assessment Sheet for Community‐based Integrated Care System‐21 items (DASC‐21) in the community‐dwelling elderly
Authors: Ono Rei , Uchida Kazuaki , Kawaharada Rika , Kido Yoshiaki , Yasuda Hisafumi , Kowa Hisatomo
Published: December 2020

Background

The Dementia Assessment Sheet for Community‐based Integrated Care System‐21 items (DASC‐21) was developed as screening tool to find early dementia. Although it is assessed by trained staff, self‐reported use has expected in community setting. The aim of this study was to examine usefulness to use the self‐reported DASC‐21 in the community dwelling‐elderly.

Method

This study design was cross sectional. We examined 2,140 elderly (≥65 years, mean age: 72.2 ± 4.6 years, females: 1,096) who were registered at Tanba city (Japanese rural area) and attended special health check‐up in 2019. DASC‐21 consisted of 21 items including institutional or basic activity of daily living and cognitive function and each item was indicated by 4‐points scale (21 to 84, ≥31 indicates dementia). Locomotive disorders (LD) were assessed by Geriatric Locomotive Function Scale‐25, which consisted of 25 items and response was graded into a 5‐point scale (0 to 100, ≥7 and ≥16 indicate pre‐LD and LD). Social frailty (SF) was examined using 5 items yes or no questions (0 to 5, 1 and ≥2 indicate SF). Depression was examined using Geriatric Depression Scale (0 to 15, ≥5 and ≥10 indicate moderate and severe depression). We also identified hypertension (systolic blood pressure ≥140mmHg and/or diastolic blood pressure ≥90mmHg), dyslipidemia (serum triglycerides ≥150mg/dL), and hyperglycemia (HbA1c ≥6.5%) from annual health check‐up. We performed statistical analyses using logistic regression, with the presence of dementia as the dependent variable, the presence of LD, SF, depression, hypertension, dyslipidemia, or hyperglycemia as the independent variable, and age, sex and years of education as confounding variables.

Result

Of them, 100 participants were identified by DASC‐21 as dementia. In logistic regression analysis, the presence of dementia was associated with the presence of LD [odds ratio (95%CI), 4.2 (2.5 – 7.2) and 10.2 (5.8 – 17.9)], SF [3.7 (2.1 – 6.8) and 9.7 (5.4 – 17.4)], and depression [3.8 (2.5 – 6.0) and 8.5 (4.2 – 17.2)]. However, the other variables were not related.

Conclusion

Using self‐reported DASC‐21 in the community‐dwelling elderly included various symptoms.
Transcriptomic profiling of diverse mouse strains identifies sex‐specific Alzheimer's‐related pathway modifications
Authors: Olayan Rawan , Uyar Asli , Onos Kristen , Howell Gareth , Carter Gregory W.
Published: December 2020

Background

Alzheimer’s disease (AD) is a heterogenous disease that is associated with complex brain changes and major alterations in gene expression. The analysis of correlated transcriptomic variation can help in understanding the biological mechanisms underlying the disease. Having a comprehensive atlas of changes in human brain transcriptome, as in the Accelerating Medicine’s Partnership for AD (AMP‐AD), enables the use of animal models to validate, assess, and compare such changes. Identifying the optimal animal model can further advance the discovery of the early disease characteristics and development of potential drugs.

Method

We performed comprehensive transcriptome profiling of brains from a panel of early‐onset AD mouse models at 8 months of age, including six distinct genetic backgrounds carrying the same APP/PS1 transgenic construct. We identified co‐expression modules in female and male mice, separately. Then, we associated strains that drive each module. Moreover, we determined which mouse modules overlapped with modules derived from the AMP‐AD transcriptome studies. Finally, we identified the altered pathways in which the mouse strain effects mimic disease effects in human modules.

Result

The majority of mouse modules are driven by strain (independent of APP/PS1 genotype). These modules are significantly overlapped with multiple AD‐related processes in AMP‐AD modules including inflammation, microglia, and neuronal systems. Our results suggested that the altered pathways in mice are sex‐specific, where female mouse strain effects are associated more with immune systems and less with neuronal system than male mouse strain effects.

Conclusion

We identified the potential mouse strain effects, in each sex, with the potential AD‐related genes that have similar genetic characteristics to human modules. We believe that using diverse mouse strains to model AD in human can facilitate the discovery of progression pattern of AD.
Evaluating technology‐based reminiscence for engagement and socialization in aged care: Time travelling with technology
Authors: Radnan Madeleine J , Stevens Catherine J , Jones Caroline , Leahy Andrew , Parker Deborah
Published: December 2020

Background

Technology offers promise of increased engagement with individuals in aged care. Reminiscence therapy (RT) stimulates discussion of past events and experiences (Woods, et al., 2018). Google Earth and Street View on a large display is readily available technology to support reminiscence. In this study, technology‐enhanced RT is operationalized as dynamic images panning the environment (High‐Tech condition), compared with static images (Low‐Tech/control condition). Behaviour and cognition were appraised pre and post the 6‐week intervention (called Time Travelling with Technology) using the NPI‐NH and discourse interviews to measure communication. If technology‐enhanced RT supports engagement, then NPI and communication scores will not worsen when pre and post intervention scores are compared.

Method

Participants were nine clients (8 female, mean age: 79, range: 72‐90, SD: 6.892) at an aged care day respite facility in Sydney, Australia, with comparable MMSE scores. Using a repeated measures and counterbalanced design, the High‐Tech and Low‐Tech condition each ran for 6 weeks, separated by a 3‐week break. The weekly sessions consisted of groups of 2‐4 clients for approximately 30 minutes. Each session displayed locations of significance to the clients on a flat screen television. Before and after the intervention, NPI‐NH and discourse interviews (Chapman, et al., 2004) were administered.

Result

Attendance was consistently high across the program (79%). Comparing pre‐ to post‐intervention, NPI‐NH scores did not worsen in either Low‐Tech (p=0.92) or High‐Tech (p=0.74) conditions. There was no significant effect of intervention or technology on communication scores, ps>0.25. Inter‐rater reliability in scoring discourse interviews was positive and strong, r(7) = 0.95, p < 0.0001.

Conclusion

The attendance rate highlights the feasibility and enjoyment of the Time Travelling with Technology program. No deterioration in NPI‐NH or communication across the program supported the hypothesis. While cautious interpretation is needed, these data are encouraging. Data collection from a larger sample for greater statistical power is underway. Further measures of engagement such as facial expressions and language change over time will also be reported.
Peripheral nerve conduction study in early cognitive impairment of Alzheimer's disease
Authors: Qian Xinyi , Xiao Shifu
Published: December 2020

Background

Mild cognitive impairment (MCI) individuals are at a higher risk to develop dementia, especially due to Alzheimer’s disease (AD). Dyskinesia, such as facial expressions, gait and postural changes, retardation and tremor, occurs even before significant clinical symptoms of AD. Besides, elders with central nervous degenerative diseases are more likely to have peripheral neuropathy. However, few studies have been devoted to exploring the relationship between peripheral nerve function and early cognitive impairment. The aim of this study was to compare MCI individuals with the normal population for peripheral nerve conduction, and to assess its relationship with cognitive function in elderly population living in Shanghai.

Method

74 MCI and 82 healthy controls (HC) underwent a peripheral nerve conduction examination and a neuropsychological evaluation. In order to minimized the effect of somatic diseases on peripheral nerve function, all the participants had no diabetes, thyroid dysfunction, Parkinson's disease and peripheral neuropathy. Nicolet EDX was used to assess peripheral nerve conduction of upper and lower limb, including median and sural sensory and median and peroneal motor nerve action potential amplitudes and velocities. Then we compared the peripheral nerve conduction results between two different cognitive groups. Furthermore, we also investigated the relationship between the peripheral nerve conduction and cognitive function.

Result

Between the two groups, MCI was older than HC (70.36±7.38 vs 68.04±6.27, p=0.07) although there was no significant difference. MCI group had less years of education (10.05±3.58 vs 11.45±2.57, p=0.009) and more depressive symptoms (3.65±4.37 vs 2.70±4.17, p=0.044), but no difference was found in gender. Median and peroneal motor nerve velocities were found slower in MCI group compared to HC group (54.51±4.18 vs 47.13±5.90, p=0.011; 56.36±4.72 vs 49.29±5.65, p=0.023). Both median (p=0.005) and peroneal (p=0.003) motor nerve velocities were correlated with MoCA. Furthermore, linear regression revealed that, after taking age, gender, education, depression and body mass index (BMI) into account as covariates, median motor nerve velocity was associated with MoCA (p=0.019).

Conclusion

Our study found that peripheral motor nerve velocity may be correlated with early cognitive impairment of AD, suggesting a new, possible research direction of early identification markers for AD.
Research‐based evaluation of a dementia support program: An analysis of input from 1164 participants
Authors: Tam Mallorie T , Robillard Julie
Published: December 2020

Background

Community support programs can improve quality of life for people living with dementia and their caregivers. Support programs act as a gateway to autonomy, empowering people living with dementia to be more involved with their own care and decreasing the burden of caregivers. Important to the successful implementation of such programs is an evaluation process that allows for ongoing improvements to meet the needs of users. The goals of this study were to conduct a research‐based program evaluation of the First Link® dementia support program provided by the Alzheimer Society of British Columbia (the Society) to identify strengths and areas for improvement to better serve B.C. and to develop a methodological blueprint for the evaluation of similar programs around the world.

Method

People living with dementia, caregivers, and healthcare providers (HCPs) who access and do not access the First Link® dementia support services were recruited from the Society, community venues, and through social media. Participants completed an online survey about their experience with the First Link® program.

Result

A total of 1164 participants completed the survey (889 caregiver, 198 HCPs, 77 people living with dementia). The overall experience of the program was positive for people living with dementia and caregivers (78%). Possible areas for improvement included promoting social interactions (70%), supporting physical health (72%), and reducing stress for persons living dementia (58%) and overall burden for caregivers (57%).

Healthcare providers were overall satisfied with the program (91%): many found the referral process easy (98%) and were able to access information about the program to share with their clients (94%).

Strengths of the survey included its broad reach, the ability to quantify the impact of the program and the identification of specific areas for improvement. Limitations included challenges in interpreting the data in relation to the services offered, and lack of depth. A second phase of the program evaluation will harness qualitative interviews to address these limitations.

Conclusion

This study will inform future research on their methodologies in program evaluations as well as improve the existing services to support people living with and impacted by dementia.
Machine‐learning‐based Alzheimer's disease dementia score using structural MRI neurodegeneration patterns: Independent validation on ADNI, AIBL, OASIS and MIRIAD
Authors: Popuri Karteek , Ma Da , Wang Lei , Beg Mirza Faisal
Published: December 2020

Background

Biomarkers for dementia of Alzheimer's type (DAT) are sought to facilitate accurate prediction of the disease onset, ideally predating the onset of cognitive deterioration. T1‐weighted magnetic resonance imaging (MRI) is a commonly used neuroimaging modality for measuring brain structure in‐vivo, potentially providing information enabling the design of biomarkers for DAT.

Method

We propose a novel biomarker using structural MRI volume‐based features to compute a similarity score for the individual's structural patterns relative to those observed in the DAT group. We employed ensemble learning framework that combines structural features in most discriminative ROIs to create an aggregate measure of neurodegeneration in the brain. This classifier is trained on 423 stable normal control (NC) and 330 DAT subjects, where clinical diagnosis is likely to have the highest certainty, and then validated on several independent datasets for subjects at various stages along the longitudinal trajectory from NC to DAT.

Result

Independent validation on 8834 un‐seen images from ADNI, AIBL, OASIS, MIRIAD Alzheimer's disease (AD) databases showed promising potential to predict the development of DAT depending on the time‐to‐conversion (TTC). Classification performance on stable versus progressive mild cognitive impairment (MCI) groups achieved an AUC of 0.81 for TTC of 6 months, and 0.73 for TTC of up to 7 years, achieving the state‐of‐the‐art results.

Conclusion

We propose and validate a novel ensemble‐learning based biomarker score based on 3D topographic patterns of MRI‐observed structural volumetric features. The output score, indicating similarity to patterns seen in DAT, provides an intuitive measure of how closely the individual's brain features resemble the DAT group. This score can be used for assessing the presence of AD structural atrophy patterns in normal aging and MCI stages, as well as monitoring the progression of the individual's brain along the disease course.
Associations between lower systolic blood pressure threshold, Alzheimer’s disease and vascular dementia among very old adults
Authors: Park Christina , Hajat Anjum , Leary Cindy S , Adam Claire , Semmens Erin O , Kaufman Joel D , Fitzpatrick Annette L
Published: December 2020

Background

Increasing evidence supports the contribution of hypertension to the risk of Alzheimer’s disease (AD) and vascular dementia (VaD). The objective of this paper is to examine whether the risk of AD and VaD is associated with a lower threshold of systolic blood pressure (SBP) than the traditional level of ≥140 mmHg.

Methods

Using data from the Ginkgo Evaluation of Memory Study (GEMS), we obtained baseline SBP measurements from 3,068 participants who were dementia‐free at enrollment. Cognition was evaluated every 6 months over 8 years; dementia and its subtypes were adjudicated by a panel of neurologists. Cutoff values for continuous SBP were estimated by the maximum Youden index (sensitivity + specificity ‐ 1) for AD (without VaD) and VaD (with or without AD). The performance of the estimated SBP cutoff values was compared with the traditional SBP threshold of 140 mmHg using the area under the receiver operating characteristic curve (AUC). Based on the estimated cutoffs, we dichotomized SBP, created Kaplan‐Meier survival curves, and calculated hazard ratios (HRs) for AD and VaD incidence using Cox proportional hazards models, adjusted for age, gender, race, education and baseline depression.

Results

The mean (± SD) age of participants was 78.6 (± 3.3) years and 46% were female. According to the Youden index, the optimal SBP cutoff values for capturing AD and VaD were 122 (sensitivity: 74.2%; specificity: 27.6%) and 131 mmHg (sensitivity: 67.3%; specificity: 47.6%), respectively. Although these estimates for SBP cutoffs were not significantly different from AUC estimates for the traditional cutoff, a greater risk of VaD at the optimized threshold (131 mmHg) was found (Figure 1, Kaplan‐Meier analysis and log‐rank test P <0.001). Using Cox models, we found that SBP ≥131 mmHg was associated with a 70% increased risk of VaD (HR:1.71, 95% CI:1.21, 2.43; P = 0.002). We did not observe an association between SBP cutoff of 122 and AD incidence.

Conclusion

A lower SBP threshold was identified in relation to risk of VaD while associations with AD were inconclusive. Further study is needed to evaluate the accuracy of lower SBP cutoff values in identifying AD and VaD in other populations.
Tauopathy in autosomal dominant and late‐onset Alzheimer disease
Authors: Chen Charles , Holden Timothy R. , Gordon Brian A. , Franklin Erin E. , Perrin Richard J. , Morris John C. , Bateman Randall J. , Benzinger Tammie L.S. , Cairns Nigel J. ,   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2020

Background

Tau PET imaging suggests greater tau pathology in autosomal dominant (ADAD) versus late‐onset Alzheimer disease (LOAD). However, this has not been validated with neuropathology. We studied how ADAD and LOAD differ in neurofibrillary tangle (NFT), neuropil thread (NT), and neuritic plaque (NP) distribution, and compared with 18F‐flortaucipir imaging.

Method

Individuals enrolled at the Knight Alzheimer Disease Research Center (n=10) and the Dominantly Inherited Alzheimer Network (DIAN, n=7) came to autopsy (Table 1). Histology was performed by DIAN Neuropathology Core protocols (Cairns et al., 2015). The burden of tauopathy (NFT, NP, and NT) was determined with PHF‐1 immunostaining from frontal (FL), temporal (TL), parietal (PL), and occipital lobes (OL), parahippocampal gyrus (PHG), and CA1 hippocampal subfield, assessed stereologically using the Area Fraction Fractionator (MBF Bioscience). 18F‐flortaucipir imaging was performed in the same cohorts, but different individuals (LOAD, n=35, ADAD, n=14), and regional SUVRs were calculated by in‐house pipelines (Su et al., 2013).

Result

NFT burden and regional SUVRs vary significantly both within and across cohorts. NFT burden was significantly elevated in ADAD versus LOAD in non‐temporal regions (FL/PL/OL); regional SUVRs mostly recapitulate this pattern (Figure 1). Within cohort, NFT burden and regional SUVRs follow similar rank order, except medial temporal lobe regions (CA1/PHG). NP burden did not vary significantly within or across cohorts (Figure 2). NT burden did not vary significantly within cohort, but was significantly elevated across most regions (FL/TL/PL/OL/PHG). Mean NP/NT burden show greater magnitude differences across cohorts than NFT burden and regional SUVRs (Figure 3).

Conclusion

Overall, there was concordance between NFT burden and 18F‐flortaucipir imaging of elevated tauopathy in ADAD versus LOAD. Exceptions involved hippocampal regions; likely due to confounds from off‐target binding in imaging. NT burden was significantly elevated across most regions and on average showed the greatest magnitude differences across cohorts, suggesting significant, previously underappreciated differences between ADAD and LOAD not captured by neuropathologic NFT burden and tau PET imaging. These differences could arise from differing causes of disease between sporadic versus mutation, age of onset, or both, and quantifying subtypes of tauopathy progression in both cohorts presents an interesting future direction.
Human MAPT knock‐in mice that harbor familial tauopathy‐causing mutations
Authors: Watamura Naoto
Published: December 2020

Background

Tauopathy is characterized by the accumulation of pathological tau in brain. In order to clarify the disease mechanisms, we aimed to develop mouse models that reproducibly display specific tau pathology without artifacts because the current tauopathy models depend on the overexpression paradigm. The purpose of this study is to develop new tauopathy mouse models by knock‐in strategy.

Method

Previously we generated human MAPT knock‐in (hTau‐KI) mice, in which the entire Mapt gene was humanized. The hTau‐KI mice express all six isoforms (Hashimoto et al., 2019; Saito et al., 2019). In this study, several tauopathy‐causing mutations were introduced into hTau‐KI mice by Base Editor, a novel CRISPR/Cas9‐based genome editing technology.

Result

We obtained several tauopathy mouse models (hTau‐KIP301L, hTau‐KIP301S, hTau‐KIP301V, hTau‐KIIntron10+3 G>A, hTau‐KIP301L; Intron10+3 G>A, hTau‐KIP301S; Intron10+3 G>A, hTau‐KIS305N; Intron10+3 G>A). Immunohistchmical analysis showed phospho‐tau positive signals in the entorhinal cortex in some of these lines. In addition, Biochemical analysis demonstrated that the Intronic mutation altered the expression patterns of 3‐ and 4‐ repeat tau.

Conclusion

We successfully introduced tauopathy‐causing mutations in hTau‐KI mice. Also, we detected the effect of mutations on MAPT gene in hTau‐KI mice. We expect these models to contribute to elucidating the mechanism of tauopathies and plan to make them available to the research community worldwide.
The clinical characteristics of cognitive impairment in patients with vascular mild cognitive impairment
Authors: Yuan Junliang
Published: December 2020

Background

To investigate the characteristics of the cognitive impairment in patients with vascular mild cognitive impairment (VaMCI).

Method

Seventy‐five patients with VaMCI and 38 age, gender‐matched healthy subjects were recruited from the department of Neurology, Beijing Chaoyang Hospital, Capital Medical University. All the participant underwent the neuropsychological tests. The Fazekas scale was used to assess the severity of white matter lesions, and the medial temporal lobe atrophy (MTA) to evaluate the atrophic severity of medial temporal lobe.

Result

The results of our study showed that patients with VaMCI were associated with comprehensive cognitive function deficits, including MMSE (25.7±2.3 vs 28.4±2.0) MoCA (22.8±3.9 vs 26.3±3.7), AVLD‐I (5.1±1.0 vs 8.9±1.9), AVLT‐D (3.7±1.0 vs 9.8±1.5) and AVLT‐R (7.6±1.9 vs 12±1.5) (P<0.05). Correlation analysis showed that the scale of medial temporal lobe atrophy had a negative relationship with the performance of MoCA (r=‐0.434, P=0.002).

Conclusion

Our findings demonstrate patients with VaMCI were closely correlated to cognitive impairment, especially with memory decline, which may be attributed to white matter lesions and the atrophy of medial temporal lobe.
Blood‐based cardiac biomarkers and the risk of cognitive decline, vascular events and mortality
Authors: Gyanwali Bibek , Liu Benedict , Lai Mitchell KP , Richards Arthur Mark , Chen Christopher , Hilal Saima
Published: December 2020

Background

Vascular pathology plays an important role in the development of cognitive decline, stroke and mortality. In this context, amino terminal pro‐brain natriuretic peptide (NTpro‐BNP), high sensitivity cardiac troponin T (hs‐cTnT) and growth differentiation factor‐15 (GDF‐15) have been proposed as important biomarkers of early vascular pathology due to their up‐regulation in inflammatory and trophic responses during tissue injury. However, little is known on the longitudinal effects of these cardiac biomarkers and their potential clinical implications. We examine the association of blood‐based cardiac biomarkers (NTpro‐BNP, hs‐cTnT and GDF‐15) with cognitive decline and risk of vascular events and mortality in a memory clinic study.

Method

A total of 414 (mean age:72.7± 9.1years, 56% women) patients with blood samples, neuropsychological assessment (baseline and at least two neuropsychological assessments obtained a minimum of one year apart), 3T neuroimaging and detailed clinical assessment were recruited. NTpro‐BNP and hs‐cTnT concentrations were measured by electrochemiluminescence immunoassay and GDF‐15 by quantitative sandwich immunoassay technique. Data on incident clinical outcomes and mortality were obtained until June 2018.

Result

Patients with higher levels of NTpro‐BNP, hs‐cTnT and GDF‐15 showed a greater decline in memory domain per year with a stronger decline observed for hs‐cTnT (p for interaction, <0.001) followed by NTpro‐BNP (p for interaction, 0.001) and GDF‐15 (p for interaction, 0.006). Additionally, hs‐cTnT was associated with accelerated decline in global cognition, executive function and visuomotor speed. During a mean follow‐up of 3 years, 26 (6.2%) patients died and 43 (10.4%) developed vascular events (heart disease and stroke). Patients with higher levels of NTpro‐BNP and hs‐cTnT were at increased risk of vascular events (OR for NTpro‐BNP:2.40, 95%CI: 1.15‐4.98 and OR for hs‐cTnT:5.59, 95%CI: 1.38‐22.72) whereas those with higher levels of NTpro‐BNP and GDF‐15 were at risk of mortality (OR for NTpro‐BNP: 4.48, 95%CI:1.59‐12.58 and OR for GDF‐15: 44.27, 95%CI:5.36‐363.46).

Conclusion

We showed that the higher levels of blood‐based cardiac biomarkers were associated with worse decline in memory. This suggests that cardiac biomarkers may be useful indicators of vascular brain damage and to identify patients at risk of adverse vascular events and death and could warrant consideration of treatment trials.
Influenza vaccination is associated with a reduced incidence of Alzheimer’s disease
Authors: Amran Albert , Lin Yaobin , Kim Yejin , Bernstam Elmer , Jiang Xiaoqian , Schulz Paul E
Published: December 2020

Background

AD is a devastating disease and its pathophysiology is still largely unknown. No treatment has been shown to be efficacious, so prevention remains a very valuable approach. The objective of this work is to statistically test the relationship between influenza vaccination and the incidence of AD to identify a candidate for AD prevention.

Method

We used the Cerner Health Fact EHR dataset and excluded patients less than 60 years of age and included patients with ICD9 code ‘331.0’, i.e. Alzheimer’s disease. From this population, we constructed a cohort (N=311,424) for statistical analysis. Then we did propensity score matching (PMS) on AD with regard to patients’ demographics and then did PMS on influenza vaccine with regard to the age of AD onset and potential confounds such as prescribed medications. We obtained a balanced data set with respect to vaccinated patients and unvaccinated patients with PMS (N=9,066). To analyze the effects of frequency of vaccination, we divided the number of vaccinations by the length of time from the first vaccination timestamp to AD onset or the end of the observation. We performed a survival analysis on the entire cohort where development of AD was the end outcome.

Result

We obtained our results using chi‐square test, uni‐variate analysis, and time‐to‐event analysis. Our main outcomes are three aspects: (1) influenza vaccine significantly decreases AD prevalence (odds ratio 0.8309 with a p‐value < 0.0001). (2) the frequency of influenza vaccine has a significant impact to inhibit AD onset (odds ratio 0.8736 with a p‐value of 0.0342). (3) time‐to‐event analysis shows taking influenza vaccine at an earlier age leads to smaller AD risk than having vaccine at an older age (when the first vaccination age increases by 1, the hazard rate increases by 1.0924, p‐value < 0.0001).

Conclusion

Analysis of a large clinical database suggests that there is a strong inverse relationship between AD and influenza vaccination. This result provides evidence that influenza vaccination may be a confounding factor in epidemiological studies of risk factors of Alzheimer’s Disease. Future studies may shed light on biological mechanisms to more deeply understand a promising, readily available candidate for preventing AD.
Imaging profiles of Alzheimer’s disease and behavioural variant frontotemporal dementia based on cortical structural correlation networks
Authors: Vuksanovic Vesna , Staff Roger , Ahearn Trevor , Murray Alison D. , Wischik Claude
Published: December 2020

Background

Reduced cortical structural properties are recognised as potential imaging marker for neurodegenerative disorders. However, networks of correlated fluctuations in cortical structural properties in Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD) have remained elusive. Here, we set out to investigate organisations of structural correlation networks in these patients, and further to show how they become (dis)organised across the cortical lobes.

Method

Structural correlation networks are estimated from magnetic resonance images (MRI) in three study groups ‐ AD, bvFTD and healthy controls ‐ each consisting of an equal number of participants (N = 200). Group‐level networks are constructed by cross‐correlating regional structural properties (e.g., thickness, surface area or volume) across all subjects within the group while controlling for confounding variables age, gender and global values.

Result

Network organisation is evaluated using several network matrices including the node degree, node strength and network density on the whole‐brain and across the brain lobes. We found that the reduced cortical properties in AD and bvFTD alter organization of the corresponding structural cortical networks at the whole brain. We also found that differences in the measured network properties are lobe specific.

Conclusion

Our results show that understanding patterns of correlated reductions in cortical structures may assist in deciphering how cortical changes underlie cognitive and behavioural processes impaired in AD and bvFTD. Reference: Vuksanović V, Staff RT, Ahearn T, Murray AD, Wischik CM. Cortical Thickness and Surface Area Networks in Healthy Aging, Alzheimer’s Disease and Behavioral Variant Fronto‐Temporal Dementia. Int J Neural Syst. 2019 Aug;29(6):1850055. https://doi.org/10.1142/S0129065718500557. Epub 2018 Nov 14. PubMed PMID: 30638083.
Cellular vulnerability in Lewy body diseases
Authors: Erskine Daniel , Hatton Chris , Perrott Abigail , Lai Nicola , Sidhpura Keval , Turnbull Doug , Attems Johannes
Published: December 2020

Background

Lewy body diseases (LBD) are characterised by Lewy body pathology, cell loss and mitochondrial dysfunction, but the overlap between these three features is not well understood. We have explored the hypothesis that neurodegeneration in LBD is the result of energy failure in cells with high energy demands, such as cortical fast‐spiking interneurons and cholinergic basal forebrain neurons, irrespective of Lewy body accumulation.

Method

We obtained post‐mortem substantia innominata, prefrontal cortex and inferior temporal cortex brain tissue from LBD cases, controls, and disease‐control groups (Alzheimer’s disease and/or mitochondrial disease cases). We conducted stereological analysis of fast‐spiking interneurons, pyramidal neurons and cholinergic neurons; neuropathological analysis of alpha‐synuclein, amyloid‐beta and tau; and immunofluorescent quantification of NDUFB8 (Complex I) and COX4 (Complex IV) normalised to mitochondrial mass.

Result

Despite not developing Lewy bodies, we observed a 40% reduction in density of fast‐spiking interneurons, whilst pyramidal neurons that are vulnerable to Lewy bodies had preserved populations. Changes in cell density were not related to any neuropathological feature. Preliminary data suggests Complex I reductions relative to VDAC1 in fast‐spiking interneurons and cholinergic nbM neurons, with more variable changes in Complex IV expression.

Conclusion

The present findings demonstrate loss of a cell population that does not develop Lewy bodies alongside preservation of proximal Lewy body‐bearing neurons. This challenges the hypothesis that neurodegeneration in LBD results from Lewy body pathology. Our preliminary findings indicate that mitochondrial impairments in cells with high reliance on energy production may more closely relate to neurodegeneration in LBD than Lewy body formation.
Endoplasmic reticulum stress induces spatial memory deficits by activating GSK‐3 in Alzheimer’s disease
Authors: Wang Xiao‐Ming
Published: December 2020

Background

Endoplasmic reticulum (ER) stress is involved in Alzheimer’s disease (AD), but the mechanism remains unclear.

Method

Tunicamycin (TM), a recognized ER stress inducer, was injected into the brain ventricle of Sprague‐Dawley (SD) rats to induce the unfolded protein response (UPR). Rats was divided into 3 groups for the brain lateral ventricle injections with DMSO, TM, or TM + SB, respectively. The behavioural test was conducted after 24 and 48 hours, respectively. Then the rats were sacrificed. Brain samples were collected for further protein analysis and specific stains.

Result

TM‐induced UPR was convinced by enhanced phosphorylation of pancreatic ER kinase (PERK), inositol‐requiring enzyme‐1 (IRE‐1), and transcription factor‐6 (ATF‐6) activation. Behavioural test demonstrated UPR induced spatialmemory deficits and impairments of synaptic plasticity in the rats. After TM treatment, GSK‐3β was activated. Phosphorylation of cAMP response element binding protein at Ser129 (pS129‐CREB) was up‐regulated with an increased nuclear co‐localization of pY126‐GSK‐3β and pS129‐CREB. Simultaneous inhibition of GSK‐3β by hippocampal infusion of SB216763 (SB) attenuated TM‐induced UPR, synaptic plasticity, and spatial memory impairment with restoration of pS129‐CREB.

Conclusion

TM‐induced UPR causes AD‐like spatial memory deficits and synapse impairments by activating GSK‐3b/pS129‐CREB pathway. GSK‐3 inhibition might be a promising therapy in AD treatment.
Education and income might protect the brain differently against white matter lesions in aging
Authors: Rodriguez Francisca S. , Lampe Leonie , Gaebler Michael , Witte A. Veronica , Villringer Arno , Riedel‐Heller Steffi G.
Published: December 2020

Background

A lower socioeconomic status (SES) is associated with poorer cognitive health in old age and with more white matter lesions in the brain. It is not clear whether education and income, the two major components of SES, contribute differently to cognitive health, given that education is believed to build up a cognitive reserve. Aim of the study was to investigate how education and income independently contribute to cognitive functioning and brain white matter in aging.

Method

Participants (age 40‐80 years) of the representative population‐based LIFE‐Adult study completed the CERAD neurological test battery and underwent MR scanning (n=2,385 without neurological diseases). The association between education and income on cognitive performance and white matter lesions was analyzed via generalized linear regression modelling adjusted for age, gender, APOE e4 allele and household size. We further tested whether health (heart disease, high blood pressure, elevated blood lipids, diabetes, depression) could explain the associations.

Result

Higher education as well as higher income were significantly associated with better performance in the CERAD and fewer total white matter hypointensities (WMH). Only higher education was associated with a lower Fazekas scale score, while only higher income was associated with fewer periventricular WMH. With increasing age, the protective effect of both, higher education and higher income, on performance in the Trail Making Test B and the total white matter volume increased. Older age additionally increased the protective effect of higher income on fewer total and periventricular WMH. The age‐related association between income and periventricular WMH was largely explained by high blood pressure.

Conclusion

Our findings suggest that higher education and higher income may protect cognitive functioning by a smaller loss of white matter in aging. While education is associated with WMH in general, income is specifically associated with periventricular WMH, an ageing‐related association that seems to be related to blood pressure. As none of the other health indicators explained our findings, more research is necessary to investigate what aspects of low educational attainment and low income bring about WMH.