bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of molecular chaperone network modulators treatment on energy and tau metabolism in human cells
Authors: Pavlov Pavel , Wang Lisha , Kumar Rajnish , Winblad Bengt
Published: December 2020

Background

Alzheimer disease (AD) is a complex multifactorial disease representing >60 % cases of dementia with no disease modifying therapies available in clinics largely due to its poorly understood pathology. One of the new proteins that recently emerged as a promising target in AD therapy is FKBP51, or FK506‐binding protein 51 kDa. FKBP51, together with its partner, a molecular chaperone heat shock protein 90 kDa (Hsp90), have been found to play an important role in metabolism of tau promoting its accumulation and aggregation. In vitro, in vivo and epidemiological studies also suggest an important role of FKBP51 in control of body weight and insulin resistance.

Method

Recently, we have successfully obtained several active compounds able to inhibit FKBP51‐Hsp90 interactions both in in vitro assays and in human cell lines. SH‐SY5Y cells, differentiated human adipocytes were treated with FKBP51‐Hsp90 interaction inhibitors. Effect of compounds on energy metabolism, lipid metabolism as well on tau accumulation was analyzed. Using RNAseq we have analyzed transcriptome changes upon compound treatment.

Result

Addition of compounds resulted in profound stimulation of energy metabolism both in SH‐SY5Y cells and differentiated adipocytes. Significant increase in mitochondrial membrane potential was also observed. Dramatic decrease in size and number of lipid droplets was observed in differentiated adipocytes upon compound treatment. RNAseq results show increased expression of genes involved in lipid catabolism, beta‐oxidation and thermogenesis. We have also observed decreased tau levels in the treated SH‐SY5Y cells.

Conclusion

Our data implicate FKBP51 as a possible target for AD treatment affecting cell energy metabolism and tau accumulation.
Cell‐type specific selective vulnerability to pathological tau in Alzheimer's disease
Authors: Turkes Emir , Duff Karen E.
Published: December 2020

Background

Region‐specific neuronal subpopulations known to be selectively vulnerable to Tau pathology, as characterized in our previous work (Fu et al., 2019), were identified across several public single‐nucleus RNA sequencing datasets from non‐diseased human in order to derive putative properties and mechanisms that drive vulnerability.

Methods

We analyzed datasets from the Allen Brain Institute (Hodge et al., 2019), Broad Institute (Habib et al., 2017), and Polo group (Grubman et al., 2019). After QC, dimensionality reduction, and clustering, vulnerable and invulnerable neuronal subpopulations were identified using anatomical metadata and marker genes. Differential expression between subpopulations were performed using the Wilcoxon test, while differential pathway analysis was carried out using the GSVA algorithm.

Result

We were able to identify putative subpopulations across a range of presumed vulnerability as defined by classical pathological staging. Several themes emerge from differential pathway analysis of these subpopulations in various comparisons, including those related to vesicle‐mediated exocytosis activity and synaptic plasticity. Following further drilling down of these pathways for their association with vulnerability, pathways will be systematically screened in a model system measuring Tau aggregation.

Conclusion

Extensive pathway analysis of neuronal subpopulations selectively vulnerable to Tau pathology in human single‐nucleus RNA sequencing data reveal significant heterogeneity between neurons that may be responsible for driving pathological status.
A sensor technology to continuously monitor changes in cognition
Authors: Bowen Mary Elizabeth
Published: December 2020

Background

Researchers are increasingly utilizing real‐time sensors with ultra‐wideband radio frequency identification device (UWB RFID) technology to continuously, automatically and unobtrusively track the behavior and movement of older adults across care settings (Bowen, Kearns, Crenshaw, & Stanhope, 2019; Bowen & Rowe, 2019; Bowen & Rowe, 2016). These systems can be integrated into the health care environment and are ecologically valid measures taken concurrently as adults perform everyday activities of daily living (ADL). The purpose of this study is to examine the use of a UWB RFID system for the early recognition of behaviors associated with cognitive decline among skilled nursing residents (N=23) of two health care facilities.

Method

Residents were assessed continuously for an average of 10 months (SD=32.16 weeks). Scoring algorithms from the UWB RFID system utilized 1663 data points developed from x, y coordinates to measure the number and distance (meters) of continuous walking activity in a path. A path is defined as at least 60 seconds of walking and ends with a 30‐second stop. Cognitive function was measured by the Montreal Cognitive Assessment (Nasreddine, et al., 2005) and the Physical and Cognitive Performance Test (Bowen, Rowe, Ersek, Ibrahim, & Shea, 2017).

Result

On average, residents walked 1522.8 meters/week (SD=1572.7) with an average of 23.2 paths/week (SD=25.6). In multilevel models, accounting for ADL ability, an increased average number of paths per week was associated with decreased cognitive functioning (β= ‐0.65; p≤0.01).

Conclusion

Continuous walking in a path may be an early indicator of cognitive decline. Using an UWB RFID system may aid in the early detection and recognition of cognitive changes in this patient population. Importantly, these changes are also associated with other health events (e.g., falls, delirium, urinary tract infection, hospitalization) that may be ameliorable to intervention.
The role of the gut microbiome in cognitive function and Alzheimer’s disease
Authors: Bonnechère Bruno , Karamujić‐Čomić Hata , Radjabzadeh Djawad , Ahmad Shahzad , Ikram M. Arfan , Hankemeier Thomas , Kaddurah‐Daouk Rima F. , Uitterlinden André G. , Amin Najaf , Kraaij Robert , van Duijn Cornelia M.
Published: December 2020

Background

Although the level of evidence suggesting a role of the gut microbiome in the pathogenesis of Alzheimer’s disease (AD) in human and animal models, the evidence in humans is currently based on small studies and cannot determine whether the gut microbiome has changed in AD patients as a cause of consequence of disease. To exclude reverse causation, we have studied the association of the gut microbiome to cognition in 1,184 healthy participants of the Rotterdam Study.

Method

Fecal microbiome of 1,184 participants from the Rotterdam Study was characterized by 16S rRNA profiling. Cognitive function was assessed using g‐factor. Linear regression was used to associate the gut microbiome to cognitive function adjusting for age, sex, time in mail, storage time, and use of proton pump inhibitors. Further, we performed a systematic literature review to assess the consistency of findings on the association of the gut microbiome in AD and mice. Finally, we assessed the relationship between these microbiota and the general cognitive function.

Result

We found that the relative abundance of the phylum Firmicutes in the gut is associated with a better cognition. The relative abundance of families Lachnospiraceae, Christensenellaceae, Rumininococcaceae and Clostridiaceae explain this association. The relative abundance of Klebsiella, a member of the Enterobacteriaceae family is associated with lower levels of cognition. These findings were independent of potential confounders such as age, BMI, alcohol, and use of medication. Of the 10 associations that we found, 9 could be replicated in the smaller case‐control studies conducted to date in AD.

Conclusion

The present study finds that the relative abundance of the phylum Firmicutes in the gut is associated with a better cognition and the relative abundance of Klebsiella with lower levels of cognition. Taken together with studies published previously about AD, we find a relative reduction in phylum Firmicutes and an increased in Klebsiella is associated with lower cognition and dementia.
Entrainment of gamma oscillations by auditory chirp stimulation in Alzheimer’s disease patients
Authors: Sedghizadeh Mohammad Javad , Hasani Hosein , Lahijanian Mojtaba , Aghajan Hamid , Vahabi Zahra
Published: December 2020

Background

High‐level cognitive processes such as binding the processed data from sensory modules with elements stored in the memory involve the activity of long‐range pyramidal cells. These excitatory neuronal populations also provide input to a population of GABAAergic inhibitory interneurons, which in turn recruit feedback links to suppress the activity of the pyramidal cells. Interneuron networks generate rhythmic synchronization in the Gamma band driven by the time constant of the GABA receptors. Disrupted or desynchronized Gamma oscillations have been observed in patients of Alzheimer’s disease (AD). Earlier works have proposed the deficit in coherence between oscillations measured by EEG electrodes across the frontal lobe in the Gamma band in response to olfactory stimulation as a diagnostic marker of AD. This study examines the strength and spatial spread of Gamma band activity induced by auditory chirp stimulation as a marker for AD. The chirp signal is designed to entrain a target frequency of 40Hz at which the populations of inhibitory interneurons are known to operate.

Method

A session comprising 11 interleaved periods of 40sec ON and 20sec OFF auditory stimuli of 5kHz tone modulated by a 40Hz chirp at 0.1 duty cycle was administered to mild AD patients and non‐AD elderly participants with memory complaints, and EEG data were collected by a 10/20 system. Magnitude of 40Hz oscillations at different scalp positions during the ON cycles was measured as an indicator of the entrained Gamma oscillations.

Result

While 40Hz oscillations were recorded across a majority of electrodes in non‐AD demented participants with particular strengths in the temporal and frontal areas, the 40Hz entrainment occurred for a limited number of electrodes in AD patients.

Conclusion

Auditory chirp stimulation at 40Hz results in spatially distinguishable patterns of entrained Gamma oscillations in AD patients and non‐AD demented participants, and hence suggests a marker for AD. Despite this difference, the fact that 40Hz entrainment still occurs in regions of the brain in AD patients offers a positive indication for the possibility to employ such stimulation to reinvigorate the operation of the involved neural circuitry in therapy campaigns. Further studies are needed to assess such possibility.
Effects of a WIN 55,212‐2‐based therapy in two mouse models of Alzheimer's disease
Authors: Schmitt Franziska , Bayer Thomas A , Ott Frederik W , Bouter Yvonne
Published: December 2020

Background

Limited therapeutic effects of current Alzheimer treatments highlight the need for new research approaches. Targeting the endocannabinoid system could be such an approach. The endocannabinoid system plays a role in brain development, memory formation, and presynaptic activity as well as in neuro‐inflammatory processes and neuroprotection (Mechoulam et al., 2014; Salzet et al., 2000). Several in vitro studies showed that cannabinoids could stimulate phagocytosis and degradation of Aβ as well as stimulate the removal of intraneuronal Aβ in vitro (Currais et al., 2016). The current study aims to investigate the therapeutic potential of a WIN‐based Alzheimer’s disease therapy using mouse models of sporadic (Tg4‐42; Bouter et al., 2013) and familial (5xFAD; Oakley et al., 2006) Alzheimer’s disease. WIN 55,212‐2 (WIN) is a synthetic cannabinoid binding more efficiently to CB1 and CB2 receptors than Tetrahydrocannabinol.

Method

Tg4‐42 and 5XFAD mice were treated by intraperitoneal injections with the synthetic cannabinoid WIN 55,212‐2 (0,2mg/kg) over a period of 42 days. Sex‐ and age‐matched control groups are treated with vehicle solution (5% ethanol, 5% Tween80 in 0,9% sodium chloride solution). Spatial reference memory was assessed using the Morris water maze, motor performance with the Rotarod and anxiety behavior was evaluated using the elevated plus‐maze and the dark‐light box. 5xFAD mice carry five mutations strongly linked to amyloid processing. The effects of WIN on the Aβ pathology in 5XFAD mice will be investigated using immunohistochemistry and presented.

Result

WIN 55,212‐22 treatment of Tg4‐42 mice showed increased spatial reference memory and increased motor performance in comparison to the control group. Preliminary data analysis of 5xFAD mice shows significant results pointing in the same direction. Analysis of 5xFAD mice will be completed and presented.

Conclusion

Our findings reinforce a cannabinoid‐based therapy as a promising strategy for treating Alzheimer’s disease with WIN 55,212‐22 as a possible candidate.
Platelet APP‐ratio correlates with CSF levels of Aβ1‐42 in Alzheimer’s disease patients
Authors: Sarno Tamires Alves , Talib Leda Leme , Joaquim Helena Passarelli Giroud , Radanovic Marcia , de França Bram Jessyka Maria , Gattaz Wagner Farid , Forlenza Orestes Vicente
Published: December 2020

Background

The cerebrospinal fluid (CSF) is reputed as the best humoral matrix to address Alzheimer´s disease (AD) biomarkers. AD‐related CSF biomarkers are largely related to intracerebral amyloidosis, and have proved useful for diagnostic purposes and prediction of dementia in high‐risk populations. Lower CSF concentrations of Aβ1‐42 have been consistently reported in AD. However, results with peripheral biomarkers have so far yielded less consistent results. Platelets are the main peripheral source of amyloid precursor protein (APP) and contain the enzymatic machinery required for its proteolytic metabolism. Previous studies have shown that platelet APP ratio (130/110 kDa sAPP) is reduced in AD.

Method

We enrolled 66 older adults (26 with AD and 40 cognitively unimpaired subjects). The expression of 110‐ and 130kDA secreted APP peptides (sAPP) was determined in platelets by Western blotting using 22C11 monoclonal antibody, to determine APP ratio (rAPP). CSF concentrations of Aβ1‐42 were determined by a multiplexed method using commercial kits (Innobia AlzBio3).

Result

There were no statistically significant differences in age (p=0.67) or gender distribution (χ2=0.155; p=0.69) across groups. Compared to controls, AD patients had lower mean platelet rAPP (AD: 1.26, SD0.5; controls: 2.07, SD0.93; p<0.001) and CSF Aβ1‐42 concentrations (AD: 319.04, SD146.7; controls: 450.84, SD 109.9; p=0.001). We also found positive correlations between platelet rAPP and CSF Aβ1‐42 (Spearman’s Rho=0.40; p=0.01).

Conclusion

Our findings confirm that platelet rAPP and CSF Aβ1‐42 are reduced in AD. We further show that these two parameters are correlated, indicating that platelet rAPP may be regarded as a surrogate marker of intracerebral accumulation of amyloid‐beta.
Socioeconomic status mediates racial differences seen using the AT(N) framework
Authors: Wisch Julie , Hudson Darrell , Coble Dean W. , Xiong Chengjie , Babulal Ganesh M. , Gordon Brian A. , Flores Shaney E. , Dincer Aylin , Benzinger Tammie L.S. , Morris John C. , Ances Beau M. , Meeker Karin L.
Published: December 2020

Background

Previous research suggests that African Americans are potentially at greater risk for developing Alzheimer disease (AD). Genetic, social, environmental, and cardiovascular factors may increase the risk of AD. The objectives of this project are as follows: (1) Assess neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences. (2) Consider mediating effects of socioeconomic status (SES) and cardiovascular risk factors on observed race differences.

Methods

Imaging measures of AT(N) (amyloid and tau positron emission tomography (PET) structural magnetic resonance imaging, and resting state functional connectivity (rs‐fc)) were collected from African American (n=169) and Caucasian (n=935) participants. Cardiovascular (white matter hyperintensities on MRI, blood pressure, and body mass index) and area‐based socioeconomic status (SES) were assessed as possible mediating factors in a multiple mediation analysis. This analysis assumed nonlinear relationships between the mediation effects and allowed for all four mediators to be considered simultaneously.

Results

Compared to Caucasian participants, African American participants had lower amyloid PET burden but greater neurodegeneration, as measured by decreased cortical volumes and decreased AD global rs‐fc signature. African American participants were substantially more likely to be female (64%) compared to Caucasian participants (55% female). Female participants had greater tau burden and decreased AD cortical signature volume; but no significant race by sex interactions were observed. African Americans had lower area‐based SES and higher blood pressure, BMI, and white matter hyperintensity volumes. These proposed mediators significantly influenced associations between race and cortical amyloid PET accumulation, AD cortical signature volume, and AD global rs‐fc signature. Area‐level SES in particular was a significant mediating factor, and BMI had a significant effect on amyloid burden.

Conclusion

Observed racial differences in AD are not primarily due to immutable, genetic differences, but rather modifiable factors fueled by differences in social contexts and resources, particularly area‐level SES. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies.
MK‐6240 imaging features, cognitive associations in preclinical Alzheimer’s disease and a case with imaging‐to‐postmortem correlates
Authors: Betthauser Tobey J. , Koscik Rebecca L. , Jonaitis Erin M. , Cody Karly Alex , Erickson Claire M , Mueller Kimberly D. , Clark Lindsay R. , Stone Charles K , Christian Bradley T. , Asthana Sanjay , Salamat Shahriar , Johnson Sterling C.
Published: December 2020

Background

Understanding imaging features and detection limits of tau PET tracers is crucial for making accurate inference about underlying tau pathology, including critical implications for clinical treatment and prevention trials. This study investigates imaging features of the tau PET tracer MK‐6240 and associations with preclinical cognitive decline and beta‐amyloid with an emphasis on elucidating the earliest detectable MK‐6240 signal. These findings are contextualized with the first report of imaging‐to‐postmortem correlates for MK‐6240.

Methods

Participants recruited from the Wisconsin Registry for Alzheimer’s Prevention underwent longitudinal cognitive assessment, and PiB and MK‐6240 PET imaging. Three regional MK‐6240 composites were generated based on MK‐6240 spatial correlations (MTL, cortical, visual cortex). Linear mixed‐effects models probed relationships between longitudinal cognitive trajectories (three‐test Preclinical Alzheimer’s Cognitive Composite; PACC‐3), amyloid chronicity (estimated duration PiB(+) at baseline PACC‐3), and MK‐6240 in each composite region. MK‐6240 imaging outcomes were compared to neuropathological assessment for a 63 year‐old from the Wisconsin ADRC clinically diagnosed with early onset AD with PiB and MK‐6240 scans ∼2 months antemortem.

Results

Inter‐regional MK‐6240 correlations indicated minimal spill‐in from extra‐axial signal for most brain regions with the lowest correlations observed in the MTL. Mixed‐effects models indicated a significant three‐way interaction between age, baseline amyloid chronicity and MK‐6240 SUVR on longitudinal PACC‐3 in all three composite regions. The three‐way interaction remained significant only in the MTL when excluding participants with Z(MK‐6240)>2 in the cortex or visual composite regions. Neuropathological assessment of the case with antemortem imaging indicated Thal phase 4 and Braak stage IV or V with grade 1 CAA. Asymmetry in the MTL and focal elevations were observed in MK‐6240 images in this case, but SUVR values were below regional cutoffs for tau positivity.

Conclusions

Similar to reports with other tau tracers, MK‐6240 imaging‐to‐postmortem correlates suggest that tau‐related PET signal may not be detectable until later neuropathological NFT stages. The neuropathology results combined with the cognitive findings suggest that MK‐6240 signal in the MTL is indicative of more extensive tau pathology than can be observed with PET and thereby is disease‐related. Further work is underway characterizing the spatial correspondence between MK‐6240 and tau pathology.
Inter‐cohort staging efficacy of gaussian process progression model for Alzheimer’s disease
Authors: Archetti Damiano , Lorenzi Marco , Oxtoby Neil P. , Alexander Daniel C. , Frisoni Giovanni B. , Redolfi Alberto
Published: December 2020

Background

Understanding the path that leads from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) provides insights into dementia pathophysiology and can inform patient stratification in clinical trials. Our objective is to train statistical computational models for estimating an average disease trajectory to better understand how patients evolve on the basis of biomarkers of from the ADNI population, then validate the model on MCI subjects from the PharmaCog cohort.

Method

The disease trajectory was built via a Gaussian Process Progression Model (GPPM) (Lorenzi et al. 2017, DOI: 10.1016/j.neuroimage.2017.08.059) trained on longitudinal biomarker data from 338 subjects in the ADNI database who had converted from MCI to AD at the time of writing. Biomarkers related to cognitive scores, cerebrospinal fluid and T13D magnetic resonance imaging were used to build the disease model. Validation was performed by staging 139 MCI subjects from the PharmaCog database, 20 of whom progressed to AD, along the progression model timeline. Only baseline cross sectional measures of biomarkers were used to stage PharmaCog subjects in order to simulate clinical settings. Measures of sensitivity, specificity, balanced accuracy and area under curve (AUC) were used to measure the staging performance.

Result

The staging of PharmaCog subjects shows a clear separation between MCI stable (sMCI) subjects and MCI progressors (pMCI) on the disease timeline. On average, sMCIs were staged at year 72.7±3.6 while pMCIs are staged 3 years later (p‐value<0.01) at year 75.5±2.8. Classification of sMCI vs pMCI subjects returned a sensitivity equal to 0.68, specificity equal to 0.85, balanced accuracy equal to 0.77 and the ROC curve (Figure 1) had AUC equal to 0.75.

Conclusion

We identified MCI converters to AD in a clinical data set (PharmaCog) using a data‐driven computational model of AD progression trained on research data (ADNI). Classification performance was comparable to other data‐driven tools (Young et al., 2014, DOI: 10.1093/brain/awu176), but performed in a more challenging clinical setting. This validates the staging efficacy of such models and shows their utility for future application in healthcare and clinical trials.
A novel interaction between AD risk genes synaptojanin 1 and reticulon‐3 potentially impacts synaptic function and endo‐lysosomal trafficking during disease development and progression
Authors: Cai Dongming , Huang Min , Cao Jiqing , Hou Jianwei , Zhu Li , Zhang Larry , Pero Adriana , Guo Lei , T.C.W. Julia , Zhong Minghao , Goate Alison M. , Zhang Bin , Yan Riqiang
Published: December 2020

Background

APOE4 is the strongest genetic risk factor for developing sporadic AD with Aβ‐dependent and Aβ‐independent effects on disease pathogenesis. However, molecular signaling mechanisms underlying the detrimental effects of APOE4 on synaptic and cognitive function are not fully elucidated.

Methods

We integrated large‐scale human postmortem RNA expression datasets from the AMP‐AD consortium with a total of 1448 human postmortem brain samples representing 5 different brain regions from hundreds of LOAD patients and non‐demented subjects to perform multiscale network analysis. Gene‐regulatory networks for female and male AD were reconstructed and modules with different functional categories and cellular specificity were identified for each network and rank‐ordered based on their relevance to LOAD pathology. The modular differential connectivity and key driver analysis were then performed to identify key drivers with sexually dimorphic expression patterns or differentially respond to APOE genotypes between sexes.

Results

In this study, we identified synaptojanin 1 (synj1), a PIP2‐degrading enzyme with functional roles implicated in AD pathogenesis by our laboratory and others, as a key driver in AD networks that is associated with key regulators of synaptic function such as reticulon 3 (RTN3). The protein expression of both synj1 and RTN3 is increased in human and mouse brains of APOE4+
carriers. We have also detected the interaction between synj1 and RTN3 in whole brain lysate and synaptosomal fraction through co‐IP that is modified by APOE genotypes and AD status. In addition, we observed enlarged lysosomes in APOE4/4 iPSC‐derived neuron and astrocyte co‐culture when compared to APOE3/3 counterparts. Down‐regulation of synj1 or over‐expression of RTN3 dramatically ameliorated these phenotypes.

Conclusions

Based on these findings, we propose a model that the interaction between synj1 and RTN3 under physiological conditions may play important roles in regulation synaptic function and endo‐lysosomal trafficking. In APOE4+
brains, increased synj1 levels may impair intracellular trafficking of RTN3 from tubular ER to vesicular compartments leading to RTN3 retention within ER tubules with reduced distribution to downstream compartments which may contribute to reduced RTN3 degradation, compromised ER integrity, and impaired synaptic function and endo‐lysosomal trafficking.
Optimized extraction of the medial temporal lobe for postmortem MRI based on custom 3D printed molds
Authors: Lasserve Jade , Lim Sydney A. , Wisse Laura , Ittyerah Ranjit , Ravikumar Sadhana , Lavery Madigan , Robinson John L. , Schuck Theresa , Grossman Murray , Lee Eddie B. , Yushkevich Paul A. , Tisdall Dylan M. , Prabhakaran Karthik , Mizsei Gabor , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , Jimenez Maria del Mar Arroyo , Munoz Monica , Romero Francisco Javier Molina , Rabal Maria del Pilar Marcos , Irwin David J. , Trojanowski John Q. , Wolk David A. , Insausti Ricardo
Published: December 2020

Background

Structural magnetic resonance imaging (MRI) biomarkers are important for early detection of Alzheimer’s Disease (AD). However, atrophy measures can be confounded by changes due to aging and comorbid non‐AD neurodegenerative pathologies. Linking postmortem MRI of the medial temporal lobe (MTL) to histopathology may identify focal patterns of change associated specifically with early AD. We implemented a pipeline of high‐resolution MRI of MTL specimens and serial histopathology imaging [REF]. However, the task of extracting the intact MTL specimen such that it fits into the MRI coil requires anatomical expertise and has proven error prone. Here we present an algorithm to automatically create 3D printed molds guiding MTL extraction.

Method

INPUTS: 7T MRI scan of a formalin‐fixed hemisphere in which the hemisphere, MTL ROI and optional second ROI to be spared during cutting (e.g. frontal lobe) have been segmented using ITK‐SNAP semi‐automatic segmentation tools. OUTPUTS: Two 3D printed molds with slits that guide cutting. Mold 1 holds the whole hemisphere, guiding four cuts orthogonal to the midsagittal plane (Figure 1). Mold 2 holds the extracted tissue block, guiding three subsequent longitudinal cuts that trim the tissue to fit into a 50mm cylindrical holder (Figure 2). The positioning of the cuts can be specified interactively by the user using ITK‐SNAP (translating and rotating 3D images representing cutting planes) or automatically by optimizing (using Powell’s method) energy functions that minimize the volume of the final piece of tissue under multiple constraints (see Figures 3 and 4).

Result

The algorithm with interactively positioned cut planes was used in four hemispheres; the automated version in one (Figure 5). For each MRI scan, the MTL was intact. By contrast, retrospective review revealed cutting errors in 48% of manually cut specimens.

Conclusion

Our image‐guided approach reduces errors and dependence on anatomical expertise; allows more tissue to be spared from each brain donation; and enables postmortem imaging at a larger scale. It is not limited to the MTL and could be of interest to brain banks and AD research centers involved in postmortem imaging.
Effects of physical exercise in dual task performance and global cognition of elders with Alzheimer's disease
Authors: Ferreira Jose Vinicius , Silva Felipe de Oliveira , dos Santos Sacramento Plácido Jessica , Laks Jerson , Deslandes Andrea Camaz
Published: December 2020

Introduction

The increased prevalence of Alzheimer’s Disease (AD) has been generating a pursuit for different strategies that may help its treatment1. Physical exercise has been getting increasing attention, considering the low coast and benefits for physical and mental health2. To evaluate the effect of 12‐week multimodal training program in dual‐task performance, and on global cognitive function in elderly with AD.

Methods

24 elderly subjects diagnosed with AD were randomized and divided into two groups: exercise group (EG) n = 10, Age = 79.2 ± 10.04 and Mini Mental State Exam = 19.90 ± 4.88; and control group (CG), n = 14, Age = 75.7 ± 7.94 and Mini‐Mental State Exam = 21.42 ± 4.18. The evaluation of global cognition was measured through the Mini Mental State Exam, and the dual task through the 8 foot up and go test performance while naming as many animals as possible. In dual task condition we analyze the performance by mean velocity (m/s), DT cost (DTC) which was calculated by the formula (DTC = ([time of the test in a single task – time of the test in a dual task] / time of the test in a single task) × 100), and the number of the animals named per second during the performance. In order to compare groups before and after 12 weeks of intervention, a two‐way ANOVA of repeated measures and Cohen’s calculus of effect size (d) were applied.

Results

After 12 weeks, the EG showed clinical and significant improvement in the DT animals (ES=0.66) and clinical, but not significant, improvement in the variables DT (m/s) (ES=0.37), and DTC (ES=0.58). In regards to the Mini Mental State Exam, the EG showed conservation of global cognitive capacity, while the control group showed deterioration.
Effects of homotaurine on DLPFC disarray in MCI and the role of GABA
Authors: Bonomi Chiara Giuseppina , De Lucia Vincenzo , Motta Caterina , Koch Giacomo , Martorana Alessandro ,   Non Invasion Brain Stimulation Unit
Published: December 2020

Background

Homotaurine has been studied for its capacity to interact with amyloid‐beta monomers preventing their aggregation to oligomers, which carry a high degree of synaptic toxicity and are thought to play an upstream role in the pathogenesis of Alzheimer’s disease (AD)1. At once, this compound directly modulates excitatory neurotransmission via its high affinity with GABA‐A receptors. A recent study showed that homotaurine improves cholinergic transmission, likely by modulating inhibitory cortical activity2. Its anti‐amyloid properties combined with the GABAergic profile make homotaurine a new potential drug for the treatment of AD. Since pathological changes long precede cognitive decline in AD, Mild Cognitive Impairment (MCI) should be looked upon as a favoured stage for interventions aimed at stopping or slowing the progression of the disease. Several neurophysiological studies also highlighted that, from the earliest stages of AD, cortical plasticity at the dorso‐lateral Pre‐Frontal Cortex (dlPFC) is impaired, with lost of physiological beta‐gamma oscillatory response to TMS. We decided to test the effects of homotaurine on dlPFC functionality in patients with MCI.

Method

We used TMS‐EEG to non‐invasively stimulate the left and right dlPFC of 5 patients that accessed to our Memory Clinic for subjective amnestic impairment (mean MMSE 28). Registration was performed at baseline and after 15 days of treatment with Tramiprosate 100 mg/day.

Result

At baseline, the response on left dlPFC was weak in frequency, with an anomalous spot on lower alpha frequencies. Instead, the stimulation on right dlPFC originated a powerful response, yet aspecific in frequency, outlining a prominent inter‐hemispheric asymmetry. Post treatment results showed (1) a spectrum of oscillation frequency more coherent with physiological registrations and (2) interhemispheric symmetry in response.

Conclusion

These data suggest that Homotaurine increases frequency of oscillation in dlPFC, and helps re‐establishing, at least partially, interhemispheric balance in terms of oscillation in patients with amnestic impairment. This rapid effect likely depends on Homotaurine‐mediated changes of cortical GABA transmission, meaning that GABA might be implicated in cortical disarray from the earliest stages of AD.
Generation of a comprehensive disease progression model across the Alzheimer’s disease continuum
Authors: Hanan Nathan J. , Sivakumaran Sudhir , Sinha Vikram , Haeberlein Samantha Budd , Gold Michael , Romero Klaus
Published: December 2020

Background

Adequate assessment of trial design optimization is an important factor to inform clinical trial design for complex disorders such as Alzheimer’s disease (AD). Critical Path Institute’s Critical Path for Alzheimer’s Consortium (CPAD) has achieved EMA qualification and FDA Fit‐for‐Purpose endorsement of the first‐ever quantitative drug development tool (the clinical trial simulator for mild‐to‐moderate AD) and is in the process of developing a disease progression model spanning the entire disease continuum, to enable clinical trial design optimization. The objective of this work is to develop a structural model that characterizes disease progression in AD patients using the integrated CPAD database and optimize experimental design using clinical trial simulations.

Method

A disease progression model characterizing the time course of clinically relevant measures (ADAS‐Cog, CDR‐SB, other clinical scales and biomarkers), will be developed using an integrated dataset comprised of multiple observational and clinical trial data sources. Covariates including demographics, time from and to diagnosis, genetic status (APOE4), co‐morbidities and medication use will be assessed using non‐linear mixed effects methods. Monte Carlo simulations will be performed to compare the statistical power by sample size in trials with and without enrichment using relevant covariates.

Result

Model selection based on the log‐likelihood ratio and goodness‐of‐fit plots will be used to select the model structure that most adequately describes the integrated database. Covariate analyses will be performed to identify variables that constitute relevant predictors of baseline severity and disease progression rates. Trial simulations for a therapeutic effect using standard drug effect models for symptomatic and disease‐modifying effects will be conducted to estimate an optimal sample size when trials are enriched with a clinically relevant covariate.

Conclusion

The simulation output from the disease progression model will enable a more efficient design of clinical studies with better informed inclusion criteria and enrichment strategies. The proposed quantitative methodology permits a comprehensive integration of relevant patient characteristics available for decision‐making.
Robots, the Alzheimer patient, and the GDPR: Policy and privacy considerations for the use of robots in care, treatment, and diagnosis
Authors: Pierce Robin
Published: December 2020

Background

Several types of robots are currently being designed and introduced to address the needs of dementia patients at various stages of the disease progression. Robots hold the potential to fill some of the gap left by nursing and other staff shortages. In recent years, smaller, lighter, and less expensive robots have entered the market. Moreover, more sophisticated robots that combine functions of “companionship” with other care functions are becoming available. Increasingly, these robots contain sensors that serve a range of monitoring functions that can alert caregivers, neighbors, and clinical staff to phenomenon that may signal the need for attention or follow‐up. Robots that employ AI and thus, through the processing and refining of outputs, are able to “evolve” to better interact with the patient.

Methods

A survey of therapeutic, social, and social care robots were assessed to identify functions, processes, and designed purpose. A legal and ethical analysis identified data protection and privacy issues that arise in the deployment of these robots. This analysis is performed within the context of queries about the appropriateness of certain types of task‐shifting to robotics in dementia care and treatment.

Result

In performing monitoring functions for clinical or safety purposes, as well as “intelligent” companionship, these robots necessarily collect a range of data. Given that ever‐increasing phenomena, including behavioral, physiological, verbal, emotional, are recognized as being informative of a dementia‐relevant event (e.g. diagnosis, progression), this processing of environmental and personal information can be helpful to clinical staff and enhance caregiving. Yet, this data‐driven technology invokes consideration of privacy concerns, particularly in view of the General Data Protection Regulation in the EU. Concerns about the collection of sensitive (health) data of the patients and others in a shared environment, e.g. a nursing home, must comport with legal and ethical requirements.

Conclusion

Beyond data protection concerns, the broader issue of privacy is triggered by these technologies, forcing questions about optimal and ethical care, monitoring of the Alzheimer’s patient, and challenges for “task‐shifting”. This paper explores privacy and data protection issues in the shifting of certain tasks, functions, and responsibilities to therapeutic robotics, and addresses related legal and ethical considerations.
Neutrophil adhesion in brain capillaries contributes to cerebral blood flow deficits in APP/PS1 mice and is dependent on oxidative stress pathways
Authors: Ruiz‐Uribe Nancy E. , Bracko Oliver , Swallow Madison , Ali Muhammad , Njiru Brendah N. , Falkenhain Kaja , Chang Hsin‐Yun , Iadecola Costantino , Park Laibaik , Nishimura Nozomi , Schaffer Chris B.
Published: December 2020

Background

Cerebral blood flow (CBF) is decreased by ∼30% in both human patients and animal models of Alzheimer’s disease (AD). Previously, we found that about 2% of cortical capillaries in the APP/PS1 mouse model of AD had stalled blood flow due to an adhered neutrophil, while only 0.4% of capillaries were stalled in wild type controls. Blocking neutrophil adhesion in the APP/PS1 mice released the adhered cells, leading to increased CBF and improved cognitive function. Here, we report on the upstream molecular mechanisms contributing to the increased neutrophil adhesion, focusing on oxidative stress pathways that have previously been implicated in endothelial dysfunction in AD, including the loss of neurovascular regulation.

Method

We inhibited NOX2‐containing NAPDH‐oxidase, a reactive oxygen species producing enzyme shown to be activated in AD, in 10‐11 month old APP/PS1 mice for two weeks.

Result

We found that, in APP/PS1 mice, the fraction of capillaries with stalled blood flow was decreased by 67%, CBF was increased by 29%, and performance on short‐term memory tasks was improved. Enzyme‐linked immunosorbent assays showed no significant changes in amyloid‐beta levels and the overall plaque load was not affected. A decrease in the brain levels of activated astrocytes was detected, suggesting that NOX2 inhibition reduces overall inflammation.

Conclusion

This study implicates the NOX2 pathway as a molecular mechanism likely underlying the vascular inflammation that contributes to capillary stalling and CBF reductions in a mouse model of AD and could represent a molecular pathway with potential therapeutic targets for AD.
Herpes simplex virus and early neuroimaging markers of Alzheimer’s disease: Hippocampal volume and white matter integrity
Authors: Linard Morgane , Baillet Marion , Letenneur Luc , Garrigue Isabelle , Catheline Gwenaelle , Dartigues Jean‐François , Pérès Karine , Helmer Catherine
Published: December 2020

Background

While previous studies suggest an implication of herpes simplex virus in the onset of Alzheimer’s disease (AD), no study has investigated its association with early neuroimaging markers of AD. Moreover, a genetic susceptibility factor, the APOE4 status, is suspected to intervene in the entry of the virus into neurons and could partly explain why, despite a high seroprevalence, some infected individuals remain healthy carriers, while others develop neurological consequences of the infection. The present study aims to evaluate the association between HSV status and early neuroimaging markers of AD according to APOE4 status.

Method

In the AMI cohort, a population‐based prospective study on aging, the associations between HSV seroprevalence and i) hippocampal volume (n=172) and ii) white matter integrity in the parahippocampal cingulum and fornix (n=117), which are the main afferent and efferent axonal bundles of the hippocampus, were assessed according to APOE4 status. Serologies were performed at inclusion and magnetic resonance imaging scans were performed at 4 years of follow‐up. Right and left hippocampal volumes were averaged and expressed as a percentage of the total intracranial volume. White matter integrity was assessed using diffusion tensor imaging parameters: fractional anisotropy (FA) and mean diffusivity (MD). High FA and low MD values reflect a well‐organized and undamaged axon fiber architecture.

Result

Among APOE4 carriers, infected subjects presented lower hippocampal volumes (p=0.04) and higher microstructural alterations of the cingulum (lower FA, p=0.04; higher MD, p<0.01) than noninfected subjects; similar nonsignificant trends were observed for the fornix. Among APOE4 noncarriers, no associations were observed.

Conclusion

While the underlying mechanism remains uncertain and may involve direct action of the virus and/or the immune response against it, our findings suggest an association between HSV infection and early signs of AD among subjects with a genetic susceptibility factor, reinforcing the need to investigate the infectious hypothesis of AD and the potential related treatments.
Fluorinated gamma‐carboline derivatives delay motor deficits in transgenic mouse model of neuronal proteinopathy
Authors: Ustyugov Aleksey , Nebogatikov Vladimir , Vikhareva Ekaterina , Aksinenko Alexey , Fedyaeva Lyudmila , Mazin Pavel , Buchman Vladimir , Bachurin Sergey
Published: December 2020

Background

Aggregation of specific proteins is a key molecular event in pathogenesis of neurodegenerative diseases known as proteinopathies. Various products of this pathological aggregation cause neuronal dysfunction and death by different mechanisms. Prevention of protein aggregation at initial stages of this multistep process is seen as an important mechanism of therapeutic intervention into pathogenesis of proteinopathies.

Method

We used FUS(1‐359) mouse model of proteinopathy that is characterized by the formation of neuronal inclusions similar in ALS patients to determine effects of oral administration of gamma‐carboline fluorinated derivatives. Chronic treatments started at the age of two month prior to first visible symptoms and continued for 60 days or until the first symptoms were registered.

Result

A statistically significant increase in the mean lifespan was observed in experimental groups treated with tested compounds compared to the non‐treated control transgenic animals. Administration of fluorinated gamma‐carboline derivatives also statistically significantly delayed the debut of clinical symptoms manifestation of the neurodegenerative process in transgenic animals. Moreover, chronic treatments prevented overall weight loss which was a characteristic feature of the undertreated controls. The most effective fluorinated gamma‐carbolines improved the disease duration leading to significant increase in animal lifespan. We used Noldus Catwalk gate analysis system to study effect of compounds on the very first signs of motor dysfunction. We performed multi‐dimension scaling analysis analyzing data from transgenic mice to identify a set of parameters distinguishing between transgenic and wild type mice prior to neurological pathology symptoms become visible. More detailed characterization of the effect of fluorinated gamma‐carboline derivates on animal nervous system at presymptomatic stage is required for better understanding of the mechanism of the drug action.

Conclusion

Overall, our study suggests that chronic administration gamma‐carbolines significantly prolongs the presymptomatic stage of FUS‐proteinopathy delaying the symptoms and enhancing the lifespan of treated animals. This study was supported by RSF 19‐13‐00378 (synthesis of compounds) and by the Program of Russian Academy of Sciences #18 (biological studies). Animals were provided by the Bioresource Collection of the Centre for Collective Use IPAC RAS (No. 0090‐2017‐0016).
PLD3 is a neuronal lysosomal phospholipase D associated with β‐amyloid plaques and cognitive function in Alzheimer’s disease
Authors: Nackenoff Alex , Hohman Timothy J. , Neuner Sarah M. , Akers Carolyn , Weitzel Nicole , Shostak Alena , Ferguson Shawn M. , Bennett David A. , Schneider Julie A. , Jefferson Angela L. , Kaczorowski Catherine C. , Schrag Matthew S.
Published: December 2020

Background

Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer’s disease (AD), although the magnitude of this effect has been controversial.

Method

Because of potential significance, we undertook a study to determine whether PLD3 is relevant to memory and cognition in sporadic AD, to observe its distribution in normal human brain and AD‐affected brain, to describe its subcellular localization, and to evaluate its molecular function.

Result

PLD3 mRNA levels in the human pre‐frontal cortex inversely correlated with β‐amyloid pathology severity and rate of cognitive decline in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers. This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β‐amyloid plaques. This distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β‐amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. The V232M coding variant significantly reduced enzymatic activity compared to wild‐type PLD3.

Conclusion

In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with β‐amyloid pathology, dystrophic neurites and memory in sporadic AD.