bluuebunny/crossref_metadata_2025 huggingface dataset:
Using linkage analysis to identify novel gene‐gene interactions in Alzheimer’s disease
Authors: Grunin Michelle , Wheeler Nicholas R. , Bush William S. , Haines Jonathan L. ,   Alzheimer’s Disease Sequencing Project
Published: December 2020

Background

Linkage analysis was a workhorse of disease gene mapping until the advent of more refined genomic scans through genome wide association studies (GWAS). However, GWAS’ ability to detect gene‐gene interactions is hampered by the required huge sample sizes. Whole Genome Sequencing (WGS) captures nearly all allelic variation enabling direct measurement of co‐segregation with disease for each allele in a family through linkage analysis without the need to consider recombination fractions. We developed an approach integrating co‐segregation data with extant biological interaction data to identify interacting genes involved in disease using WGS of multiplex Alzheimer’s Disease (AD) families.

Method

Two point linkage (MERLIN) was performed on WGS of 46 AD Sequencing Project (ADSP) families. Per family, an empirical maximum LOD score (MaxLOD) was calculated. Interactions between proteins were identified by querying multiple functional/pathway databases. Variants reaching a family‐specific MaxLOD were filtered by high/moderate impact (missense+stop/loss) and functional interaction. Further families from the ADSP are being analyzed using the same pipeline.

Result

Genes of interest were defined as genes of known interaction where at least 2 biologically interacting loci per family reached a family‐specific MaxLOD and were found in >1 family, creating a single shared transchromosomal locus. The transchromosomal MaxLODs were combined across multiple families sharing the same biologically interacting loci. Multiple families had biologically interacting genes with individual variants attaining a MaxLOD>1.2. One interaction of shared gene pairs/family had a transchromosomal MaxLOD across 3 families of 4.05, linking variants in SLC10A6, DHCR7, SOAT1, ABCA1 and SREBF2 in the cholesterol metabolism and lipid processing pathways. An additional 5 families had MaxLOD variants in at least one of these genes. 4 families had interacting pairs with a transchromosomal MaxLOD score >2.4 unique to the family.

Conclusion

This approach utilizes biological interactions to identify potential disease loci despite genomic distance, thus identifying possible epistatic effects not easily observable in case‐control datasets. It is easily applicable to any complex disorder having multiplex families.
Platelet APP levels from subjects with Alzheimer’s disease and mild cognitive impairment
Authors: Magno Augusto , Bram Jessyka Maria de França , Talib Leda Leme , Joaquim Helena Passarelli Giroud , Gattaz Wagner Farid , Forlenza Orestes Vicente
Published: December 2020

Background

The clinical diagnosis of Alzheimer’s disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process as Mild Cognitive Impairment (MCI). Beta‐amyloid peptide (Aβ) accumulation is one of the hallmarks of AD. It is well‐known that the main mechanism of Aβ production, whose accumulation is one of the hallmarks of AD, is from abnormalities in amyloid‐beta precursor protein (APP) metabolism. APP is an integral transmembrane protein widely expressed in neuronal and peripheral tissues and the enzymatic machinery needed to process APP in neurons is also present in platelets. The aim of the present study was to compare the protein level of APP to discriminate cases of AD and MCI from controls.

Method

The APP protein levels were measured in platelets from non‐medicated older adults with AD (n=10), MCI (n=17) and healthy elders (n=12) by western blotting. The densitometries of 130kDa and 110kDa were used to estimate the levels of APP and APP–ratio. Each sample was analyzed in duplicate and for normalization of platelet assay values we used β‐actin as loading (internal) control. All statistical analyses were performed with the aid of the software Statistical Package for the Social Sciences (SPSS) ‐ version 14. Differences in sociodemographic characteristics and platelets APP concentrations at baseline were analyzed using the Kruskal‐Wallis.

Result

There was no difference regarding gender distribution or age among the three groups (p=0.310 and p=0.088, respectively). We found a down expression of 110kDa‐APP‐fragment in AD compared to MCI and controls. In contrast, there was no difference nor in 130kDa‐APP‐fragment (p=0.212) either APPratio (p=0.736).

Conclusion

Our findings indicate that 110kDa‐APP‐fragment is down regulated in AD and may be a marker of altered APP metabolism in platelets since MCI state when compared to controls.
Awake two‐photon fluorescence imaging in the TgF344‐AD Alzheimer’s disease rat model
Authors: Al‐Azzawi Zaid A.M. , Joo Illsung L. , Koletar Margaret M. , Hill Mary E. , Mester James R. , Stefanovic Bojana , McLaurin JoAnne
Published: December 2020

Background

Inextricably linked with the manifestations of Alzheimer’s disease (AD) is vascular compromise which arises early during disease progression. Vascular compromise leads to subsequent failure in neurovascular coupling, plaque clearance, and oxygen delivery. Previous imaging studies have relied on the use of anesthetics to study vascular compromise. It is widely recognized that anesthetics have a wide range of effects on normal brain physiology including dampening neurovascular coupling, slowing neuronal responses, and decreasing brain metabolism. Therefore, there is a need for better imaging models which examine vascular responses during the early stages of AD without the confounds of anesthesia. The aim of this study is to develop the methodology for non‐anesthetized 2‐photon fluorescence imaging using the TgF344‐AD rat model to examine vascular compromise in the ‘prodromal’ phase of AD.

Method

The TgF344‐AD rat recapitulates the age‐dependent nature of AD exhibiting a ‘prodromal’ phase wherein underlying neuropathological changes are occurring without overt cognitive deficits. A prominent change during this period is vascular compromise. Recent advancements in 2‐photon fluorescence microscopy (2PFM) have allowed for high depth imaging of live tissues and has been significantly used in deciphering neuro‐vascular responses within the brains of various animals. 2PFM allows for the direct measurement of blood flow changes within blood vessels in response to neuronal activation. A cranial window is implanted into 4‐month old rats to gain optical access to the barrel cortex.

Result

In order to track vascular responses along branching points of major diving vessels within the barrel cortex, a 1.5mm microprism is implanted adjacent to the barrel cortex providing sideways visualization into the vasculature within the region. A 3D‐printed motorized treadmill was constructed in order to calm and distract the conscious animal while imaging is undertaken. Preliminary results in anesthetized animals show that qualitative images can be obtained through the prism within the barrel cortex.

Conclusion

This method shows promise in providing a more naturalistic model for studying functional vascular responses over time. It provides a platform for generating novel insights into neurovascular coupling in disease and healthy conditions.
Modeling and evaluating the effects of hyaluronic acid degradation on human microglia activation using multi‐interpenetrating polymer networks (mIPNs) as 3D in vitro models
Authors: Munoz‐Pinto Dany J. , Jimenez‐Vergara Andrea C. , Cagle Tyler , Jolliffe Alyssa
Published: December 2020

Background

Numerous recent studies have focused on the role of microglia in the onset and progression of neurodegenerative diseases including Alzheimer’s disease (AD) (Lee et al. 2015). One of the areas of interest is the study of the physiological changes microglia elicit in response to neural damage. Macromolecules such as collagen type IV, laminin, and hyaluronic acid (HA) characterize the extracellular matrix (ECM) landscape of the central nervous system (CNS). These components contribute to the regulation of microglia activation and phenotype modulation. In response to tissue injury or trauma, the normal composition of the ECM can be altered to induce microglia activation.

Methods

In this work, we modeled and evaluated the effects of HA molecular weight (MW) on human microglial cells (HMC3) under in vitro conditions using multi‐interpenetrating polymer networks (mIPNs). We fabricated and characterized a family of mIPNs comprised of poly(ethylene glycol) diacrylate (PEGDA), collagen type I (Col I), and HA of high (HAH, ∼1.5 MDa) or low (HAL, ∼40 kDa) MW via sequential infiltration (Van Drunnen et al. 2019). The viscoelastic properties of mIPNs were evaluated using dynamic mechanical analysis (DMA). In these scaffolds, the effects of HA MW on microglia activation were studied independently of scaffold mechanical performance. After 3 days in culture, changes in the expression of microglia pro‐inflammatory (M1) markers TNFα, IL‐1β, iNOS, and CD86, and the alternatively activated (M2) marker CD206 were measured at the protein level using immunofluorescence. Cell phenotypic expression at the protein level was quantified using confocal microscopy imaging and the ImageJ 2 (FIJI) program. Cell morphology was assessed using confocal microscopy.

Results

The overall HMC3 viability in the mIPNs exceeded 85%. Microglia morphology appears to be modulated by HA MW. On day 3, the reduction in HA MW in the mIPN formulations promoted a significant increase in the expression of the M1 and M2 markers iNOS, IL‐1β, and CD206 respectively.

Conclusion

With the proposed engineered scaffolds, we demonstrated that the reduction in the MW of HA — which is normally associated with tissue degradation — is a significant contributing factor for human microglia activation.
Microstructural alterations of regional white matter tracts predict tau deposition in the Alzheimer’s disease signature regions
Authors: Yi Dahyun , Byun Min Soo , Lee Jun Ho , Byeon Gihwan , Lee Younghwa , Ahn Hyejin , Joung Haejung , Moon Seok Woo , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2020

Background

We first aimed to investigate the association between regional white matter (WM) microstructural alterations with tau deposition in Alzheimer’s disease (AD) signature cortical regions. We also tried to develop models to predict pathological tau deposition positivity with regional WM microstructural alterations.

Method

One‐hundred nine older adults with normal cognition or mild cognitive impairment recruited from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease (KBASE) cohort were included in the analyses. All Participants underwent structural MRI (T1), diffusion tensor imaging, PiB‐PET and Tau‐PET (AV‐1451) scans. AD signature cortical regions for tau deposition included the angular gyrus, posterior cingulate, and inferior temporal cortical regions (Jack et al. 2017). Pathological tau positivity was determined by the presence of significantly high deposition in the Braak regions III‐VI according to the ADNI cutoff (Baker et al. 2017).

Result

Mean diffusivity (MD) of the posterior corona radiata, fornix, and posterior thalamic radiation were significantly associated with tau deposition in AD signature regions (F(1,107) = 13.48, p < 0.005; F(1,107) = 17.38, p < 0.001; F(1,107) = 15.92, p < 0.001, respectively) (Fig 1). Fractional anisotropy (FA) of the bilateral posterior thalamic radiation was also significantly associated with tau deposition in AD signature regions (F(1,107) = 17.14, p < 0.005) (Fig 1). Pathological tau positivity prediction model based on FA value of the posterior thalamic radiation, MD values of the posterior corona radiata and fornix had area under the curve (AUC) of receiver operating characteristics curve of 0.73 [0.62‐0.84] (Fig. 2a). With additional information on amyloid beta positivity, the AUC increased to 0.86 [0.78‐0.95] (Fig. 2b).

Conclusion

The findings indicate that microstructural alterations of the specific regional WM tracts closely linked to AD‐signature cortical regions are strongly correlated with tau deposition in the same cortical regions. Moreover, the findings also support propagation of tauopathy through WM tracts. The information on regional WM alteration may be used for the prediction of pathological tau deposition.
Hippocampal subfield volumetry in subjects at high risk of dementia: The PREVENT‐Dementia study
Authors: Dounavi Maria‐Eleni , Mak Elijah , Wells Katie , Ritchie Karen , Ritchie Craig W. , Su Li , O'Brien John T.
Published: December 2020

Background

It is now well‐established that pathological brain alterations in Alzheimer’s disease (AD) patients start occurring decades before symptom onset. The earliest detectable neuroimaging finding during the disease’s preclinical stage is amyloid plaque deposition. During the disease’s prodromal period, hippocampal atrophy is observed. However, it has been suggested that individual hippocampal subfields might demonstrate atrophy at an earlier stage. Our goal in the present study was to investigate the volume of individual hippocampal subfields along with their rate of volumetric change in cognitively normal middle‐aged subjects at high risk of AD using multi‐modal MRI.

Method

PREVENT‐Dementia study participants were recruited based on their dementia family history (FH). The participants’ age ranged between 40 and 59 years old and they were scanned at two time‐points (visit 1: 183 participants; visit 2: 155 participants). Hippocampal subfields were segmented using Freesurfer and information from a T1‐weighted MPRAGE scan (TR=2.3s /TE=2.98ms ,voxel size=1mm3) and a high‐resolution T2 coronal hippocampal acquisition (TR=9s/TE=94ms, voxel size=0.4x0.4x4.0mm3). The volume of the subiculum, CA1, CA2‐3, dentate gyrus & CA4, molecular layer, hippocampal fissure, hippocampal tail and the whole hippocampus were quantified and normalised to total brain volume. The volume of each subfield along with its rate of volumetric change were compared between FH positive and negative subjects and APOE ε4 carriers and non‐carriers using linear regression with age, sex and years of education as covariates.

Result

APOE ε4 carriers had a significantly decreased molecular layer volume (figure 1) compared to controls at both study time‐points (visit 1: p < 0.01; visit2: p = 0.02). There were no other differences in the examined subfields, whole hippocampal volume and the rate of volumetric change between the groups.

Conclusion

The molecular layer encompasses the stratum radiatum lacunosum and moleculare which is one of the earliest regions to be influenced in AD and has demonstrated high efficiency in separating amyloid positive and negative subjects. Our results suggest that the molecular layer could be amongst the first hippocampal subfields to demonstrate an atrophic pattern in mid‐aged APOE ε4 carriers, in the absence of whole hippocampal, CA1 or subiculum atrophy.
Cortical thickness and mean diffusivity AD signatures at average age 56 predict 12‐year progression to mild cognitive impairment
Authors: Williams McKenna E. , Elman Jeremy A. , McEvoy Linda K. , Dale Anders M. , Fennema‐Notestine Christine , Franz Carol E. , Gillespie Nathan A. , Hagler Donald J. , Lyons Michael J. , Neale Michael C. , Panizzon Matthew S. , Puckett Olivia K. , Kremen William S.
Published: December 2020

Background

Alzheimer’s disease (AD) brain signatures based on cortical thickness, with or without hippocampal volume, predict progression from mild cognitive impairment (MCI) to AD. It would be advantageous if AD signatures could predict earlier progression to MCI. Toward that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: 1) AD signatures in cognitively normal middle‐aged adults can predict progression to MCI; and 2) Gray matter mean diffusivity (MD) may capture earlier microstructural changes associated with AD.

Method

We investigated the ability of a published cortical thickness/volume signature and a novel MD signature to predict incident MCI in 261 cognitively normal middle‐aged men from the Vietnam Era Twin Study of Aging (VETSA) (baseline age=56.28±2.56; follow‐up age=67.50±2.61). The thickness/volume signature was a weighted average of 8 bilateral regions found to maximally discriminate AD from healthy controls. The same weights were applied to MD in these regions to create an MD signature in 206 subjects with diffusion‐weighted MRI data at baseline. Logistic regression and ROC curves were used to compare models with baseline thickness/volume signature, MD signature, age, and an AD polygenic risk score (ADPRS) predicting MCI at follow‐up.

Result

Thickness/volume signature, MD signature, age, and ADPRS together predicted progression to MCI an average of 12 years later with 77.85% specificity, 80% sensitivity, and area‐under‐the‐curve (AUC) of 0.822 (95% CI=0.729‐0.914) (Figure 1). Age and ADPRS alone yielded a significantly lower AUC of 0.633 (95% CI=0.561‐0.705; n=601). Adding the MD signature significantly improved prediction over age and ADPRS (AUC=0.811 vs. 0.633; p=.002) but adding the thickness/volume signature did not (AUC=0.746; p=.069).

Conclusion

AD brain signatures can predict 12‐year progression to MCI among cognitively normal adults who are only in their 50s, but our novel MD signature may be more sensitive to AD‐related changes than traditional thickness/volume signatures. Notably, the MD signature was limited by being yoked to the thickness/volume signature weightings. An independently derived MD signature may provide even stronger prediction. The results are thus promising with respect to early identification of AD and the potential value of MD‐ and/or multimodal AD brain signatures.
Three plasma metabolites in elderly patients differentiate mild cognitive impairment and Alzheimer’s disease: A mass spectrometry study
Authors: Talib Leda Leme , Costa Alana Caroline , Joaquim Helena Passarelli Giroud , Forlenza Orestes Vicente , Gattaz Wagner Farid
Published: December 2020

Background

Membrane metabolites are important mediators of neuronal function. The metabolomic profile of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) may suggest potential diagnostic biomarkers and provide information on the pathophysiology of dementia.

Method

We investigated the metabolomic profile of 79 older adults with primary cognitive impairment (34 patients with AD and 20 with MCI) and 25 physically and cognitively healthy elders (controls). We quantified plasma metabolites including membrane phospholipids, sphingomyelins, and acylcarnitines using the AbsoluteIDQ® p180 followed by flow injection analysis coupled with mass spectrometry.

Result

A cluster analysis revealed that a combination of acylcarnitines (C12‐DC, C12) and phosphatidylcholine (PC aa C26:0) could differentiate the patients according to diagnostic groups. As a general trend, phosphatidylcholines, acylcarnitines and sphingomyelins levels were lower in AD and MCI subjects compared to healthy controls, and this decrease was even more significant in MCI. The concentration of lysophospholipids was higher in AD and decreased in MCI, as compared to controls.

Conclusion

Future studies should combine metabolomic profiles with other biomarkers to identify diagnostic groups.
The development of a multi‐sensory intervention for people with dementia living in care homes
Authors: D'Andrea Federica , Tischler Victoria , Dening Tom
Published: December 2020

Background

Multi‐sensory intervention is a sensory stimulate approach that has received great interest within the field of dementia treatment, particularly for the management of responsive behaviours (Strøm, et al., 2016). The encouraging results on handling objects activities (Camic et al., 2019) and the unique relationship between olfaction, memory and emotion (Herz, 2016), prompts the interest to develop a multi‐sensory intervention (MSI), using olfactory, tactile and visual stimulation for people with dementia living in care homes, based on the Medical Research Council framework (2008).

Method

A background literature on multi‐sensory interventions and olfactory stimulations as well as a scoping review on object handling interventions were conducted to identify evidence and theories. To inform the MSI development, interviews with archivists and experts on olfaction (smell) took place prior to design the intervention and drafting the materials. In addition, a series of taster sessions with stakeholders and people with dementia were conducted to identify areas for refinement and to ensure MSI was appropriately tailored to the needs of people with dementia.

Results

The results of the scoping review and background literature form an evidence base from which the multi‐sensory intervention was developed. Interviews with experts helped to answer a number of questions in relation to the identification of intervention materials and procedure, which helped to create the first version of the intervention (MSI‐1). The results of the taster session will inform the development of the final version of the MSI.

Conclusion

The present study describes the development of an evidence‐based intervention, offering an important contribution to the literature supporting the need for developing intervention through a rigorous approach in order to establish clear evidence of the effectiveness of interventions that can help decision makers and budget holders to consider using those treatments.
Hippocampal volumetric variability is associated with memory in subjective cognitive decline
Authors: Ziegler Gabriel , Heinzinger Nils , Metzger Coraline D. , Yakupov Renat , Bittner Daniel , Glanz Wenzel , Spottke Annika , Brosseron Frederic , Bürger Katharina , Fließbach Klaus , Heneka Michael T. , Laske Christoph , Nestor Peter J. , Peters Oliver , Priller Josef , Ramirez Alfredo , Schneider Anja , Speck Oliver , Teipel Stefan J. , Wiltfang Jens , Wagner Michael , Düzel Emrah , Jessen Frank
Published: December 2020

Background

Subjective cognitive decline (SCD) has been proposed as an early symptomatic representation of Alzheimer’s disease (AD). Per definition SCD implies patient’s memory being subjectively impaired while broad neuropsychological indicators are still in normal range (Fig.1A). SCD might show early signs of atrophy in networks typically affected during AD disease progression. Among individuals with SCD, the prevalence of older adults who are on a declining AD trajectory are more frequent than in cognitively normal (CN) elderly. The key distinction between SCD and MCI would be a higher offset in memory ability in SCD and a larger proportion of individuals who have progressed further along the AD spectrum. This predicts that brain volume variability would be higher in SCD than in CN and non‐complaining older adults.

Methods

We used sMRI at 3T to quantify anatomical differences using VBM in the DELCODE cohort in a subsample of 755 nondemented elderly (including 221 CN, 376 SCD & 158 MCI). We characterise memory ability using a composite score based on factor modelling (Wolfsgruber et al., under review) of neuropsychological tests. We explore group differences and the association of memory to local brain morphometry using GLM and SPM. We further analyze variability of local volumes across groups using voxel‐based Brown‐Forsythe‐Tests.

Results

While there were significant volumetric differences of MCI but not in SCD as compared to healthy controls (Fig1 C left & right panel), volumetric variability (across subjects) was higher within the SCD (and MCI) as compared to CN in hippocampus (Fig. 2A). Individual differences in memory‐ability were positively associated with posterior hippocampal volume in SCD, but showed no association with brain volume in CN (Fig. 2B‐C). In MCI, variability in memory‐ability was also related to posterior hippocampal volume and in addition also to the volume of the anterior hippocampus and entorhinal cortex.

Conclusions

In terms of morphometric variability and the association between morphometric measures and memory ability, the SCD group shows partial overlap with MCI and is distinct to cognitively normal, non‐complaining older adults. The posterior hippocampal region could be an area that explains interindividual memory variability in early stages of the Alzheimer’s disease spectrum.
Automatic early detection of cognitive decline
Authors: Maimon Neta , Molcho Lior , Loterrman Tomer , Pressburger Narkiss , Sasson Ady , Intrator Nathan
Published: December 2020

Background

While it is agreed that cognitive decline is underdiagnosed, there is still no single universally accepted and affordable screening method that satisfies all needs in the detection of cognitive impairment. The goal of this presentation is to demonstrate an automatic cognitive decline assessment with Neurosteer Aurora, utilizing a novel EEG analysis as a method for characterization of cognitive activity and detection of early cognitive impairment.

Method

Neurosteer has developed a miniature wearable neurological sensor combined with an automatic assessment tool for a wide range of brain monitoring and treatment needs. It is based on a single EEG channel and relies on advanced mathematical analysis for a decomposition of the EEG signal into multiple components. These components are then processed with machine learning algorithms to create high level biomarkers for real‐time brain activity interpretation. Additionally, Neurosteer has developed a fully automatic assessment and biomarkers for cognitive decline. It is based on a verbal and musical cognitive assessment during brain activity recording. Machine learning algorithms analyze the combined data to produce a simple‐to‐read report indicating the level of different aspects of cognitive decline. We applied this technology on three different healthy population (N=14, 40, 215) and cognitively impaired (N=24, 10, 9, 8) undergoing several automatically administered cognitive tasks.

Result

A few biomarkers were extracted using machine learning tools on the collected data. The biomarkers distinguished between different levels of cognitive load as well as resting state patterns. The new groups of cognitively impaired populations were examined with Neurosteer Aurora, completing short and automatic auditory assessments. The patterns of the predefined biomarkers were significantly different for each population, differentiating between clinical populations and negatively correlated with the severity of cognitive decline.

Conclusion

Using the novel brain activity interpretation and biomarkers enables an automatic and easy‐to‐administer cognitive decline assessment in the clinical population. Such assessment is a step forward towards a wide‐spread screening, allowing early and personalized intervention to slow down cognitive decline, improving health and quality of life outcomes.
Two APOE splice sQTLs reduce Alzheimer’s disease risk in APOE 4/4 carriers
Authors: Belloy Michael E. , Eger Sarah J. , Guen Yann Le , Napolioni Valerio , Greicius Michael D. ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Are there genetic variants in the APOE locus that alter APOE4‐related risk for AD? Do these putative variants exert their effect through altering availability of the APOE protein? With these questions in mind, we investigated whether the APOE splice quantitative trait loci (sQTL; variants that alter post‐transcriptional splicing) affect risk for AD, age‐at‐AD‐onset, and APOE protein levels, in analyses stratified to APOE 2/4, 3/4 and 4/4 carriers, respectively.

Method

Genetic and phenotypic data was available from 35,760 eligible participants across twenty‐two independent AD‐related studies. Genetic data underwent standard quality control (Plink v1.9) and ancestry determination (SNPweights v.2.1). Included participants were ages 60+, non‐Hispanic, of European ancestry, had APOE genotype available, and were diagnosed as cases or controls (Table 1). From 17 APOE sQTL variants reported in GTEx, only rs157580 and rs439401 were genotyped in >80% of the available sample and further investigated (Figure 1). The role of APOE sQTL SNPs on AD risk was evaluated through logistic regression analyses under a case‐control design, and on age‐at‐onset through multiple linear regression. Associations with APOE protein levels were evaluated in post‐mortem tissue from the dorsolateral prefrontal cortex (dlPFC, n = 655), in which rs157580 alters excision rates of an intron on the APOE‐203 transcript variant. Given the relative paucity of subjects carrying APOE 2/4‐4/4 (n = 11‐11), protein level analyses were restricted to APOE 3/4 carriers (n = 161). Study design and model details/covariates are shown in Figure 1.

Result

rs157580 and rs439401 reduced AD risk in APOE 4/4 carriers (Table 2). rs157580 also showed a trending effect to increase age‐at‐AD‐onset in both APOE 4/4 and APOE 3/4 carriers (Table 3). Finally, rs157580 increased APOE protein levels in the dlPFC of APOE 3/4 carriers (Figure 2). Supplemental analyses suggest that the sQTLs and APOE4 must be in phase in order to confer protection.

Conclusion

Our results bring new insights into (genetic) mechanisms that alter APOE expression and how this affects APOE4‐related AD risk. This is crucially relevant for the development of AD drug therapies aimed at APOE4 and genetic risk counseling. Future work is needed to more precisely evaluate how haplotypes of the common APOE*2/3/4 polymorphisms and sQTLs affect AD risk.
Validation of circadian rhythm parameters derived from a user‐friendly activity monitor for long‐term continuous monitoring of brain health
Authors: Reynolds Christina L , Beattie Zachary , Au‐Yeung Wan‐Tai M , Kaye Jeffrey
Published: December 2020

Background

Fragmentation of sleep patterns is one of the earliest symptoms of Alzheimer’s disease and related dementias (ADRD) and is debilitating to both patients and caregivers. Interdaily stability and intradaily variability can be used to characterize the strength of an individual’s circadian rhythms. The utility of these parameters could be increased by applying this analysis to activity data collected over long periods, enabling longitudinal studies of changes in circadian rhythms as ADRD progresses.

Method

Activity data was collected for seven study participants (mean age = 73 years; 2 men, 5 women) for two weeks each. Over the two week period, participants simultaneously wore an ActiGraph wGT3X‐BT actigraph at the waist and on the nondominant wrist and a Withings Activite watch also on the nondominant wrist. The Withings watch was chosen for our study because of its watch‐like form factor, low cost and long battery life (up to six months). MATLAB functions were written to calculate interdaily stability and intradaily variability from the data collected from all three devices for each participant. Interdaily stability and intradaily variability calculated from the Withings watch data were compared with the same parameters calculated using both data from the actigraph worn on the wrist and the actigraph worn on the waist.

Result

Each participant contributed 144 hours of device data. High correlations were found in each of the comparison cases. For interdaily stability, the KS p‐value of correlation between the data produced by the watch and the actigraph was 0.68 for the actigraph at the waist and 0.65 at the wrist. In the case of intradaily variability, the KS p‐value was 0.86 at the waist and 0.92 at the wrist.

Conclusion

These results demonstrate the validity of a user‐friendly, low cost, consumer grade activity monitor to generate standard metrics of circadian function (interdaily stability and intradaily variability) in longitudinal studies of circadian rhythms. Low cost mass‐market activity monitors can be a valuable addition to studies of life patterns because they facilitate data collection both over long periods of time and from large numbers of study participants.
Hormetic effects of galactose could be explained by rapid metabolic network disinhibition of the protective oxidative pentose phosphate pathway flux
Authors: Homolak Jan , Perhoc Ana Babic , Knezovic Ana , Barilar Jelena Osmanovic , Salkovic‐Petrisic Melita
Published: December 2020

Background

Long‐term oral galactose treatment prevents and rescues cognitive deficits in rat model of Alzheimer's disease. In contrast, long‐term parenteral galactose treatment‐induced oxidative stress is used to model aging in rodents. The aim of this study was to provide new information on the effects of single acute oral galactose treatment, elucidate mechanisms responsible for both detrimental and protective effects, and explore their association with oxidative stress.

Method

Male Wistar rats were acutely treated with D‐galactose (200mg/kg) by orogastric gavage and sacrificed 30, 60 or 120 minutes after the treatment. Oxidative stress, metabolic parameters and proteins of interest were analyzed by spectrophotometry, electrochemistry, western blotting, ELISA and novel method for spatiotemporal reductive analysis. Data was tested for normality and analyzed by exploratory factor analysis of mixed data. Most significant determinators of two primary components were identified and tested for group and intraexperimental differences by Wilcoxon test, intragroup and combined Pearson correlation coefficient.

Result

Contribution analysis identified hippocampal NADP and NADPH, oxidative stress (superoxide dismutase (SOD) activity and redox couple oxidation‐reduction potential (rcORP)) and hippocampal expression of c‐fos and cytochrome c oxidase as primary determinants of the first component, and GLP‐1 total and active fractions as determinants of the second component. Acute oral galactose treatment increased hippocampal NADP, NADPH, cytochrome c oxidase, catalase activity and lipid peroxidation. Protein sulfhydryl content, SOD activity, and c‐fos were decreased by the treatment. Total amount of reduced glutathione and rcORP remained unchanged.

Conclusion

Acute oral galactose treatment induced increase in oxidative stress markers with no effect on net tissue reductive potential suggests endogenous compensation of oxidative challenge. Rapid metabolic shift towards phosphorylation of nicotinamide adenine dinucleotides and decreased cellular activity points to oxidative pentose phosphate pathway disinhibition‐mediated activation of conserved protective reactive oxygen species detoxification mechanism as a potential mediator of galactose‐associated hormetic effects. This work was funded by the Croatian Science Foundation (IP‐2018‐01‐8938). Research was co‐financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic‐ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund).
Time from symptom onset to specialist consultation and associated factors in the assessment of dementia in a dementia clinic in Southern Brazil
Authors: Chaves Marcia L Fagundes , Tello Brunna Jaeger , Castilhos Raphael Machado
Published: December 2020

Background

In the Brazilian unified health system (SUS) most dementia cases are referred by the general practitioner to the specialist for diagnosis, which may increase complexity of the process and can cause delay for diagnosis.

Method

A cross‐sectional database study with 245 dementia patients from an outpatient clinic in a tertiary university hospital in Southern Brazil was carried out to evaluate time from onset of symptoms to specialist consultation and associated factors in the assessment of dementia. The outcome variable was time from symptom onset to specialist assessment, reported by informants in the first consultation. For the analysis, participants were classified into two groups according to time for diagnostic evaluation (≤ and > 1 year; 20% x 80%). An univariate analysis was used to test the potential related factors associated with the delayed specialist assessment, and a multivariate logistic regression model was used to test association with the outcome.

Result

The mean time to theh specialist assessment was 3.3 ± 3.3 years. In the unadjusted analysis, individuals who were assessed after 1 year were diagnosed with Alzheimer’s isease, while who came before 1 year were most likely diagnosed with vascular dementia and other dementia types, had more sudden and subacute onset, neuropsychiatric symptoms at presentation, rapid progression, alcohol and antipsychotics use (p < 0.05). In the multivariate analysis, the effects of personality changes and onset presentation persisted, even controlling for other significant characteristics. The mean time to the specialist assessment was 3.3 ± 3.3 years. In the unadjusted analysis, individuals who were assessed after 1 year were mostly diagnosed with Alzheimer’s disease, while those who came before 1 year were most likely diagnosed with vascular dementia and other dementia types, had more sudden and subacute onset, more personality changes at presentation, rapid progression, and alcohol and antipsychotics use (p < 0.05). In the multivariate logistic regression, personality changes and onset presentation kept the association with time for assessment.

Conclusion

We found a long time from symptoms onset to specialist assessment in the public system. Individuals with more disrupting presentations such as personality changes and a faster presentation were referred earlier.
Comorbidity to dementia: The contributions of focal subclinical ischemia to pathogenesis in a mouse model of Alzheimer’s disease
Authors: Liu Mingzhe , Beckett Tina , Dorr Adrienne , Stefanovic Bojana , McLaurin JoAnne
Published: December 2020

Background

Although stroke and Alzheimer’s disease (AD) are distinctly different diseases, the risk for both substantially increase with aging, with stroke survivors being twice as likely to develop dementia. Although subclinical ischemic events do not present with outward symptoms, they share similar risk factors and outnumber overt ischemic events >9 to 1, with 31% of adults over the age of 65 experiencing at least one such event. The ischemic cascade may initiate neuropathological changes, leading to an increased susceptibility to develop AD. Hence, there is a need to elucidate the relationship between subclinical ischemia and AD pathogenesis.

Method

The endothelin‐1 (ET1) model of ischemia was utilized for subclinical focal stroke induction, while the inducible APPsi:tTA mouse was used to model AD, as it allows for temporal control of APP gene expression. To examine the impact of focal ischemia on AD, bigenic (tTA/APP) (DTg) and control (tTA) mice underwent unilateral stereotaxic ET1 or sham (vehicle) surgery in the medial prefrontal cortex and allowed to recover, before turning on APP gene expression. Structural MRI one week following surgery allowed for evaluation of the size and location of the stroke. Behavioral tests were performed to examine for changes as a result of subclinical focal ischemia and post‐APP expression. Immunohistochemistry and immunofluorescence were conducted for changes in amyloid load (6F/3D), astrocytes (GFAP), microglia (Iba1) 7 weeks post‐APP expression.

Result

Analysis of MRI confirmed the presence of subclinical ischemic events in ET1 DTg tTA mice. ET1 DTg animals showed significant behavioral deficits in marble burying, nest‐building, open field and Y‐maze, post expression of APP when compared to tTA controls. DTg animals also showed an increase in astrocyte and microglial activation post‐APP expression, but no differences were found in amyloid load between ET1 DTg and sham DTg animals.

Conclusion

The APPsi‐tTA mouse model allowed for controlled APP transgene expression– where the AD pathogenesis occurs independently after the initial subclinical event. Results show that subclinical ischemic insult to the brain enhance AD pathogenesis and allow for better understanding of the impact of comorbidities to AD progression.
Association of multi‐domain cognitive performance, cortical thickness and amyloid levels in cognitively unimpaired elderly adults with sub‐threshold amyloid levels
Authors: Delrieu Julien , Udeh‐Momoh Chinedu T , Price Geraint J , Jager Celeste A , Robb Catherine , Giannakopoulou Parthenia , Middleton Lefkos T
Published: December 2020

Background

Amyloid deposition assessed by Positron Emission Tomography (PET) is typically dichotomized to classify asymptomatic subjects as positive or negative, as part of the NIA‐AA Research Framework AT[N] biomarker‐based classification. Cerebral “amyloid negative” status represents a typically under‐studied group of individuals who may be on a trajectory for further amyloid and tau accumulation and associated cognitive decline, particularly when accounting in the presence of other AD risk factors. Thus, asymptomatic subjects excluded from AD observational and interventional prevention studies post amyloid status determination for being “amyloid negative”, present a unique opportunity to better evaluate them clinically and for MRI evidence of neurodegeneration.

Method

Cognitively normal participants aged 60‐85 years from the CHARIOT:PRO (Cognitive Health in Ageing Register: Investigational, Observational, and Trial studies in dementia research; Prospective Readiness Cohort Study) Sub‐study with negative amyloid PET (n=561) were included in our analysis. We separated a “sub‐threshold” group from the “clearly negative” and “extreme negative” individuals, defined respectively by intermediate, low and very low amyloid load on the centiloid scale and assess multi‐domain neurocognitive performance with RBANS (testing global cognition, memory, attention, visuospatial and language domains) and cortical thickness in AD‐pathology sensitive areas of the two groups, adjusting for confounders.

Result

In this cross‐sectional analysis, there were “within limits” discrete differences between “sub‐threshold” and “clearly negative” amyloid groups. On RBANS indices, the “sub‐threshold” group had modestly higher attention z‐score (0.68 vs 0.43, p=0.025) and index (112.46 vs 109.11, p=0.012) than the clearly negative group. There were no differences in RBANS memory or other domain indices, but trends noted in attention and visuospatial indices between subthreshold and extreme negatives (112.37 vs 109.65, p=088). Global cognition was correlated to AD‐related cortical thickness in the « sub‐threshold » group (r2=0.033, p=0.030) versus the « clearly negative » group (r2=0.002, p=0.384). APOE4 carrier status was noted in 28.30% of the “sub‐threshold” and 18.90% in the “negative” group.

Conclusion

Our results suggest that the association between AD‐related cortical thickness and global cognition may be driven by amyloid load in the “sub‐threshold” group. “Sub‐threshold” status in asymptomatic subjects could be a potential target for prevention trials, involving pharmacological and non‐pharmacological intervention.
Race modifies putamen connectivity in Alzheimer’s disease
Authors: Misiura Maria , Howell J Christina , Tannahill Amber , Parker Monica W , Turner Jessica , Hu William T
Published: December 2020

Background

African Americans (AAs) are twice as likely to develop Alzheimer’s Disease (AD) in their lifetime than Non‐Hispanic Whites (NHWs), but exhibit slower decline and lower tau in the presence of dementia. Increased prevalence of lifestyle risk factors for AD including of type 2 diabetes and vascular disease do not fully account for this disparity. To uncover biological mechanisms that contribute to these differences, we must continue to characterize the biomarker profile of AAs. Functional neuroimaging is a biomarker that warrants further characterization by race. Previous work identified increases in connectivity in AAs with dementia within the default mode network (DMN), an area that exhibits decreased connectivity in NHWs with dementia. This study investigated putamen functional connectivity differences between AAs and NHWs to determine whether they may be race‐specific regions vulnerable to disease. Previous research identified a relationship within AAs between putamen volumes and tau.

Method

We obtained structural and resting‐state functional MRI from 72 AAs and 65 NHWs. We defined regions in the left and right hemispheres in the putamen, as well as posterior cerebellum, superior frontal, and precentral gyri (as these regions are structurally connected to the putamen), and calculated connectivity between the putamen and each other region for both hemispheres. We constructed a multivariate model with connectivity values as outcome variables, and race, age, gender, and diagnosis as independent variables, and included a race x diagnosis interaction.

Result

Of the functional connectivity pairs we investigated, connectivity patterns among diagnostic categories between the posterior cerebellum and anterior putamen were significantly different between races such that in AAs, connectivity was higher in mild cognitive impairment compared to controls (t(43)=2.44, p=0.02), and lower in individuals with AD compared to MCI (t(13)=2.39, p=0.03).

Conclusion

AAs exhibited disease‐related connectivity patterns, but in novel regions. Putamen to cerebellum connectivity patterns are consistent with studies that have identified increased DMN connectivity in individuals with mild cognitive impairment, followed by lower connectivity in Alzheimer’s disease. The race‐specific decreased putamen connectivity in AAs lends further support to the compensatory role of the DMN in previous studies indicated by an increase in connectivity as AD burden increased.
Verification of gas sensors to detect Alzheimer’s disease biomarkers with diabetic rats
Authors: Emam Shadi , Nasrollahpour Mehdi , Kulkarni Praveen , Ekenseair Adam , Ferris Craig , Sun Nian‐Xiang
Published: December 2020

Background

Evidences prove that individuals with Type‐2 insulin resistant diabetes have a two‐three folder greater risk for Alzheimer’s disease (AD). The abnormal glucose metabolism leads to the increased production of reactive oxygen species (ROS) a hallmark of diabetes and AD. ROS‐induced lipid peroxidation can lead to neuronal damage and cell death and is thought to be a contributing factor to disease progression in AD.

Method

Recently, we introduced an array of electrochemical gas sensor to detect volatile organic compounds (VOCs) biomarkers in the exhaled breath. The sensors were later tested with a rat model that combined the human ApoE4 gene with aging and the Western diet. Gas sensors fabricated from molecularly imprinted polymer‐graphene were engineered to react with alkanes and small fatty acids (butylated hydroxytoluene, pivalic acid and, 2,3 dimethyl heptane) associated with lipid peroxidation. With a detection sensitivity in parts per trillion, the sensors were sensitive against the breath of wild‐type and APOE4 male rats with 100% sensitivity, specificity and, accuracy. The results were matching with the resting state BOLD functional connectivity which is used to assess hippocampal function.

Result

The present study was designed to test the Alzheimer’s sensor on diabetic rats. Since diabetes and AD share the same vascular problem, the question was that whether they share the same biomarkers as well or not. So, six rats with diabetic symptoms were tested with AD sensors and the result was negative. None of the sensors was sensitive to the breath of diabetic rats.

Conclusion

This result is confirming that the sensors are detecting biomarkers that are only specific to Alzheimer's disease, not to a very similar disease such as diabetes.