bluuebunny/crossref_metadata_2025 huggingface dataset:
Adult hippocampal neurogenesis is impaired in patients with Alzheimer’s disease
Authors: Flor‐García Miguel , Terreros‐Roncal Julia , Moreno‐Jiménez Elena P , Llorens‐Martin María
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common type of dementia. This devastating disease is characterized by progressive memory impairments and other behavioral alterations. The hippocampus is one of the brain areas mostly affected by AD progression. Importantly, the hippocampus hosts a unique phenomenon that occurs in the mammalian brain, namely the addition of new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), is involved in hippocampal‐dependent memory and confers an extraordinary degree of plasticity to the entire hippocampal circuitry. AHN has been extensively characterized in rodents and other mammalian species during the last decades. Determining the occurrence of AHN during physiological and pathological aging in humans has an unquestionable therapeutic potential.

Method

We studied AHN in a collection of post‐mortem hippocampal samples obtained from 13 neurologically healthy subjects and 45 AD patients distributed among the six neuropathological Braak stages of the disease. We quantified the presence of various sub‐populations of immature neurons in the hippocampal dentate gyrus (DG) of these subjects. Importantly, we tightly controlled tissue processing methodologies and used state‐of‐the‐art histological procedures.

Result

Thousands of immature neurons positive for the gold‐standard marker Doublecortin (DCX) were identified in the DG of these subjects up to the tenth decade of life. In contrast, we observed an early and sharp decrease in the number of new neurons in patients with AD. Strikingly, the number of cells further decreased as the disease progressed, even though the number of mature neurons positive for the neuronal nuclei (NeuN) remained unchanged. Accordingly, specific decrease in the ratio between immature/mature neurons was observed along the progression of the disease. Importantly, AHN impairments occurred before the generalized presence of neurofibrillary tangles or senile plaques in the DG.

Conclusion

Our data demonstrate the persistence of AHN during physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits that occurs in AD. Therefore, the putative detection of AHN impairments by non‐invasive techniques might turn this phenomenon into a relevant biomarker for AD progression.
TREM2 Alzheimer’s variant R47H causes similar transcriptional dysregulation to TREM2 knockout in human IPSC‐derived macrophages
Authors: Roberts Hazel Hall , Agarwal Devika , Daniel Elena Di , Webber Caleb , James William S , Mead Emma , Davis John B , Cowley Sally A
Published: December 2020

Background

TREM2 is a microglia‐specific gene, with mutations linked to Alzheimer’s disease, including R47H (1). In AD mouse models, knockout (KO) of TREM2 impairs microglial clustering around amyloid and prevents microglia from being activated into a “disease‐associated” transcriptional state (2). The R47H mutation has been proposed to reduce ligand binding and therefore reduce TREM2 function (3).

Method

We generated primitive macrophages from human induced pluripotent stem cell (iPSC) harbouring isogenic R47H TREM2 and TREM2 KO mutations gene‐edited onto a healthy genetic background, as a practical, simple model of human microglia. We performed bulk RNA‐seq and compared significant differentially‐expressed genes (DEGs: FDR corrected p<0.05) between the R47H and KO versus WT. Selected hits were validated by qPCR, flow cytometry and western blotting. We also used a bioinformatics approach to predict potential upstream regulators of sets of DEGs.

Result

TREM2 KO resulted in a transcriptional signature hallmarked by dysregulation of genes involved with immune processes, calcium homeostasis, cell cycle, cell activation and chemotaxis. Although 3‐fold fewer DEGs were identified for R47H TREM2, 90% of these were also dysregulated in the KO, with directionality preserved. Validation confirmed specific defects in integrin expression in the R47H and KO. A candidate upstream regulator from the bioinformatics analysis was explored in cell assays, to shed more light on the underlying molecular mechanisms linking TREM2 KO to changes in adhesion and motility.

Conclusion

The overlap in transcriptional defects between R47H TREM2 and KO (with R47H intermediate between WT and KO) supports the hypothesised partial loss‐of‐function effects of this mutation in humans. Guerriero et. al. (2013) N Engl J Med. 368 (2):117‐27. Krasemann et al. (2017) Immunity 47, 566–581. Kober et al. (2016). eLife, 5, e20391.
Harmonizing the preclinical Alzheimer cognitive composite for multi‐cohort studies
Authors: Hampton Olivia L , Mukherjee Shubhabrata , Properzi Michael J , Schultz Aaron P , Crane Paul K , Gibbons Laura E , Hohman Timothy J , Maruff Paul T , Lim Yen Ying , Amariglio Rebecca , Papp Kathryn V , Johnson Keith A , Rentz Dorene , Sperling Reisa A , Buckley Rachel F
Published: December 2020

Background

Versions of the Preclinical Alzheimer Cognitive Composite (PACC) and within cohort standardization models have been implemented in multiple observational and clinical trials. Harmonizing PACC data across studies, however, requires modern psychometric approaches to reflect the psychometric, testing, and demographic nuances between cohorts and enable meta‐analyses. We present a method for harmonizing PACC across four cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4), Harvard Aging Brain Study (HABS), and Australian Imaging, Biomarker & Lifestyle Study of Ageing (AIBL).

Method

Tables 1 and 2 show the demographic and neuropsychological test data used to form each PACC. The ADNI dataset was defined as the anchor for harmonization. The final visit data were used to set factor score loadings for each PACC (except A4) to maximize cognitive variability in the sample for calibration purposes. First, we used confirmatory factor analysis (CFA) on the ADNI dataset to ascertain raw loadings and thresholds of each test onto a latent PACC factor (lPACC). These loadings were then applied to the longitudinal ADNI dataset (Fig.1). For the other studies, common items (MMSE and Logical Memory) were set as “anchors” to freely estimate unique items. Common items in HABS were set as anchors for A4 (FCsrt and DSST). Longitudinal lPACC scores were generated once all item parameters were estimated for all cohorts. We performed validation analyses to assess the quality of integration using lPACC scores versus within‐cohort standardized PACC (zPACC).

Result

LPACC scores largely aligned with zPACC, particularly when examining within‐cohort relationships with baseline demographic variables (Table3) and comparing slope distributions across cohorts (Fig2B). Notable differences between the scores include: a) shifted baseline distributions for lPACC relative to zPACC, reflecting cohort demographic heterogeneity (Fig.2A), and b) constricted slope distribution for lPACC slopes compared with zPACC slopes (Fig.2B), suggesting reduced variability (Fig.2B/C). When the cohorts were combined, the point estimate for strength of association between baseline amyloid and longitudinal cognitive change was higher using the lPACC than the zPACC (Fig.3).

Conclusion

LPACC scores reflect within cohort patterns, while reducing slope variability. Using advanced psychometrics, a harmonized PACC can be pooled across studies, facilitating robust multi‐cohort analyses.
Instagram live tour: How are COVID‐19 and dementia being faced by healthcare workers in Brazil?
Authors: Peres Fernando Aguzzoli
Published: December 2020

Background

Promoting live interviews with health workers from all Brazilian regions to address the increased challenges of dementia, quarantine, COVID‐19 and the local specificities of the crisis. The project aims to reach those sheltered in place with positive key content to face misinformation, fear and increasing fake news.

Method

Informal "chat" style targeting audiences with different levels of knowledge. Brazil is a continental country with more than 200 million inhabitants, different cultures, demographic factors and several inequalities. Each live sessions have a central topic (e.g. "Self‐care in quarantine times The one‐hour live sessions have a central topic (e.g. "Self‐care in quarantine times") discussed with a professional from that location. The recording is after available in the interviewer's instagram feed with 16,000 followers. The professionals are geriatricians, psychiatrists, psychologists and neurologists, all associated with large institutions such as the Brazilian Alzheimer's Association or the Brazilian Geriatrics and Gerontology society.

Result

The virtual interviews (6 to date) had significant engagement, excellent numbers of attendees during the live session (between 200 and 600 people), queries and comments posted (more than 100 interactions in each session), and views in the subsequent 48‐hour period (between 1,100 and 1,600).

Conclusion

The project is cost‐effective, being a collaboration between interviewer and interviewee without any fee, accessible due to the approach chosen, wide‐ranging in knowledge levels, and dynamic due to the interaction with the public. The project also avoid social isolation of those in quarantine, turning into physical distancing.
The impact of ligature‐induced periodontitis on an experimental mouse model of Alzheimer’s disease
Authors: Wang Rachel Pei‐Hsuan , Leung Wai‐Keung , Goto Tetsuya , Ho Janice Yuen Shan , Chang Raymond Chuen‐Chung
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common form of dementia characterized by the presence of amyloid plaques, neurofibrillary tangles and the activation of the brain immune system. Studies from the public health have shown that activation of the immune cells in the periphery can lead to neuroimmune responses, which can initiate or perpetuate neurodegenerative brain changes that underlie cognitive impairment. One of the common sources of chronic systemic inflammation is periodontitis, which is an inflammatory disease that destroys gums and teeth. We hypothesize that periodontal bone loss due to periodontitis gums may intensify the neuroimmune responses in AD and exacerbate the disease conditions.

Method

A 5‐0 silk ligature was placed around the maxillary upper second molars in female 3xTg mice for 5 weeks to induce periodontal bone loss. Open field test was performed to assess the sickness behavior; Spontaneous Y maze and puzzle box test were used to assess the cognitive functions of the mice. Following behavioral testing, the upper maxillary jaws were dissected out and subjected to histological analysis to examine periodontal bone loss. Different brain regions were harvested for biochemical analysis.

Result

After 5 weeks, ligature‐induced periodontitis led to a significant loss of periodontal bone level in 3xTg mice. It also induced inflammation in the hippocampus and frontal cortex regions. A significant reduction of exploratory motivation was also observed in ligated AD mice compared to WT control. No impairment of short‐term memory was observed in ligated AD mice, but they exhibited significant reduction in the total arm entries, which is also an indicator of a reduction in exploratory behavior. In the puzzle box test, ligature‐induced periodontitis induced long‐term memory impairment in ligated AD mice

Conclusion

Altogether, ligature‐induced periodontitis led to increase neuroimmune responses in the brains of AD mice, a reduction of exploratory motivation as well as long term memory impairment. As bone loss induced by ligation led to increased neuroinflammation. Future work will aim to elucidate the mechanism of how periodontal bone loss and the cytokine innate response lead to neuroimmune response. Acknowledgement: The study is supported by Health and Medical Research Fund (HMRF 04151216) to RCCC.
Laparotomy: A non‐bacterial endotoxin mouse model for investigating the impact of systemic inflammation on neuroinflammation and cognitive functions
Authors: Cheng Wai‐Yin , Ho Yuen‐Shan , Chang Raymond Chuen‐Chung
Published: December 2020

Background

Increasing lines of evidence have shown that systemic inflammation may contribute to neuroinflammation and accelerate the progression of neurodegenerative diseases. In this study, a non‐bacterial endotoxin mouse model of laparotomy is adopted to address the systemic inflammation triggered by surgery. We aim at investigating whether laparotomy induces systemic inflammation, neuroinflammation and cellular changes such as tau phosphorylation leading to cognitive dysfunction.

Method

Male wild‐type C57BL/6J mice were randomly divided into two groups: control group under sevoflurane anesthesia and laparotomy group under sevoflurane anesthesia. Expression of mRNA for cytokines in the liver, frontal cortex and hippocampus was examined at 4 h and day 1 after laparotomy by quantitative RT‐PCR and tau protein phosphorylation was comparatively determined on post‐operative day (POD) 1 by western blot analysis.

Result

First, laparotomy induced peripheral inflammation and neuroinflammation. At 4 h after laparotomy, significant increase of interleukin‐1β (IL‐1β) and MCP‐1 were detected in the liver of the laparotomy group (p < 0.05). Expression of IL‐1β was also significantly upregulated in the hippocampus after laparotomy. On POD 1, no significant differences of IL‐1β, IL‐6, TNF‐ α and MCP‐1 mRNA expression were observed at the liver. It implies that the induced systemic inflammation is transient. Meanwhile, the level of IL‐1β remained high in the hippocampus after surgery. Second, on POD 1, there was no significant difference in the total tau protein level between the laparotomy and control groups in the frontal cortex. It could be possible that the changes in protein expression level could not be reflected within a relatively short time period after laparotomy.

Conclusion

This study reveals that laparotomy induces systemic and neural inflammation. Further studies will be performed to examine the infiltration of monocytes into the brain and cognitive dysfunction induced by laparotomy. Acknowledgement: The study is supported by General Research Fund (17123217) to RCCC.
Anticoagulant prescribing in atrial fibrillation and risk of incident dementia: A UK population‐based cohort study
Authors: Cadogan Sharon L , Powell Emma , Wong Angel Y , Wing Kevin , Smeeth Liam , Warren‐Gash Charlotte
Published: December 2020

Background

Dementia risk is approximately doubled among patients with atrial fibrillation (AF) 1‐3, who are often recommended to take blood‐thinning drugs (anticoagulants) to prevent stroke. Recent evidence has also shown that taking anticoagulant drugs may help to delay the onset of dementia among individuals with AF4, however, we do not know which types of anticoagulants drugs are most beneficial and for which groups of patients. Hence, the aim of this study was to compare the effect of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on risks of incident dementia and mild cognitive impairment (MCI) among patients with newly diagnosed atrial fibrillation (AF).

Method

Using linked electronic health records data from the Clinical Practice Research Datalink (CPRD) in the United Kingdom, we conducted a historical cohort study among first‐time oral anticoagulant users with patients with incident non‐valvular AF diagnosed from 2012 to 2018. Crude incidence rates of dementia and MCI were calculated overall and separately for DOACs and VKAs. Cox proportional hazards regression models were then used to compare the incidence of clinically coded dementia and MCI between patients prescribed VKAs and DOACs, adjusting for sociodemographic and lifestyle factors, clinical comorbidities and medications.

Result

Of 39,200 first time oral anticoagulant users (44.6% female, median age 76 years, IQR 68‐83), 20,687 (53%) were prescribed a VKA and 18,513 (47%) a DOAC at baseline. Overall, 1,258 patients (3.2%) had GP‐recorded incident dementia, incidence rate 14.9 per 1,000 person‐years and 1,483 patients (3.9%) received a diagnosis of MCI, incidence rate 19.29 per 1,000‐person years. DOAC treatment for AF was associated with a 15% reduction in dementia risk compared to VKA treatment in the whole cohort (HR 0.85, 95% CI: 0.73, 0.98) and with a 20% reduction in MCI risk (HR 0.80, 95% CI: 0.71‐0.91).

Conclusion

The risks of incident EHR‐recorded dementia and MCI were lower among patients prescribed DOACs for new AF compared to those prescribed VKAs. The cognitive risk profile of a patient should help to inform choice of oral anticoagulant treatment for AF among older individuals.
3D neural circuit visualization by neural tracing and tissue clearing for dementia study
Authors: Lai Michael Siu‐Lun , Lee Krit , Sørensen Maja Højvang , Chang Raymond Chuen‐Chung
Published: December 2020

Background

To date, different techniques were developed for mapping neural connections, including diffusion tensor imaging (DTI) and neural tracers. DTI allows tracing of connections in macroscale but with low resolution. While neural tracers can allow visualization at single cell level, their signals are usually visualized in 2D sections. This results in missing information from the damages of brain tissues during tissue sectioning and inaccuracy of computation reconstruction. Therefore, we decided to trace neural circuits by using neural tracers in 3D intact tissues instead of 2D sections. In this study, we aim to establish 3D visualization protocol by combining neural tracing and tissue clearing techniques. We tested the potential of this protocol on tracing the neural circuit involved in Parkinson’s disease dementia (PDD) by using both chemical‐based and viral‐based neural tracers. Medial forebrain bundle (MFB) connects striatum, substantia nigra and frontal cortex. We at first focused on dopaminergic pathway projecting from MFB.

Method

Cholera toxin subunit B (CTB) conjugated with Alexa Fluor‐647 (CTB‐647) or adeno‐associated virus (AAV) expressing nerve growth factor and green fluorescent protein (AAV‐NGF‐GFP) was injected into MFB by stereotaxic injection. The rats were then euthanized by perfusion at different day points (10 days for CTB‐647; 5 weeks for AAV‐NGF‐GFP) after the injection. The brains were treated with 4% sodium dodecyl sulfate (SDS) plus Optical Properties‐adjusting Tissue Clearing agent (OPTIClear) solution for 5 days and then incubated into OPTClear solution for 2 days. The fluorescent signals were visualized by confocal microscopy.

Result

CTB‐647 and AAV‐NGF‐GFP signals were detected in striatum. It showed that the CTB‐647 can travel from MFB to striatum through nigrostriatal pathway, while AAV‐NGF‐GFP can be absorbed by the neurons projecting from MFB to striatum to express green fluorescent proteins. It is feasible to trace neural circuits by neural tracing with tissue clearing.

Conclusion

Taken together, nigrostriatal pathway, connecting substantia nigra and striatum, can be traced by using neural tracers together with tissue clearing. With this protocol, the neural circuits related to the dementia processes in PD can be further studied. Acknowledgement: The study is supported by Seed Funding for Translational and Applied Research (201910160016) to RCCC.
Contribution of specific gray matter volumes to insomnia severity
Authors: Martínez Neus Falgàs , Allen Isabel Elaine , Mumford Paige S , Essanaa Youssef M , Le Michelle M , You Michelle , Grinberg Lea Tenenholz , Neylan Thomas , Rosen Howard J , Kramer Joel H , Walsh Christine M
Published: December 2020

Background

There is an increasing awareness that sleep disturbances are a risk factor for dementia (Sindi, 2018). Prior case‐control studies have suggested that certain alterations in brain structure could be associated with insomnia status (Sexton, 2014; Grau‐Rivera, 2019). Specifically, they mainly described smaller cortical volumes in orbitofrontal and cingulate areas. However, it remains unclear whether there is a gradient association between these regions and the severity of insomnia. Therefore, our goal was to investigate the association between gray matter (GM) and white matter (WM) regions with insomnia severity. We hypothesized that a smaller orbitofrontal and cingulate cortex is associated with greater insomnia severity.

Method

122 healthy subjects (age 74.7±5.7 years old, 55.7% female) were recruited from the Healthy Aging Study at Memory and Aging Center, UCSF. All participants were determined to be cognitively healthy following a neurological evaluation, neuropsychological assessment and informant interview. Participants had a 3T brain MRI and completed the Insomnia Severity Index (ISI), a subjective measure of insomnia (Bastien, 2001). FreeSurfer was used to obtain GM and WM volumes. We used linear regression models to evaluate the relevance of regional GM and WM volumes to ISI, controlling for age and total intracranial volume.

Result

Distribution of ISI scores ranged from 0 to 16 (4.8±4.2). Regression models showed that smaller pars orbitalis (β=‐0.29, p=0.008), supramarginal (β=‐0.26, p=0.019), transverse temporal (β=‐0.24, p=0.018), postcentral (β=‐0.24, p=0.027), rostral anterior cingulate (β=‐0.23, p=0.044) and isthmus cingulate (β=‐0.23, p=0.045) GM regions were associated with higher ISI scores. White matter regions were not associated with ISI.

Conclusion

Lower volumes in certain cortical regions contributed to a higher degree of perceived insomnia severity. Conversely, white matter regions had no effect. Our results not only reinforce the involvement of orbitofrontal and cingulate regions with the presence of insomnia (Sexton, 2014; Grau‐Rivera, 2019) but furthermore, extend this showing that insomnia severity is associated with volumetric values in these areas. Further studies are needed to clarify how these insomnia‐related brain changes in healthy subjects align with an increased risk of dementia.
A head‐to‐head comparison between senolytic therapies, dasatinib plus quercetin and fisetin, indicates sex‐ and genotype‐specific differences in translationally relevant outcomes
Authors: Garbarino Valentina R , Tran Sydney , Glassman Jordan E , Kirkland James L , Musi Nicolas , Seshadri Sudha , Orr Miranda E
Published: December 2020

Background

Senescent cells accumulate with advanced age and contribute to dysfunction and disability. We recently discovered that tau protein accumulation induces cellular senescence in Alzheimer’s disease and other tauopathies, a group of brain diseases characterized by the deposition of tau protein (Musi et al., 2018). Treating mice with senolytics, drugs that specifically target senescent cells for their removal, reduced pathology and improved brain structure and function in tauopathy mice. Our initial study focused on dasatinib plus quercetin (D+Q). We now report results from directly comparing D+Q to fisetin (FIS) to determine differences in efficacy, toxicity, and sex and genotype as we work to translate this therapy to clinical studies.

Method

Fourteen‐month old male and female wild type (WT) and tau transgenic (rTg4510) mice were treated intermittently (3 days on, 11 days off, for 6 cycles) with D+Q, FIS, or vehicle by oral gavage. Physical and behavioral outcomes were measured before and after treatment.

Result

Both senolytic therapies significantly enhanced female rTg4510 mouse performance in the y‐maze (increased preference for novel arm (p = 0.00093 and p = 0.0015, D+Q and FIS, respectively); no treatment changes were noted in WT females or male mice. Pre‐ and post‐treatment comparisons of body weight revealed that D+Q uniquely increased body weight in female mice (WT: p=0.0005 and t: p = 0.024). Similarly, body length was increased by D+Q in WT (p= 0.0012) and rTg4510 (p= 0.0457) females, and WT males (p= 0.0481). Physical performance measures included run speed whereby D+Q increased WT female (p= 0.0002) and male (p=0.0267) velocity. FIS only affected WT males (p= 0.0022) but not females; and rTg4510 male (p=0.0015) but not female mice. Additional genotype, sex and treatment specific effects were observed in measures of frailty, grip strength, stride length, and nerve conduction. Our on‐going analyses of brain volumetry changes (MRI), axon integrity, transcriptomics, tau pathology, and inflammatory changes among the groups will provide mechanistic insights responsible for these behavioral phenotypes.

Conclusion

Our study suggests that tailoring senolytic therapies to specific individuals based on sex and disease state may provide the most benefit as we translate this promising therapy to clinical use.
Functional impact of cholinergic dysfunction on retrosplenial circuits in the 5xFAD mouse model of Alzheimer’s disease
Authors: Jedrasiak‐Cape Izabela , Ahmed Omar J
Published: December 2020

Background

The retrosplenial cortex (RSC) is critical for learning, memory and spatial navigation and is one of the first brain regions to show dysfunctional activity in the earliest stages of Alzheimer’s disease. RSC receives dense cholinergic inputs from multiple basal forebrain regions. While decreased cholinergic tone is one of the hallmarks of the Alzheimer’s disease, it is not known how this change impacts retrosplenial cells and circuits. In wild‐type mice, cholinergic agonists induce persistent firing in limbic areas such as the entorhinal cortex and the prefrontal cortex. This persistent firing has been proposed as an important neuronal substrate for working memory and successful spatial navigation.

Method

Here, we investigated cholinergic‐induced persistent firing in the retrosplenial cortex in the 5xFAD model of Alzheimer’s disease. We combined pharmacological and whole‐cell patch clamp techniques to characterize the response of retrosplenial cortex cells to carbachol (20 uM), a non‐specific cholinergic agonist, in both wild type and 5xFAD mice aged P30‐P75.

Result

In wild type animals, persistent firing in response to carbachol in deep layers of the retrosplenial cortex was commonly observed (66.6% of all cells tested). This persistent firing was blocked by atropine (10uM) indicating that it is dependent on muscarinic cholinergic receptors. Retrosplenial cells in 5xFAD animals rarely showed persistent firing (20%, p<0.05, binomial test comparing wild type vs 5xFAD).

Conclusion

Cholinergic hypofunction resulting from damage to basal forebrain neurons early in Alzheimer’s disease has widely been linked to cognitive impairment. Our results point to a complementary mechanism impacting cholinergic control of cortical circuits: muscarinic receptor downregulation in the earliest stages of Alzheimer’s disease. These changes prevent retrosplenial cortex cells of 5xFAD mice from responding to cholinergic activation with the kind of persistent firing that is important for working memory and spatial navigation, suggesting a mechanistic explanation for how cholinergic dysfunction leads to impaired spatial encoding by retrosplenial circuits.
Explainable deep learning models for dementia identification via magnetic resonance imaging
Authors: Gallay Charles , Draganski Bogdan , Kherif Ferath
Published: December 2020

Background

Today, to diagnose dementia, clinicians evaluate cognitive tests performed by patients and briefly analyze brain imaging data to look for biomarkers. While valuable information is present in MRI scans, these latter remain challenging to analyze and interpret. Artificial intelligence models have shown promising results to improve the current practice by supporting practitioners in the evaluation of imaging data. Nonetheless, the majority of developed statistical models are more often than not black‐box systems that issue predictions without any clear interpretability, hindering their practical applications.

Methods

We propose an interpretable method based on deep learning that works on minimally preprocessed T1‐weighted 3D scans of the brain. Relying on FullGrad [1], we can dissect the predictions of the model given an input scan. Once the model is trained, it can not only give an automated diagnostic but also generate a heatmap highlighting the regions of the brain that our model points to be responsible for its prediction of dementia. To ensure practicality, we integrate our model in a convenient app that can smoothly be run from a browser, as shown in the attached screenshot.

Results

We trained and evaluated our model on the OASIS dataset [2]. The specific explanation obtained by our model points at well‐known biomarkers, notably by highlighting the voxels of the hippocampus of patients with dementia. Interestingly, as it can be seen in the second annex, we notice that across individuals, our model focuses more on the voxels located in the right hippocampus.

Conclusions

In this study, we show how machine learning can identify dementia patients using MRI images while ensuring interpretable decisions of the models. Our tools, including the bespoke "explainer" viewer overlaid on each patient's brain, will enable the development of better and more reliable machine‐learning based diagnostics and nurture the trust of practitioners in computer‐aided diagnostics. Furthermore, this will help to discover currently unknown biomarkers and thus lead to a better understanding of the disease. References: 1) Full‐Gradient Representation for Neural Network Visualization, Suraj Srinivas, Francois Fleuret, 2) OASIS‐3: Longitudinal Neuroimaging, Clinical, and Cognitive Dataset for Normal Aging and Alzheimer Disease, Pamela J LaMontagne.
What factors explain racial differences in memory‐related gray matter volume regions of interest among cognitively normal older adults?
Authors: Godina Sara L , Rosano Caterina , Gianaros Peter , Aizenstein Howard J , Carlson Michelle C , Rosso Andrea L
Published: December 2020

Background

Previous studies indicate there are racial differences in the prevalence of Alzheimer’s Disease or other dementias, suggesting older Blacks are about twice as likely to have dementia as older Whites. Incorporating neuroimaging measures is necessary to understand the neural pathology underlying the mechanisms of these racial disparities, however limited data exists on neuroimaging outcomes among racially diverse adults of advanced age.

Method

We examined cross‐sectional associations of race and memory‐related gray matter volume (GMV) regions of interest (ROIs) in 263 community‐sampled adults (mean age 83, 57% female, 39% Black) from the Healthy Brain Project, a substudy of the Health, Aging, and Body Composition Study. Generalized linear models were used to test associations between race and memory‐related GMV ROIs (hippocampus, posterior cingulate cortex, parahippocampal gyrus, and entorhinal cortex), quantified using magnetic resonance imaging.

Result

Compared to Whites, Blacks consistently showed smaller GMV in four memory related ROIs, cross‐sectionally. Racial differences in GMV remained in the parahippocampal gyrus (β=‐433.42, 95% CI: ‐642.96, ‐233.87) and entorhinal cortex (β=‐159.18, 95%CI: ‐245.89, ‐72.48), after adjusting for demographic, environmental, and psychosocial covariates.

Conclusion

The association between gray matter volume of memory‐related ROIs and race is only partially explained by the demographic, environmental, and psychosocial factors considered in the present study. Quantitative bias analysis will be used to address whether these findings are the result of selection bias due to racial differences in recruitment.
Lipid profiling of healthy and Alzheimer’s‐affected mouse brains by using DESI imaging mass spectrometry: How lipid dyshomeostasis can contribute to Alzheimer’s disease
Authors: Lazarian Artur , Menon Vilas , Fowler Brandon , McIntire Laura Beth
Published: December 2020

Background

Alzheimer’s disease (AD) is one of the biggest health challenges that we face worldwide, which causes millions of deaths annually and costs reach many billions. Yet, the cause of the disease is not fully understood and therefore no effective treatment is available up to date. Lipidomic data from autopsy brain, human plasma and animal models highlights severe lipid dyshomeostasis in AD. Thus, the disruption of lipid metabolism and the homeostasis are thought to play a crucial role in the development of Alzheimer’s pathology. The importance of lipid metabolism in AD is supported by GWAS studies which have identified multiple lipid modifying enzymes and interacting proteins. It is likely then that specific pathways in lipid metabolism underlie AD disease mechanisms leading to behavioral impairment. Specifically, previous studies have shown that the loss of polyunsaturated fatty acids among multiple phospholipid classes is common in AD affected human brain and mouse models.

Method

Therefore, it’s of high importance to screen the lipid species in both healthy and AD affected human and mouse brains. By applying Mass Spectrometry (Synapt G2‐Si), we aim at setting up a workflow for high‐throughput quantitative and qualitative lipidomics profiling for healthy and AD affected brains.

Result

Here, we show the phylogenetic comparisons of genes and their SNPs that were found by GWAS studies to be risk factors in AD. These SNPs in humans were compared to that of primates and other animals. In addition, preliminary Mass Spectrometry runs were carried out for setting up a lipid screening workflow.

Conclusion

As supported by our preliminary data, the MS will allow us to detect broad range of versatile lipid species by applying targeted and untargeted analysis, Ion Mobility Separation, and DESI Imaging.
Granulovacuolar degenerating body markers accumulate alongside dysfunctional lysosomes in dystrophic neurites and correlate with cognition in Alzheimer’s disease
Authors: Schrag Matthew S , Mahoney Emily R , Shostak Alena , Nackenoff Alex , Dumitrescu Logan , Akers Carolyn , Jefferson Angela L , Hohman Timothy J
Published: December 2020

Background

Recent decades have brought a renaissance in understanding lysosomes and autophagy in neurobiology and neurodegenerative diseases. Neuronal endolysosomes are defective in Alzheimer’s disease (AD), most notably in dystrophic neurites where large numbers of enzymatically inactive lysosomes accumulate, distending axons around β‐amyloid plaques. Granulovacuolar degeneration bodies (GVDBs) are another well‐documented neuropathology associated with AD. These pathological neuronal organelles have two membranes, the outer containing lysosome‐associated membrane proteins suggesting these organelles are a product of frustrated autophagy. To implicate GVDBs in the pathogenesis of AD, we evaluated if GVDBs are present in dystrophic neurites and whether the expression of key GVDB genes are correlated with cognition in AD.

Methods

Human brain with AD and brains from 5xFAD mice were examined with immunohistochemistry and confocal microscopy for the established GVDB marker CK1δ. We also evaluated the recently discovered GVDB marker Golgin a4 and its binding partner ARL1 (implicated in the formation of autophagosomes). Finally, we assessed the association of mRNA levels of these genes in frontal cortex at autopsy with cognition and β‐amyloid pathology in 600 participants in Rush University’s Religious Orders Study and Memory and Aging Project (ROS/MAP).

Results

We discovered that CK1δ, Golgin 4a and ARL1 accumulate in dystrophic neurites in mouse and human AD brain, partially co‐localizing with the lysosomal enzyme cathepsin B, indicating a portion of the organelles accumulating in dystrophic neurites are likely GVDBs. In ROS/MAP participants, golgin a4 expression inversely correlated with cognitive trajectory (β=‐0.003, p=6.0x10‐4) and β‐amyloid plaque density (β=0.01, p=0.001), while ARL1 directly correlated with longitudinal cognition (β=0.004, p=7.0x10‐4) and β‐amyloid plaque density (β=‐0.01, p=0.027) in a model covarying for age at death, sex, education, APOE genotype, and interval between last visit and death. From these results we constructed a conceptual model of the molecular interaction between dysfunctional lysosomes and dysfunctional autophagic organelles in dystrophic neurites.

Conclusions

GVDBs accumulate in dystrophic neurites in AD, indicating the presence of defective autophagic organelles in addition to the known dysfunctional lysosomes. Transcriptomic data demonstrating a correlation of GVDB markers with cognition and β‐amyloid pathology suggests this discovery is likely functionally relevant.
Cognitive profile of mild behavioral impairment (MBI) in brain health registry participants
Authors: Kassam Farzeen , Chen Hung‐Yu , Nosheny Rachel L. , Williams Tirzah , Mackin R. Scott , Weiner Michael W. , Ismail Zahinoor
Published: December 2020

Background

Non‐cognitive markers may be utilized in dementia risk assessments. Mild behavioural impairment (MBI) is a validated neurobehavioural syndrome developed by an Alzheimer’s Association‐ISTAART working group including the following criteria: 1) later life emergent and persistent neuropsychiatric symptoms; 2) representing a change from longstanding personality or patterns of behaviour; 3) not better accounted for by psychiatric conditions or life stressors. MBI as an at‐risk state for cognitive decline and dementia and may be the earliest manifestations of disease for some. We investigated whether MBI, measured with the MBI checklist, was associated with cognitive changes in older adults in the Brain Health Registry (BHR).

Methods

We analyzed data from 5225 participants in BHR. Participants were included if they completed Lumosity cognitive tests (memory span, reverse memory span, trailmaking, go‐no‐go) and an informant‐rated MBI‐C. We excluded participants with major neurological, psychiatric or developmental disorders. Using cutpoints to dichotomize MBI+ and MBI‐ participants (MBI‐C > 5, 6, 7), univariate ANOVA was used to determine whether people with MBI also showed impairment in cognitive test performance. ANOVAs covaried for age, sex, education, and time between test administration and MBI‐C completion. All assessments were completed remotely, using the BHR online registry.

Results

The final sample included 802 participants with a mean age of 66.97(SD 10.71), of which 515/802 were females (64.21%). The number and percent of MBI‐C+ participants was 62 (7.7%), 53 (6.6%), and 48 (6.0%) at cutpoints of MBI‐C >5, >6, and >7 respectively. MBI+ participants had significantly poorer memory span, poorer reverse memory span, longer trail‐making completion time, and more trail‐making errors (see Table 1 for statistical reporting). A significantly greater number of men were classified as MBI+ at all 3 cutpoints (p< 0.001).

Conclusions

In a large cohort of older adults in BHR, MBI assessed remotely and unsupervised using an online interface, was associated with poorer cognition in the domains of memory and executive function compared to those without MBI. Utilizing the MBI‐C in case finding may be a simple, efficient, and scalable way to detect individuals with subtle cognitive changes, for further assessment and workup, or potential inclusion in clinical trials.
Ameisensäure‐unterstützte selektive Hydrogenolyse von 5‐Hydroxymethylfurfural zu 2,5‐Dimethylfuran über bifunktionale Pd‐Nanopartikel auf N‐dotiertem mesoporösem Kohlenstoff als Träger
Authors: Hu Bin , Warczinski Lisa , Li Xiaoyu , Lu Mohong , Bitzer Johannes , Heidelmann Markus , Eckhard Till , Fu Qi , Schulwitz Jonas , Merko Mariia , Li Mingshi , Kleist Wolfgang , Hättig Christof , Muhler Martin , Peng Baoxiang
Published: December 2020

Aus Biomasse gewonnenes 5‐Hydroxymethylfurfural (HMF) gilt als vielversprechende Plattformchemikalien zur Herstellung von 2,5‐Dimethylfuran (DMF) als flüssigen Transportkraftstoff. Pd‐Nanopartikel auf N‐haltigen und N‐freien mesoporösen Kohlenstoffmaterialien wurden hergestellt, charakterisiert und bei der Hydrogenolyse von HMF zu DMF unter milden Reaktionsbedingungen eingesetzt. Die quantitative Umwandlung von HMF zu DMF wurde in Gegenwart von Ameisensäure (FA) und H2 über Pd/NMC innerhalb von 2 h erreicht. Der Reaktionsmechanismus wurde durch Variation der Wasserstoffquelle, des Additivs und des Substrats sowie durch In‐situ‐ATR‐IR‐Spektroskopie erforscht. Die Hauptrolle von FA besteht darin, den dominanten Reaktionsweg von der Hydrierung der Aldehydgruppe zur Hydrogenolyse der Hydroxymethylgruppe über die Protonierung durch FA an der C‐OH‐Gruppe zu verlagern, wodurch die Aktivierungsbarriere der C‐O‐Bindungsspaltung gesenkt und somit die Reaktionsgeschwindigkeit deutlich erhöht wird. XPS‐Ergebnisse und DFT‐Berechnungen zeigten, dass Pd2+‐Spezies, die mit pyridinartigen N‐Atomen interagieren, die selektive Hydrogenolyse der C‐OH‐Bindung in Anwesenheit von FA aufgrund ihrer hohen Fähigkeit zur Aktivierung von FA und zur Stabilisierung von H− deutlich verbessern.
The Discrete Breast Cancer Stem Cell Mammosphere Activity of Group 10‐Bis(azadiphosphine) Metal Complexes
Authors: Xiao Zhiyin , Johnson Alice , Singh Kuldip , Suntharalingam Kogularamanan
Published: December 2020

We report the anti‐breast cancer stem cell (CSC) properties of a series of Group 10‐bis(azadiphosphine) complexes 1–3 under exclusively three‐dimensional cell culture conditions. The breast CSC mammosphere potency of 1–3 is dependent on the Group 10 metal present, increasing in the following order: 1 (nickel complex) <2 (palladium complex) <3 (platinum complex). Notably, 3 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC‐active compound, or any reported anti‐CSC metal complex tested under similar conditions. Mechanistic studies suggest that the most effective complexes 2 and 3 readily penetrate CSC mammospheres, enter CSC nuclei, induce genomic DNA damage, and trigger caspase‐dependent apoptosis. To the best of our knowledge, this is the first study to systematically probe the anti‐CSC activity of a series of structurally related Group 10 complexes and to be conducted entirely using three‐dimensional CSC culture conditions.
Diastereodivergent Synthesis of β‐Amino Alcohols by Dual‐Metal‐Catalyzed Coupling of Alkoxyallenes with Aldimine Esters
Authors: Zhu Minghui , Zhang Qinglong , Zi Weiwei
Published: December 2020

Both syn‐ and anti‐β‐amino alcohols are common structural motifs in natural products, drug molecules, chiral ligands and catalysts. However, the currently available methods for synthesizing these motifs are limited to generate only one diastereoisomer. Therefore, development of a unified method for stereoselective access to complementary diastereomers would be highly desirable. Herein, we report a method for dual‐metal‐catalyzed diastereodivergent coupling of alkoxyallenes with aldimine esters. By carefully selecting the two metals and appropriate chiral ligands, we could synthesize both syn‐ and anti‐β‐amino alcohol motifs with high enantioselectivity and diastereoselectivity from the same set of starting materials. Furthermore, stereodivergent syntheses of all four stereoisomers of β‐amino alcohols could be achieved. We demonstrated the synthetic utility of this method by concisely synthesizing two β‐amino alcohol natural products, mycestericins F and G.
Palladium‐Catalysed C−H Bond Zincation of Arenes: Scope, Mechanism, and the Role of Heterometallic Intermediates
Authors: Garçon Martí , Mun Nicolette Wee , White Andrew J. P. , Crimmin Mark R.
Published: December 2020

Catalytic methods that transform C−H bonds into C−X bonds are of paramount importance in synthesis. A particular focus has been the generation of organoboranes, organosilanes and organostannanes from simple hydrocarbons (X=B, Si, Sn). Despite the importance of organozinc compounds (X=Zn), their synthesis by the catalytic functionalisation of C−H bonds remains unknown. Herein, we show that a palladium catalyst and zinc hydride reagent can be used to transform C−H bonds into C−Zn bonds. The new catalytic C−H zincation protocol has been applied to a variety of arenes—including fluoroarenes, heteroarenes, and benzene—with high chemo‐ and regioselectivity. A mechanistic study shows that heterometallic Pd–Zn complexes play a key role in catalysis. The conclusions of this work are twofold; the first is that valuable organozinc compounds are finally accessible by catalytic C−H functionalisation, the second is that heterometallic complexes are intimately involved in bond‐making and bond‐breaking steps of C−H functionalisation.
Ti–Mn coating prepared by tungsten inert gas cladding and its inhibiting coking property
Authors: Li Jingpeng , Yu Xiaochun , Wang Runqiu , Wang Zhiyuan , Wang Laizhi , Zhou Jianxin
Published: December 2020

The Ti–Mn cladding layers with different ratios were prepared on the surface of 310S steel using tungsten inert gas (TIG) technology for inhibiting coking in ethylene cracking, and the cladding specimens were oxidized by muffle furnace for 10 h at 800°C. The coking evaluation tests of the oxidized specimens with different Ti–Mn powder ratios were carried out with light naphtha at 850°C. The results show that when the ratio of Ti to Mn was 3:1, a protective layer of TiO2–TinO2n‐1–Mn5O8 was formed on the surface of specimen, and with the decrease of Ti element content, unstable Fe‐Ti spinel compounds appeared on the surface. When the ratio of Ti to Mn is 1:3, 1:2, and 1:1, the coking inhibition rate was 40%, 46%, and 59%, respectively. Catalytic coke formed on the surface of coating. When the ratio of Ti to Mn was 3:1, the inhibiting coking rate on the surface of the coating reached 80%, and the inhibiting coking performance was optimal, which inhibited the catalytic coking of Fe and Ni metal particles. With the increase of Ti content and the decrease of Mn content, the graphitization degree of coke decreased according to Raman spectrum.
Practical two‐step chain extension method to prepare sulfonated waterborne polyurethanes based on aliphatic diamine sulphonate
Authors: Mou Jing , Wang Xiaojun , Yu Dongmei , Wang Shengpeng , Miao Yulong , Liu Qin , Chen Bajin
Published: December 2020

We reported a novel synthesis route to fabricate sulfonated aliphatic waterborne polyurethane dispersions (SWPU) only based on 2‐[(2‐aminoethyl) amino] ethane sulphonate sodium (AAS‐Na) by two‐step chain extension method with the assistance of acetone and water cosolvent. When AAS‐Na was added, only less than 50% of AAS‐Na was incorporated into polyurethane chain in the first‐step chain extension and the residual AAS‐Na formed molecular aggregates which were insoluble in acetone due to the high polarity of AAS‐Na. Subsequently, the mixture of acetone and water was added, the residual AAS‐Na aggregates dissolved, undertaking the further second‐step chain extension reaction, and the ultimate reaction conversion of AAS‐Na rose to more than 90%. The mechanism for acetone and water cosolvent to affect the preparation of SWPU dispersions was studied, as well as the water resistance, mechanical properties and hydrolysis resistance of as‐prepared SWPU dispersions. With the decrease of AAS‐Na content from 2.0% to 1.2%, the peak area of the melting peaks for SWPU films increased, as well as the water resistance. And the as‐prepared polyester SWPU exhibited good hydrolytic stability.