bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex
Authors: de Leeuw Francisca A , Schneider Julie A , Agrawal Sonal , Leurgans Sue E , Morris Martha Clare
Published: December 2020

Background

Higher intake of vitamin E has been associated with a lower risk of Alzheimer’s disease (AD), however the underlying mechanisms are unclear. One explanation might be that anti‐inflammatory properties of tocopherols prevent microglia activation. In this study we investigated the association of brain tocopherol levels with microglia activation in elderly humans.

Method

We included 113 deceased participants (88.5±6 years, 60% female) from the prospective Memory and Aging Project. Brain levels of α‐ and γ‐tocopherol were measured by HPLC coupled to electrochemical detection. Microglia presence was assessed in three stages of activation, based on morphology; i.e. I – not activated, II – activated, III – most activated. Microglia densities and tocopherol levels were log‐transformed when not normally distributed, standardized and averaged across two cortical and two subcortical brain regions. Linear regression analyses examined associations between tocopherol levels and microglia densities (outcome) in two models; a model adjusted for age, sex, education, APOE ε4 genotype and post mortem time interval (model 1), and a model additionally adjusted for total amyloid load and neurofibrillary tangles severity (model 2).

Result

Total microglia density (stage I‐III) was lower in cortical versus subcortical brain regions (153.2 (111.2‐194.0); 209.2 (175.8‐224.1), p<0.001). Levels of α‐ and γ‐tocopherol and activated microglia (II/III or III only) density did not differ between brain regions. Higher α‐ and γ‐tocopherol levels were associated with lower total and activated microglia densities in cortical (range (B(SE) ‐0.25,‐0.19 (0.09,0.10) p<0.05) but not in subcortical brain regions (range B(SE) ‐0.01, 0.12 (0.09,0.10) p>0.05). When we additionally adjusted for AD neuropathology effect estimates diminished and lost significance except for the association between α‐tocopherol and total microglia density in cortical brain regions (B(SE) ‐0.20 (0.09), p=0.03).

Conclusion

These results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.
Gene‐diet interaction and dementia risk: The example of coffee and CYP1A2 gene
Authors: Lefèvre‐Arbogast Sophie , Dartigues Jean‐François , Tzourio Christophe , Berr Claudine , Helmer Catherine , Samieri Cécilia
Published: December 2020

Background

Coffee consumption has been associated with a decreased risk of dementia, although findings have been inconsistent. Among the numerous coffee bioactives, caffeine may improve neurotransmission by acting as antagonist of adenosine receptors. There exists a large inter‐individual variability in caffeine metabolism in relation to the cytochrome P450 1A2 (CYP1A2), and some studies suggest that specific genes of CYP1A2 may module the relationship between coffee and chronic diseases (cancer, cardiovascular disease, Parkinson’s disease). Our objective was to evaluate the association between coffee consumption and dementia risk in the French Three‐City (3C) cohort of older persons, taking into account the potential modulatory effect of CYP1A2 rs762551 genotype.

Method

We included 5,963 participants, free of dementia at baseline when they reported their daily coffee consumption and who were followed for incidence dementia up to 14 years. All included participants had available genome‐wide genotyping. We tested the interaction between coffee consumption (number of cups/day) and CYP1A2 rs762551 (number of alternative allele C) on the risk of dementia using Cox proportional hazard models adjusted for age (as time scale), sex, level of education and ApoE‐ε4. Multivariate associations between coffee consumption and the risk of dementia were then investigated according to CYP1A2 rs762551 genotype that induce “faster” caffeine metabolism (A/A) or “slower” caffeine metabolism (C/A‐C/C).

Result

Participants were 74 (sd 5) years‐old on average at baseline and 61% were women. The mean coffee consumption was 1.6 cups/day (sd 1.3; min 0; max 10 cups/d) and 78% of participants reported the consumption of at least 1 cup/d. In total, 52% of participants were carriers of at least one rs762551 C allele. Over a median follow‐up of 8.6 years, 756 cases of dementia were diagnosed. Daily coffee consumption was associated with a decreased risk of dementia only among carriers of the CYP1A2 rs762551 C allele, with each additional cup of coffee being associated with a 10% reduced risk of dementia (95%CI: 2‐18%; p for interaction=0.007).

Conclusion

In our study, coffee consumption was associated with a reduced risk of dementia among older persons with a genetic predisposition towards a slow caffeine metabolism.
Alzheimer’s disease brain atrophy subtypes are associated with incident dementia in subjective cognitive complaint and mild cognitive impairment
Authors: Planche Vincent , Bouteloup Vincent , Mangin Jean‐Francois , Dubois Bruno , Habert Marie‐Odile , Tison François , Chêne Geneviève , Dufouil Carole ,   MEMENTO
Published: December 2020

Background

Alzheimer’s disease (AD) brain atrophy subtypes on structural MRI have been associated with rate of cognitive decline in AD and prodromal AD. However, previous works were based on selected amyloid‐positive and/or cognitively‐impaired patients. The clinical relevance of brain atrophy subtypes categorization in people referred to Memory Clinics for subjective cognitive complaint (SCC) or mild cognitive impairment (MCI), without any a priori assumptions regarding their amyloid status, is currently unknown.

Methods

We investigated 2118 subjects from the French Memento cohort presenting either with SCC or MCI and for whom both hippocampal and cortical volumes were available at baseline. Among them, 883 also had Amyloid‐PET and/or CSF biomarkers. They were prospectively followed during 4 years for dementia status and neuropsychological performances. MRI scans at baseline were used to define groups with “limbic predominant atrophy”, “hippocampal sparing atrophy”, “typical/diffuse atrophy” and “no evidence of brain atrophy”, based on previously described algorithms.

Results

In Cox proportional‐hazards models, “typical/diffuse atrophy” and “limbic predominant atrophy” were associated with an increased risk of developing dementia over time (HR=3.67; 95%CI 2.63–5.13 and HR=1.77; 95%CI 1.05–2.98 respectively), independently of age, gender, educational level, ApoE4 genotype and CDR‐SB at baseline. Brain atrophy subtypes categorization was more informative than hippocampal and/or cortical volumes separately, when comparing Akaike information criteria of Cox models. Very similar results were found when analyses were restricted to the sample of amyloid‐positive participants (n=236) (HR=3.69; 95%CI 2.03–6.70 for “typical/diffuse atrophy” and HR=2.40; 95%CI 0.96–5.96 for “limbic predominant atrophy”).

Conclusion

AD brain atrophy subtypes are associated with conversion to dementia in patients with SCC or MCI consulting in Memory Clinics, agnostic of any a priori assumptions regarding their amyloid status. Because this categorization based on structural MRI is more informative than hippocampal and/or cortical volumes, it could be widely used as a biomarker in future epidemiological and clinical studies.
Utility of DTI as a prognostic biomarker in MCI: Beyond AD biomarkers
Authors: Pillai Sheela Kumari Raghavan , Przybelski Scott A. , Reid Robert I. , Graff‐Radford Jonathan , Lesnick Timothy G. , Zuk Samantha M. , Knopman David S. , Machulda Mary M. , Mielke Michelle M. , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi
Published: December 2020

Background

Given that a proportion of mild cognitive impaired (MCI) individuals are amyloid negative and have cerebrovascular disease (CVD), there is a need for biomarkers that can complement AD biomarkers (amyloid and neurodegeneration) for the prediction of future cognitive decline in MCI. The aim of our study was to determine the utility of diffusion tensor imaging (DTI) as a CVD marker for prediction of future cognitive decline in individuals with MCI in conjunction with amyloidosis and neurodegeneration.

Method

We identified 132 MCI individuals ≥60 years old (55 % were amyloid positive and 59 % were male) from the population based sample of Mayo Clinic Study of Aging (MCSA) who had structural MRI, DTI, amyloid PET, and at least one clinical follow‐up after the imaging at the time of their clinical visit as MCI. All imaging scans were acquired and processed using in house developed protocols and pipelines. We used fractional anisotropy in the genu of corpus callosum (FAGCC), as a CVD marker, education/occupation score as a resilience variable, and global cognitive z‐score as the cognitive outcome. Using mixed effect models for cognitive decline, we evaluated three models to test the prognostic ability of (i) DTI marker alone, (ii) DTI marker and amyloid PET, (iii) DTI marker, amyloid PET, and neurodegeneration (cortical thickness). The final parsimonious models included the significant interactions of potential predictors with time, main effects nested within those interactions, and other significant main effects. Since the adjustment for conventional CVD measures like WMH was important to determine the utility DTI over traditional measures, we further assessed the value of FAGCC in conjunction with white matter hyper intensity (WMH).

Result

We found: i) FAGCC was associated with cognitive decline after adjusting for amyloid PET neurodegeneration (Figure 1 and Table 1) and ii) FAGCC was associated with cognitive decline even after controlling for WMH and WMH was no longer significant after accounting for FAGCC (Table 2).

Conclusion

DTI has significant utility for prediction of cognitive decline in MCI from population‐based samples and will provide complementary information to AD biomarkers.
Hyperhomocysteinemia as a model of VCID
Authors: Weekman Erica M. , Lee Tiffany , Price Brittani R. , Woolums Abigail E. , Hawthorne Danielle , IV Charles E. Seaks , Wilcock Donna M.
Published: December 2020

Background

Vascular contributions to cognitive impairment and dementia (VCID) are increasingly recognized as a significant cause of dementia. Furthermore, VCID co‐morbid with Alzheimer’s disease (AD) is estimated to occur in at least 60% of AD cases. While the contribution of VCID to clinical dementia is increasingly recognized, the mechanistic underpinnings of VCID has been lacking.

Method

We have previously shown that induction of hyperhomocysteinemia (HHcy) via diet in both wildtype (WT) and APP/PS1 mice produces cerebrovascular pathologies. While the pathological characteristics of HHcy have been identified in both models, the time course for these changes is unclear. We examined neuropathological changes along a time course of 2, 4, 6, 10, 14 and 18 weeks on diet in our models.

Result

In both the WT and APP/PS1 mice on the HHcy diet, increased microglial staining began at 6 weeks and was accompanied by a significant increase in several pro‐inflammatory markers. Several astrocytic end feet markers were significantly decreased at 10 weeks in the WT mice on HHcy diet. Cognitive decline also began at 10 weeks on diet in both models. Prussian blue staining revealed a significant increase in microhemorrhages starting at 14 weeks on the HHcy diet. Finally, in the co‐morbidity model, induction of HHcy resulted in redistribution of amyloid from the parenchyma to the vasculature starting at 14 weeks on diet.

Conclusion

Overall, induction of HHcy in both WT and APP/PS1 mice leads first to neuroinflammation, followed by astrocytic end foot disruption and cognitive decline, and finally, microhemorrhages, and redistribution of amyloid to the vasculature in the APP/PS1 mice. Taken together, this data suggests that neuroinflammation is an initiator in HHcy mediated VCID alone and when amyloid plaques are present, providing a possible common target for therapeutics in both VCID and co‐morbid patients.
Anatomical correlates of age‐related basal forebrain dysfunction
Authors: Somera Brandy Lynn , Woodruff Jennifer L. , Grillo Claudia A. , Reagan Lawrence P. , Fadel James R.
Published: December 2020

Background

The basal forebrain (BF) is comprised of several nuclei including the substantia innominata, medial septum, nucleus basalis and diagonal band of broca, which are involved in cognitive functions including attention, motivation, and arousal. BF neurons are particularly vulnerable to dysfunction and degeneration in aged humans and, more dramatically, in diseases such as Alzheimer's disease (AD). Age‐related BF dysfunction may reflect diminished afferent regulation, as well as an altered local glial environment. We have previously shown reduced orexin/hypocretin innervation of BF in aging, a phenomenon that may link afferent dysfunction with altered microglial homeostasis. There is little research examining these relationships involving afferent neuronal and glial cell populations in the BF as it relates to aging. The purpose of this study is to compare specific neuronal and glial populations to identify anatomical factors susceptible to age‐related homeostatic dysfunction in the BF.

Methods

Several lines of evidence demonstrate the responsiveness of the BF to homeostatic stimuli including food related stimuli. Using a food‐paired stimulus to examine effects of aging on physiologically‐relevant afferent stimulation, we deposited the retrograde neuronal tracer cholera toxin B (CTb) in BF of aged (26‐28 months) and young (2‐3 months) F344/Brown Norway F1 hybrid rats and trained them for 7 days. We then combined neural tract‐tracing with functional and phenotypic markers of activation to elucidate neural circuits that may underlie age‐related loss of activation of BF neurons using immunohistochemistry. Additionally, to show that loss of orexin afferents affects inflammation in the BF via microglial dysregulation, we administered a miRNA‐expressing lentivirus designed to knock down Orexin Receptor 2(OXR2) expression in the BF in young and aged rats. We then analyzed phenotypic changes in microglia using immunohistochemistry and ELISA against a panel of inflammatory cytokines.

Results

Aged rats showed altered activation of BF afferents located in the medial prelimbic cortex, infralimbic cortex, nucleus accumbens, and ventral tegmental area. Furthermore, changes in morphological and cytokine correlates of microglial activation following OXR2 loss can be seen in aged rats.

Conclusion

Together, these studies compare specific neuronal and glial populations of young and aged rats to identify anatomical factors susceptible to age‐related dysfunction.
Little progress in reducing relative racial disparities in the incidence and prevalence of dementia in the United States, 2000‐2016
Authors: Power Melinda C , Bennett Erin , Ciarleglio Adam , Glymour M Maria , Turner Robert , Dowling Maritza , Gianattasio Kan Z
Published: December 2020

Background

In the United States (U.S), risk of dementia is higher in non‐Hispanic black or African American populations than in non‐Hispanic white populations. Recent reports suggest declining or stable dementia prevalence and incidence, which may impact the degree of racial disparities. Our objective was to examine whether racial disparities in dementia prevalence or incidence have changed in the U.S. from 2000 to 2016.

Method

We leverage data from non‐Hispanic white and non‐Hispanic black participants ages 70 and older from the 2000 to 2016 waves of the U.S. nationally‐representative Health and Retirement Study (HRS). For analyses of secular trends in racial disparities in dementia prevalence, we consider each HRS wave separately. For analyses of secular trends in racial disparities in dementia incidence, we created seven sub‐cohorts, which followed all eligible persons without dementia classification at baseline for seven distinct four‐year intervals: 2000‐2004, 2002‐2006, 2004‐20108, 2006‐2010, 2008‐2012, 2010‐2014, and 2012‐2016. Participant race/ethnicity was based on participant response to closed‐ended survey questions. We determined dementia status for all HRS participants at each wave using three previously developed and validated algorithms designed for use in HRS‐based studies of racial/ethnic disparities in dementia. These algorithms assign dementia status based on information gathered at HRS study visits, and were designed to have similar out‐of‐sample sensitivity and specificity across non‐Hispanic white and non‐Hispanic black subgroups. We characterized disparities using ratio measures.

Result

While overall dementia prevalence declined from 2000 to 2016 in age‐ and sex standardized analyses, overall dementia incidence remained stable from 2000 to 2016. There was no evidence of secular trends in the magnitude of relative racial disparities in dementia prevalence or incidence. The prevalence of dementia in older non‐Hispanic black Americans remained approximately twice the prevalence in non‐Hispanic white Americans, and the incidence of dementia in non‐Hispanic black Americans was approximately 50‐60% greater than that observed in non‐Hispanic white Americans from 2000 to 2016

Conclusion

There is no evidence to suggest U.S. racial/ethnic disparities in dementia risk changed between 2000 and 2016. Additional efforts to identify and mitigate the source of these disparities is warranted.
Assessing accelerometric, gait and physiological parameters of induced spatial orientation in people with MCI or mild dementia and older healthy cohorts
Authors: Hinz Charlotte Alexandra , Amaefule Chimezie O , Lüdtke Stefan , Kirste Thomas , Teipel Stefan J
Published: December 2020

Background

Persons with dementia often experience spatial disorientation. They may benefit from the use of assistive technological devices to support outdoor navigation. One requirement for such systems is the automated detection of spatial disorientation to provide real time support. Previous studies showed that accelerometry and physiology signals could be informative in detecting phases of disorientation in real time. In an earlier field study, we developed a pattern recognition model of disorientated behavior based on accelerometric data from a real‐word environment. Here, we use the hybrid virtual and real‐world environment of the Gait Real‐Time Analysis Interactive Lab (GRAIL) (Figure one) to investigate accelerometric, gait and physiological parameters of induced spatial orientation among people with dementia and older healthy people.

Method

We implemented a 3D virtual environment (VE) of the Rostock city center into the GRAIL system, which consists of an instrumented treadmill and a 180° projection screen. Cognitively healthy older participants (age: 60‐85, MMSE ≥ 28) and PwD (age: 60‐85, MMSE ≥ 15 und ≤ 27) are included in this ongoing study. Participants walk a predefined route in the VE twice. In the first walk, they learn the route guided by the experimenter and then are asked to find the way to the goal destination unguided. Spatial disorientation is induced by manipulating landmarks in the 3D environment (for only the healthy older subjects in the experimental group), and resulting phases of spatial disorientation are video recorded for later offline annotation using a customized annotation scheme. Participants are equipped with wearable sensors which record heart rate, accelerometry and skin conductance. Afterwards, participants fill questionnaires examining usability and immersion.

Result

Recruitment is currently ongoing. Four old healthy participants (mean age = 67.5 , SD = 3.69) (3 female) and one (male) PwD (age = 79) have been measured so far. All participants completed the experiment. Evaluation of questionnaire responses indicates an overall suitability of our setup. Further results will be presented at the conference.

Conclusion

Our study serves as a basis for the development of situation‐aware sensor‐based ATD that support PwD in wayfinding. This study contributes towards improving independent mobility among PwD.
Deep volumetric super‐resolution improves the detection of amyloid‐related cross‐sectional group differences in MCI
Authors: Hesterman Jacob , Avants Brian , Greenblatt Elliot , Tustison Nicholas J.
Published: December 2020

Background

Super‐resolution (SR) methodology has emerged as a practical tool that may improve the interpretability and reliability of clinical MRI [Zhao2019, Xie2019] for structural measurements. Despite promise in neurodegenerative disease populations, relatively little work has been performed to validate SR image analysis. We hypothesize that deep learning SR methodology will improve inference about the relationship between surrogate measurements of AD pathology and in vivo measurements of cortical thickness. We test this hypothesis in ADNI subjects with baseline measurements of AV45 PET and diagnosis of mild cognitive impairment.

Method

We employ a 3D variant of the deep back projection network optimized with both distortion minimizing and perceptual losses [Haris2018]. The network was not optimized in any way for ADNI data. ANTsR and ANTsRNet [Muschelli2019] were used onT1w MRI for brain extraction, registration, anatomical labeling, bias correction, segmentation, and cortical thickness estimation. Segmentation and thickness estimation were done at the resolution of the native or SR image, respectively (Figure 1). Demographic data for the ADNI cohort (n=120) used in this study are shown in Figure 2. We interrogate p‐values of both the AV45 PET SUVR predictor and the data collection site predictor, enabling evaluation of the effect of SR on both predictors of interest and nuisance variables. We also control for age at baseline, gender and APOE status.

Result

(1) The model relating APOE, gender, age and SUVR in left temporal lobe explained 42.9% of the variance using native resolution estimates compared to 47.1% for SR. All predictors were significant. The p‐value for SUVR was 5e‐4 for native resolution and 9e‐5 for SR. (2) MR sequence effect mitigated by super‐resolution (p = 6.7e‐7 ). (3) Main biological effects are improved (gender, APOE4, AV45, age) while nuisance (site and quality) effects are reduced. (4) SR thickness predicts amyloid level ‐ after controlling for low resolution estimate of thickness.

Conclusion

Volumetric super‐resolution methodology may provide a useful preprocessing step in the structural analysis of neuroimages in MCI populations. Future work should evaluate impact on longitudinal processing, quantification of functional data, optimization for clinical signal detection, and additional validation efforts in other AD and non‐amyloid pathology.
A pilot study on Alzheimer’s disease‐related biological and cognitive markers in dementia and history of mild traumatic brain injury
Authors: LoBue Christian , Champagne Patricia , Munro Catherine E , Womack Kyle B , Kelley Brendan , Abdullah Kalil , Cullum Munro
Published: December 2020

Background

Mild traumatic brain injury (mTBI) has been associated with a higher risk for developing dementia later in life. Several mechanisms have been proposed, with most relating to TBI accelerating AD‐linked pathological changes or decreasing neuronal and/or cognitive reserve. The purpose of this study was to compare AD‐linked biomarkers and measures of neuronal and cognitive functioning in AD participants with and without a history of mTBI.

Method

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset was used to identify participants with dementia due to AD and a history of mTBI (n = 10),compared with a group of AD patients without TBI (n = 20) similar in gender, age (±5 years), education (± 3 years), and apolipoprotein ε4 status. Baseline cerebrospinal fluid (CSF)‐derived markers of amyloid and tau, and FDG PET glucose metabolism for three regions of interest (angular, temporal, and posterior cingulate), along with neuropsychological measures (i.e., Alzheimer’s Disease Assessment Scale–Cognitive Subscale 13 items, Rey Verbal Learning Test, Wechsler Memory Scale Logical Memory, Trail Making Test), were compared between groups.

Result

AD mTBI and control groups did not significantly differ in glucose metabolism using PET across regions often reduced in AD (p=0.53). CSF‐derived markers of amyloid formation also did not differ between the groups (p=0.76), though interestingly, there was a trend for higher phosphorylated tau (p=0.07) and total tau (0.08) markers in the mTBI group (Mptau=41.0, SD=15.0; Mttau=409.9, SD=133.7) relative to the control group (Mptau=31.5, SD=9.8; Mttau=319.5, SD=93.4). The groups were similar across neuropsychological measures (p’s=0.16 – 0.90).

Conclusion

A history of mTBI was not associated with greater markers of amyloid formation, lower cerebral glucose metabolism, or worse cognitive functioning in those with AD dementia. While not statistically significant, AD participants with mTBI did have a trend for higher tau levels compared to those with no history of TBI in this preliminary study. The findings may indicate a link between mTBI and greater accumulation of tau in some individuals that needs further evaluation in future studies with larger samples.
Amyloid BETA‐42 peptides facilitate the entry of gastrointestinal tract microbiome‐derived lipopolysaccharide into human neurons
Authors: Lukiw Walter J. , Li Wenhong , Bond Taylor , Zhao Yuhai
Published: December 2020

Background

Lipopolysaccharide (LPS) derived from the human gastrointestinal (GI)‐tract microbiome: (i) has been recently shown to target, accumulate within, and eventually encapsulate neuronal nuclei of the human central nervous system (CNS) in Alzheimer’s disease (AD) brain; and (ii) recent evidence indicates that this action appears to restrict the outward flow of genetic information from neuronal nuclei. It has previously been shown that in LPS‐encased neuronal nuclei in AD brain there is a specific disruption in the output and expression of two AD‐relevant, neuron‐specific markers encoding the cytoskeletal neurofilament light (NF‐L) chain protein and the synaptic phosphoprotein synapsin‐1 (SYN1) involved in the regulation of neurotransmitter release. The biophysical mechanisms involved in the facilitation of the targeting of LPS to neuronal cells and nuclei, and eventual nuclear envelopment and functional disruption are not entirely clear.

Method

Isolation of lipopolysaccharide (LPS), bacterial amyloid(s), enterotoxin(s) and small non‐coding RNAs (sncRNAs) from Gram‐negative anaerobic bacilli of the human gastrointestinal (GI) tract; isolation of human temporal lobe neocortical, hippocampal and retinal tissues; aging 5xFAD (amyloid over‐expressing; C57BL6 background); RNA sequencing; LED Northern dot blots; Western analysis, immunocytochemistry; biostatistics, bioinformatics

Result

In this presentation we will (i) provide novel evidence in human neuronal‐glial (HNG) cells in primary co‐culture that the incubation of LPS with amyloid‐beta 42 (Aβ42) peptides facilitates the association of lipoglycans such as LPS with neuronal cells; and (ii) that a similar phenomenon is observed in the brains of 5xFAD transgenic mice, an amyloid over‐expressing transgenic model of AD as well as in AD‐affected neocortex and hippocampal CA1.

Conclusion

These novel findings: (i) support a novel pathogenic role for Aβ42 peptides in neurons via the formation of pores across the nuclear membrane and/or a significant biophysical disruption of the neuronal nuclear envelope; and (ii) advance the concept that the Aβ42 peptide‐facilitated entry of LPS into brain neurons, accession of neuronal nuclei, and down‐regulation of neuron‐specific components such as NF‐L and SYN1 may contribute significantly to neuropathological deficits as are characteristically observed in AD‐affected brain.
Gene‐ and age‐informed enrichment method for preclinical Alzheimer’s disease trials: Approach and estimated cost savings
Authors: Spencer Barbara E. , Digma Leonardino A. , Jennings Robin G. , Brewer James B.
Published: December 2020

Background

Elevated β‐amyloid (Aβ) is used to enroll clinically normal (CN) individuals in preclinical Alzheimer’s disease (AD) trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment of these individuals while reducing costs. We hypothesized that by combining a polygenic hazard score (PHS) and age‐specific risk for AD we could predict elevated Aβ in CN individuals.

Method

AD incidence rates and each participant’s PHS were used to adjust the participant’s chronological age based on protective or deleterious genetic factors, thus creating an ADAge. An individual’s ADAge is defined as the chronological age at which there is equivalent AD risk in the population. Meng’s test was used in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to assess whether the ADAge was more correlated with Aβ than was chronological age. An ADAge cutpoint was chosen to optimally predict Aβ positivity among 306 CN participants from the ADNI and applied to 1000 bootstrap samples of an independent validation cohort of 80 CN participants from the UC San Diego Shiley‐Marcos Alzheimer’s Disease Research Center. The differences in means between samples enrolled by each strategy (ADAge enrichment vs no enrichment) were calculated to determine the efficiency of ADAge‐informed Aβ screening for preclinical AD trials as well as to determine the impact of ADAge enrichment on trial population demographics. The screening cost for enrolling 1000 Aβ+ CN participants in a clinical trial using each enrollment strategy was compared.

Result

Compared to chronological age, ADAge was more correlated with Florbetapir SUVR in the ADNI cohort (p < .001). In the validation cohort, the ADAge‐enriched sample had a higher proportion of individuals with elevated Aβ (difference[95% CI] 0.19[0.07–0.33]) than the unenriched sample. The ADAge‐enriched sample was older than the unenriched sample (difference 3.00[0.94 – 5.22]). However, the samples were similar in the proportion of APOE ε4 carriers, the dementia rating scale score, and the proportion of female participants. ADAge enrichment lowered screening costs by $5.3 million (34%) in a clinical trial scenario.

Conclusion

ADAge enrichment provides for a more efficient and cost‐effective means to enroll CN individuals with elevated Aβ in clinical trials.
A systematic overview of evidence for cognition‐oriented treatments in older persons
Authors: Gavelin Hanna Malmberg , Lampit Amit , Hallock Harry , Sabatés Julieta , Bahar‐Fuchs Alex
Published: December 2020

Background

Cognition‐oriented treatments (COTs) – commonly categorized as cognitive training, cognitive rehabilitation and cognitive stimulation – are promising approaches for the prevention of cognitive and functional decline in older people. We conducted the first systematic overview of meta‐analyses investigating the efficacy of COTs on cognitive and non‐cognitive outcomes in older people with or without cognitive impairment. This presentation will describe the methodology, main findings, and implications from this overview and provide future directions for research and research synthesis in the field.

Method

We conducted a systematic search to identify eligible reviews. Study characteristics, methodology and reported effect estimates were extracted and review quality assessed by two independent reviewers using AMSTAR 2. The effect estimates were summarized graphically to provide an overview of the available evidence across the different populations, interventions and outcomes. Meta‐regression was used to investigate the moderating effect of methodological variables on the overall effect estimate of cognitive outcomes.

Result

The search yielded 51 eligible reviews, 46 of which were included in the quantitative synthesis. The confidence ratings were “moderate” for 9 (20%), “low” for 13 (28%) and “critically low” for 24 (52%) of the 46 reviews. While most studies provided pooled effect estimates for objectively measured cognition, non‐cognitive outcomes of potential relevance to patients and caregivers, such as clinical or functional status and caregiver burden, were more sparsely reported. The mean effect estimate on cognition was small for cognitive training in healthy older adults (Hedge’s g 0.32, range 0.13‐0.64, 19 reviews), mild cognitive impairment (Hedge’s g 0.40, range 0.32‐0.60, five reviews), and dementia (Hedge’s g 0.38, range 0.09‐1.16, seven reviews), and small for cognitive stimulation in dementia (Hedge’s g 0.36, range 0.26‐0.44, five reviews). Meta‐regression revealed that higher AMSTAR score was associated with larger effect estimates for cognitive outcomes.

Conclusion

The available evidence supports the efficacy of COTs in improving cognitive performance in older people with and without cognitive decline. The extent to which such effects are of clinical value remains unclear, due to the scarcity of high‐quality evidence and heterogeneity in reported findings. For meta‐analyses in the field, there is a need for better adherence to methodological standards.
Novel mechanism underlying the APOE ε2 protective effect for Alzheimer disease implicated by integrative genome and transcriptome analysis
Authors: Panitch Rebecca , Zhu Congcong , Hu Junming , Chung Jaeyoon , Stein Thor D. , Farrer Lindsay A. , Jun Gyungah R.
Published: December 2020

Background

The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer disease (AD) and the ε2 allele is known to mitigate risk of AD. While potential mechanisms accounting for AD risk associated with ε4 have been extensively studied, the mechanism underlying the protective effect of ε2 is largely unknown.

Methods

We evaluated transcriptome‐wide (TW) differential gene expression (DGE) analysis in autopsied brains from 568 participants (339 AD, 229 controls) of the Religious Orders Study and Memory and Aging Project (ROSMAP), 162 subjects (82 AD, 80 controls) in the Mayo Clinic Study of Aging (MAYO), and 193 participants combined from the Framingham Heart Study and Boston University Alzheimer’s Disease Center (FHS/BUADC:64 AD, 129 controls). Results were combined across datasets by meta‐analysis. Analyses were focused on APOE 2/3 (E23) persons including 42 AD cases and 72 controls. The TW significance level was set at p < 10−6. Co‐expressed gene‐networks were created separately in AD cases and controls using Weighted Co‐expression Network Analysis. To validate AD enriched networks, we conducted gene enrichment analysis using lists from our top ranked DEGs and AD genes from a recent genome‐wide association study by Kunkle et al. In addition, we tested association of expression profiles from the top‐ranked DEGs with neuropathological traits in ROSMAP and FHS/BUADC.

Results

C4A (P = 1.9 × 10−5), GFAP (P = 3.8 × 10−5), and C4B (P = 4.8 × 10−5) were the most significant DEGs in the E23 group and TW significant in the total sample. The top‐ranked co‐expressed gene‐network in the E23 AD cases contained complement pathway genes such as C4A, C4B, and CR1, with significant enrichment for DEGs from the E23 subgroup (P = 0.05), DEGs from the total sample (P = 4.3 × 10−32), and known AD risk genes (P = 1.2 × 10−5). In FHS/BUADC, C4A expression was significantly associated with increased pTau181/tTau ratio (P = 0.01) and pTau231/tTau ratio (P = 1.0 × 10−5).

Conclusion

The complement pathway was previously implicated in AD, but to our knowledge this is the first biological link between APOE ε2 and the complement pathway. Together with a recent study showing direct binding between ApoE and C1q, our findings suggest that further studies of the interaction of APOE ε2 with complement pathway genes may lead to novel therapeutic targets for AD.
Quantifying what matters most to patients and care partners in Alzheimer's disease
Authors: Hauber Brett , Paulsen Russ , Callahan Leigh F. , Potashman Michele , Lee Daniel , Hartry Ann , Wunderlich Glen , Hoffman Deborah , Wieberg Dan , Kremer Ian N. , DiBenedetti Dana B.
Published: December 2020

Background

The Alzheimer's Disease Patient and Caregiver Engagement (AD PACE) Initiative works to identify and measure treatment‐related needs, preferences, and priorities of individuals across the continuum of AD. In the What Matters Most (WMM) study, we identified concepts of interest among patients and care partners and derived 42 items from these concepts.

Method

Respondents were recruited primarily from US clinical sites and assigned by a clinician to one of five groups: (1) AD risk factors without subjective memory complaints (SMC), (2) AD risk factors and SMC, and (3) mild AD, and care partners of patients with (4) moderate AD or (5) severe AD. Survey was administered online. Items were individually rated using a 5‐point verbal rating scale from 1 (Not at all important) to 5 (Extremely important). Responses were analyzed by group. Care partners (groups 4 and 5) rated item importance for themselves, not as patient proxies.

Result

Two hundred seventy‐four respondents (50‐65 in each group) completed the survey. Among all respondents, 193 (70.4%) were female, 173 (63.1%) identified as white, and 221 (80.7%) had education beyond high school. Among the three patient groups, the minimum (maximum) mean importance rating for any item was 3.4 (4.6) indicating all items were at least moderately to very important. Among care partners of patients with more severe AD, the minimum (maximum) mean importance rating was 2.1 (4.4); most items were rated as at least moderately important. One item (driving) was rated as less than a little important in group 5. Five items were among the most important for all groups: taking medications correctly, not feeling down or depressed, not feeling anxious, worried or stressed, being able to stay safe, not feeling like a burden to others.

Conclusion

For SMC and mild AD patients and those at risk for AD, all items were important. Among care partners of more severe patients, most items were important, and one was unimportant. These results may indicate that the 42 items in the WMM survey capture symptoms and behaviors that are meaningful to patients and care partners and should be considered when evaluating impacts of potential AD treatments.
Māori Assessment of Neuropsychological Abilities (MANA): A cognitive, functional and wellbeing screening tool for dementia in older Māori
Authors: Dudley Makarena Diana
Published: December 2020

Background

In New Zealand (NZ) in 2013, 5.4% of Māori (the Indigenous people of NZ) were over the age of 65 years and in the last decade the number of Māori kaumātua (elderly) living beyond the age of 80 years has more than doubled. This increase is likely to be accompanied by increases in the prevalence of dementia for Māori. In 2011, 1,928 Māori were estimated to have dementia and is expected to increase to 4,493 by 2026, although numbers are likely to be much higher because many with dementia remain undiagnosed. Cognitive screening and assessment tools commonly used in the diagnosis of dementia in NZ have not been validated on Māori despite these tools having poor specificity and sensitivity when applied to people from culturally and linguistically diverse backgrounds. Cultural bias in cognitive testing has been well established in the international literature and reiterated in studies conducted with Māori. The authors therefore developed the Māori Assessment of Neuropsychological Abilities (MANA) to address this disparity.

Method

Two hundred and fifty kaumātua representing all the major Māori tribes were interviewed in focus‐group settings about their understandings and experiences of dementia. A team, comprised of Māori and non‐Māori specialists in dementia, neuropsychology, and biostatistics in collaboration with Māori health researchers, Māori elders, and Māori dementia health workers, identified information from the data that paired with those domains commonly assessed for dementia in NZ. This data was then applied to develop a dementia screening tool for Māori consisting of a cognitive, functional and wellbeing interview schedule. We are conducting a Pilot study, N=40 in 2020 to test item content and relevance, scoring criteria, adequacy of floor and ceiling effects, clarity of instructions, and administration procedures. Receiver‐operating characteristic (ROC) curve analysis will also be used to determine the predictive accuracy of the assessment tools and to identify the best cut‐ off points for detecting cognitive and functional impairments.

Result

We will present preliminary results of the pilot study.

Conclusion

We hypothesise that a culturally validated and appropriate screening tool will provide improved accuracy in the diagnosis of dementia in Māori.
Functional characterizations of APP VAL604MET by CRISPR/CAS9
Authors: Kim Danyeong , Shim KyuHwan , Van Vo Giau , Bagyinszky Eva , An Seong Soo
Published: December 2020

Background

Many variants near the amyloid‐beta peptide (Aβ) of Amyloid Precursor Protein (APP) gene were reported major pathogenic mutations in Alzheimer's disease (AD), especially in early‐onset Alzheimer's disease (EOAD). Even though several mutations were investigated for the functional studies with cell and animal models, larger number of mutations were not investigated for the verification of the AD pathology. Previously, APP V604M was found from a EOAD patient with family history from Thailand. Since APP V604M was located outside of the Ab region, its causal pathogenic relationship could be questioned. In this study, APP V604M was introduced to a HEK293 cell line with CRISPR/Cas9 technology for the clarification of the functional pathogenicity.

Method

The guide RNA (gRNA) of APP V604M was introduced to a HEK293 cell line with CRISPR/Cas9 technology as previously reported. In CRISPR/Cas9, gRNA and donor DNA were designed for the APP V604M mutation and used to transfect HEK293 cells with Cas9 protein. The functional study of APP V604M was conducted using Aβ ELISA test. Aβ oligomers were measured by the Multimer Detection System (MDS).

Result

Transfection of APP V604M was confirmed using restriction enzymes. The mutation was identified by Sanger sequencing after single cell isolation. Next, the effects of the mutation were examined with gamma‐secretase activity, Aβ 42 productions and the presence of Aβ oligomers. MDS result showed the elevated levels of Aβ oligomers in APP V604M cells than the control, suggesting the mutation could be pathogenic. Additional biomarker results of gamma‐secretase activity and Aβ42 productions will be presented.

Conclusion

Transfection with CRISPR/Cas9 technology could help in understanding the pathogenicity of a mutation. APP V604M in HEK 293 was produced and biomarker study supported the pathogenicity.
Detecting cortical signatures of suspected non‐amyloid pathology using large harmonized datasets
Authors: Rane Swati
Published: December 2020

Background

Suspected non‐amyloid pathology (SNAP) MCI individuals constitute 7‐25% of the total MCI group and have a high risk of progression to AD. They are categorized by low amyloid accumulation but significant neurodegeneration as A‐T+[N] as opposed to A‐T‐[N] MCI individuals who have neither a high amyloid burden nor neurodegeneration. The low prevalence of SNAP makes it difficult to evaluate robust biomarkers for this group. In this work we leverage the GAAIN platform to harmonize anatomical imaging data from multiple repositories across the world to determine and compare cortical thickness differences and longitudinal rates of atrophy in SNAP‐MCI and A+T+[N] MCI groups.

Method

ADNI, EDSD, ARWiBo, and PharmaCog databases were queried using the GAAIN platform for individuals with T1 imaging and AD biomarker status. A total of 218 A+T+[N] MCI individuals, and 107 A‐T+[N] SNAP MCI individuals were identified. Cross‐ sectional differences in cortical thickness was evaluated using FreeSurfer. The differences were re‐evaluated following harmonization to remove any site related systematic differences. Next, longitudinal rates of atrophy were computed using FreeSurfer using the 2‐step model and a cluster wise threshold of p=0.05 with multiple comparisons correction using family‐wise error. Longitudinal data was available in 18 NC, 137 MCI, and 34 SNAP subjects. All comparisons were adjusted for age and gender.

Result

Before harmonizing across site‐related differences, cross‐sectionally, MCI individuals have lower cortical thickness with age in the superior frontal gyrus, caudal middle frontal gyrus, rostral middle frontal gyrus, precentral gyrus, and postcentral gyrus (Figure 1). The SNAP‐MCI individuals only had lower cortical thickness with age in the superior temporal gyrus and precentral gyrus. No group differences were observed. After harmonization, there was minimal difference in outcome. Comparing longitudinal rate of atrophy SNAP‐MCI individuals had a faster rate of atrophy in the superior and medial frontal gyri (Figure 2).

Conclusion

We did not find cortical thickness differences between MCI and SNAP individuals. We however show that MCI subjects have more widespread cortical thinning with age compared to SNAP‐MCI subjects. Comparing longitudinal rates of cortical atrophy, SNAP‐MCI individuals have faster rates of atrophy than MCI individuals in the frontal cortex.
Relationship between cerebral microbleeds, ventricular enlargement and white matter hyperintensities in Alzheimer’s disease
Authors: Kuroda Takeshi , Honma Motoyasu , Mori Yukiko , Futamura Akinori , Sugimoto Azusa , Yano Satoshi , Kinnno Ryuta , Murakami Hidetomo , Ono Kenjiro
Published: December 2020

Background

To investigate whether the number of cerebral microbleeds (CMB) could be a useful indicator to predict glymphatic system dysfunction in Alzheimer’s disease (AD) patients, by comparing the degree of cerebral spinal fluid (CSF) and interstitial fluid (ISF) stasis.

Method

Forty probable AD patients were included, with those exhibiting two or more CMB were included in the multiple CMB group (mCMB, n = 21, mean = 11.1), and none or one CMB included in the non‐multiple CMB group (nmCMB, n = 19, mean = 0.84). CMB were defined in axial gradient recalled echo (GRE) T2*‐weighted images. Evans index (EI) was calculated to measure lateral ventricle enlargement, Voxel‐based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) software was used to determine the extent of gray and white matter atrophy, and Fazekas scale (FS) was used to determine white matter hyperintensities (WMH).

Result

EI was significantly larger in mCMB than in nmCMB, while the gray and white matter volume was not different between groups. Thus, the difference in lateral ventricle enlargement between AD with and without multiple CMB reflects a combination of the degree of brain atrophy and the extent of CSF stasis. FS was higher in mCMB than in the nmCMB, suggesting the failure of ISF elimination was more severe in mCMB cases.

Conclusion

The difference in lateral ventricle enlargement and WMH between AD with or without multiple CMB may reflect a difference in the degree of CSF/ISF stagnation.