bluuebunny/crossref_metadata_2025 huggingface dataset:
Low doses of lithium and gene ontology analysis: Different action of dose response in neurons
Authors: De‐Paula Vanessa V.J. , Forlenza Orestes Vicente , Brentani Helena Paula
Published: December 2020

Background

The pharmacological mechanisms of lithium are not completely understood, but current evidence suggests the direct involvement of classic pharmacological targets affecting neurotransmission and signal transduction. These include the modulation of cell‐surface receptors, the release of second‐messengers and downstream signaling molecules, and the subsequent effect on the activity of important regulatory systems, with an impact on the release of transcription factors and gene expression. The aim of this work was to analyze the gene ontology of sub therapeutic and therapeutic doses of lithium in the hippocampus and correlate with lithium response and response to the GSK3B pathway.

Method

We made a gene block network, called “GSKome” and a “LITHIome”, based on protein‐protein interaction data, to identify genes with direct interaction. For this we used the program STRING (v 10.5) and PathCards (v 4.6). All selected proteins for Rattus norvegicus (microarray from primary culture of hippocampal neurons treated with different lithium doses: 0.02mM, 0.2mM and 2mM) had their nomenclature modified in r v3.6.1 (Bioconductor). In the Gene Ontology (GO) analysis we listed the top 5 FDR (false dicover ratio) of GSKome and LITHIome. ClueGO package (Cytoscape) were used for comparative analysis of the gene ontology (GO) between lithium doses with GSKOma and LITIOma.

Result

GSKoma and LITIOma lists were compared with 0.02mM, 0.2mM and 2mM neurons samples. The 0.2mM lithium doses compared with LITIOma presents Biological processes presented the highest number of pathways, 27 in total. The Cell Component presented only the caveoline pathway and in the Molecular Functions four altered pathways. The GO analysis of 0.02mM lithium treated samples compared to GSKOma showed no statistical difference in Biological Processes, Cellular Component and Molecular Functions. The 0.2mM dose of lithium‐treated neurons compared with GSKOma were statistically significant in two of the three GO categories. Biological processes presented three pathways: caveolin (40%), axons (40%) and transcription factor (20%) and Molecular Functions, also with three altered pathways: protein kinase (53.64%) DNA transcription (27.27%) and DNA regulation (19.09%).

Conclusion

The lithioma block was related to the ontological pathways of protection in therapeutic and subtherapeutic doses of lithium.
Biomarker profiles for staging of pre‐dementia patients
Authors: Kuehnel Line , Bouteloup Vincent , Lespinasse Jérémie , Chêne Geneviève , Dufouil Carole , Raket Lars Lau
Published: December 2020

Background

Patient cohorts in clinical trials for Alzheimer’s disease are often highly inhomogeneous affecting statistical power to detect treatment effects. Objective methods that enable better staging of patients can be used to design inclusion criteria that result in less variability in progression and hereby increase statistical power. Furthermore, better prediction of disease stage is a key issue to determine when an intervention may have highest chance of success.

Method

Continuous time‐progression of cognitive decline was estimated via a nonlinear mixed‐effects disease‐progression model. The model simultaneously estimated evolution of MMSE scores over the course of the disease and predicted patient disease stage. To investigate if combinations of baseline CSF and imaging biomarkers were predictive of disease stage, AIC‐based forward selection was used to include biomarker effects on disease stage in the disease‐progression model. In addition to biomarkers, effects of education, sex and age were also investigated. The included biomarkers were MRI cortical thickness signature, FDG PET, and core CSF biomarkers (total tau, phosphorylated tau, aβ42, aβ40, and aβ42/aβ40 ratio). To investigate the utility of biomarker profile on the model’s ability to predict disease stage, its performance in predicting future progression on MMSE was compared to a model that did not include biomarkers. The model was fitted to individuals with subjective or mild cognitive impairment (SCI/MCI) from the French MEMENTO study. The results of the model were validated in individuals with either significant memory complaints or MCI in ADNI.

Result

There were 312 individuals with SCI/MCI and complete biomarkers available at baseline. The optimal model included effects of total tau, MRI cortical thickness, and aβ42 on patients’ disease stage measured via MMSE scores. A model with the same terms was fitted to data from 609 individuals from ADNI to validate the findings. Inclusion of selected biomarkers was shown to improve staging of patients and to have similar directional contributions as in MEMENTO.

Conclusion

We demonstrated that biomarker profiles are predictive of disease stage in pre‐dementia. We found that a combination of MRI cortical thickness, CSF total tau and CSF aβ42 was predictive of disease stage in the French MEMENTO cohort and validated this finding in ADNI.
The reliability of a deep learning model in external memory clinic MRI data: A multi‐cohort study
Authors: Mårtensson Gustav , Ferreira Daniel , Granberg Tobias , Cavallin Lena , Oppedal Ketil , Padovani Alessandro , Rektorova Irena , Bonanni Laura , Pardini Matteo , Kramberger Milica G. , Taylor John‐Paul , Hort Jakub , Snædal Jón , Kulisevsky Jaime , Blanc Frédéric , Antonini Angelo , Mecocci Patrizia , Vellas Bruno , Tsolaki Magda , Kloszewska Iwona , Soininen Hilkka , Lovestone Simon , Simmons Andrew , Aarsland Dag , Westman Eric
Published: December 2020

Background

Deep learning (DL) has provided impressive results in numerous domains in recent years, including medical image analysis. Training DL models requires large data sets to yield good performance. Since medical data can be difficult to acquire, most studies rely on public research cohorts, which often have harmonized scanning protocols and strict exclusion criteria. This is not representative of a clinical setting. In this study, we investigated the performance of a DL model in out‐of‐distribution data from multiple memory clinics and research cohorts.

Method

We trained multiple versions of AVRA: a DL model trained to predict visual ratings of Scheltens' medial temporal atrophy (MTA) scale (Mårtensson et al., 2019). This was done on different combinations of training data—starting with only harmonized MRI data from public research cohorts, and further increasing image heterogeneity in the training set by including external memory clinic data. We assessed the performance in multiple test sets by comparing AVRA’s MTA ratings to an experienced radiologist’s (who rated all images in this study). Data came from Alzheimer’s Disease Neuroimaging Initiative (ADNI), AddNeuroMed, and images from 13 European memory clinics in the E‐DLB consortium.

Results

Models trained only on research cohorts generalized well to new data acquired with similar protocols as the training data (weighted kappa κw between 0.70‐0.72), but worse to memory clinic data with more image variability (κw between 0.34‐0.66). This was most prominent in one specific memory clinic, where the DL model systematically predicted too low MTA scores. When including data from a wider range of scanners and protocols during training, the agreement to the radiologist’s ratings in external memory clinics increased (κw between 0.51‐0.71).

Conclusion

In this study we showed that increasing heterogeneity in training data improves generalization to out‐of‐distribution data. Our findings suggest that studies assessing reliability of a DL model should be done in multiple cohorts, and that softwares based on DL need to be rigorously evaluated prior to being certified for deployment to clinics. References: Mårtensson, G. et al. (2019) ‘AVRA: Automatic Visual Ratings of Atrophy from MRI images using Recurrent Convolutional Neural Networks’, NeuroImage: Clinical. Elsevier, 23(March), p. 101872.
Neuroprotection of cholinergic neurons with tau aggregation inhibitor and rivastigmine in L1 mice with Alzheimer’s‐like tauopathy
Authors: Steczkowska Marta , Zadrozny Maciej , Wydrych Malgorzata , Gasiorowska Anna , Niewiadomski Wiktor , Riedel Gernot , Wischik Claude M. , Niewiadomska Grazyna
Published: December 2020

Background

Basal forebrain cholinergic dysfunction, likely linked to tau aggregation pathology, is a characteristic feature of AD. Cholinergic neurons contain choline acetyltransferase (ChAT) and high‐affinity tropomyosin‐related kinase A (TrkA) and send efferents to cortex and hippocampus where they release acetylcholine (ACh). The vesicular acetylcholine transporter (VAChT) is responsible for loading ACh into secretory vesicles and acetylcholine esterase (AChE) hydrolyses ACh in the synaptic cleft. We here aimed to evaluate the cholinergic phenotype in the Line 1 animal model of tauopathy and to determine the effect of the choline esterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor hydromethylthionine on the cholinergic system.

Method

Line 1 (L1) and control NMRI mice, 8‐9 months old, divided into 13 groups (n = 5 each), were treated with rivastigmine (0.1 and 0.5 mg/kg) and hydromethylthionine (5 and 15 mg/kg) and their combinations for 11 weeks. Immunohistochemical staining in brain sections was performed for ChAT, TrkA, VAChT and tau with a repeat domain monoclonal antibody (TauRx Therapeutics Ltd.). AChE activity was measured histochemically. The state of the cholinergic system was determined by stereological counting of ChAT‐ir and TrkA‐ir neurons, while Relative Optical Intensity (ROI) was used to tau immunoreactivity in basal forebrain, and cholinergic projections were evaluated using VAChT and AChE ROI.

Result

Number of ChAT‐ir, TrkA‐ir neurons and ROI value for VAChT and AChE were significantly lower while ROI value for tau was higher in vehicle‐treated L1 mice compared with wild type control. Numbers of ChAT‐ir, TrkA‐ir neurons and ROI value of VAChT and AChE in L1 mice were increased and tau ROI was decreased by hydromethylthionine treatment. Combined treatment decreased numbers of ChAT‐ir, TrkA‐ir neurons and ROI for VAChT and AChE compared to L1 groups treated with hydromethylthionine alone.

Conclusion

There was a significant loss of cholinergic basal forebrain neurones, impaired cholinergic projection and increased tau staining in L1 mice. Monotherapy with hydromethylthionine improved the cholinergic neurons phenotype, enhanced their projection and reduced tau pathology. Combination therapy interacted negatively attenuating the effect of hydromethylthionine given alone.
Influence of microglial activation on structural and functional connectivity in mild cognitive impairment subjects
Authors: Leng Fangda , Hinz Rainer , Dani Melanie , Hampshire Adam , Gentleman Steve , Brooks David J. , Edison Paul
Published: December 2020

Background

Activated microglia is present in both Alzheimer’s subjects (AD) and mild cognitive impairment (MCI) subjects and can be visualised by both pathological evaluation and in‐vivo imaging studies. It has been established that neuroinflammation plays a vital role in Alzheimer’s trajectory and disruption in structural and functional connectivity is also a key event in Alzheimer’s disease. However, the mechanism by which microglial activation influence brain structural and functional connectivity remains to be elucidated. 11C‐PBR28 PET is a marker of translocator protein (TSPO) reflecting microglial activation and 18F‐Flutematemol PET is a marker of amyloid deposition.

Method

25 amnestic MCI and 17 healthy controls (HC) were recruited and underwent T1‐weighted, diffusion tensor and resting‐state functional MRI, 11C‐PBR28 and 18F‐Flutemetamol PET scans. 11C‐PBR28 and 18F‐Flutemetamol scans were analysed using target‐to‐cerebellar ratio. Tract‐Based Spatial Statistics was performed on DTI scans. RS‐fMRI scans were analysed using medial prefrontal cortex (MPFC) as a seed. The relationship between tracer uptake and structural integrity of white matter tracts or brain functional connectivity with MPFC was analysed using linear regression corrected for age and gender.

Result

MCI cohort showed significantly decreased functional connectivity between MPFC and posterior cingulate and precuneous regions. Cortical 11C‐PBR28 uptake but not 18F‐Flutemetamol was negatively correlated with FA in the corpus callosum, bilateral inferior frontal‐occipital fasciculi and inferior longitudinal fasciculi. MPFC 11C‐PBR28 uptake was correlated with increased MPFC functional connectivity to anterior frontal regions and reduced connectivity to posterior frontal, temporal, parietal and cingulate regions; while frontal amyloid load was correlated with reduced MPFC connectivity with frontal and temporal cortices. Regression analysis with both 18F‐Flutemetamol and 11C‐PBR28 demonstrated that MPFC 11C‐PBR28 was significantly associated MPFC connectivity with posterior frontal, parietal and cingulate regions.

Conclusion

The findings suggest that MPFC microglial activation is associated with increased functional connectivity with the nearby regions and decreased connectivity with the distal regions to MPFC in MCI subjects. Findings from DTI analysis showed negative correlation with structural integrity of the long fibre tracts which are connecting distal regions. These findings suggest that neuroinflammation is involved in the structural and functional connectivity disruption and probably remodelling in AD trajectory.
Specific targeting of a highly toxic subpopulation of Aβ42 oligomers for the treatment of Alzheimer’s disease
Authors: Sandberg Anders , Rodriguez Rosa Crespo , Kettunen Petronella , Rosengren Malin , Correa Ernesto Berenjeno , Morrema Tjado , Hoozemans Jeroen J.M. , Scheper Wiep
Published: December 2020

Background

Non‐clinical data on the etiology of Alzheimer’s disease (AD) suggest that only a very small fraction of soluble oligomeric Aβ42 carries most of the neurotoxic potency. But the study of Aβ42 soluble species has been hampered by their intrinsic heterogeneous and dynamic nature. A unique oligomer‐stabilizing technology, AβCC, enables the development of therapies that target these specifically. We here demonstrate the development such immunotherapies that exhibit unique Aβ oligomer targeting activity which translates into high efficacy in non‐clinical models of the disease.

Method

Stable synthetic Aβ42CC peptide oligomer derivatives were used as antigens in an active vaccine and were used to develop a murine monoclonal antibody, ALZ‐201. Efficacy was evaluated on brain extracts from AD patients and controls. These brain extracts were immunodepleted with ALZ‐201 and control antibodies. Toxicity assays were then performed in primary mouse neuronal cultures using an automated cell imaging platform. In addition, acute neurotoxicity effects on memory formation in zebrafish were assessed following intracranial injections of the brain extracts.

Result

The AβCC oligomers were able to generate truly oligomer‐specific antibodies. AD extracts exhibited higher levels of toxicity in contrast to non‐AD extracts in both cells assays and in zebrafish. This toxicity was highly dependent on Aβ, shown by immunodepletion with 4G8. Comparable toxicity was observed for brain extracts immunodepleted with ALZ‐201 as for extracts immunodepleted with 4G8. Interestingly, the soluble Aβ42 species captured by ALZ‐201 were below the limit of detection with the standard biochemical techniques used for analysis.

Conclusion

The data support the hypothesis that a specific subtype of Aβ42 oligomers has large neurotoxic effects in the central nervous system that can affect synaptic plasticity, learning and memory. These oligomers are present in very small amounts and, due to the inaccessible environment, are not likely to be targeted with non‐specific anti‐Aβ immunotherapies. In contrast, targeting them specifically may serve as effective future treatments.
Joint trajectories of episodic memory and odor identification in older adults: Patterns and determinants
Authors: Dintica Christina S. , Haaksma Miriam L. , Olofsson Jonas , Bennett David A. , Xu Weili
Published: December 2020

Background

Emerging evidence suggests that olfactory function is closely linked to memory function. The aims of this study were to assess whether olfactory and episodic memory functions follow similar age‐related decline trajectories, to identify different patterns of decline, as well as determinants of the patterns.

Methods

Using data from the Rush Memory and Aging Project, 1023 dementia‐free participants were identified at baseline and followed for up to 8 years with annual assessments for episodic memory (composite of 7 tests) and odor identification (Brief Smell Identification Test). Data on demographics, medical conditions, social and lifestyle factors were collected by self‐report or medical examination. Trajectories of episodic memory and olfactory function were first modeled individually and then jointly over time using growth mixture models, to identify latent classes (patterns) of the joint trajectories. Multivariate logistic regression was used to identify predictors of the patterns.

Results

Both episodic memory and olfactory function showed similar trends over the follow‐up interval. Three distinct patterns of joint trajectories, across both functions, were identified; Class 1‐ stable average performance in both functions (n=690, 67.4%); Class 2‐ stable average episodic memory and declining odor identification (n=231, 22.6%); and Class 3‐ decline in both functions (n= 102, 10.0%). Compared to Class 1, people in Class 2 were more likely to be older and male. People in Class 3 were more likely to be older, apolipoprotein ε4 carriers, participate less in cognitive activity, and have lower BMI.

Conclusions

Episodic memory and olfactory function often show similar trajectories in aging, which can be jointly characterized as stable, olfactory decline only, and joint decline.
Is it time to use predictive models to boost power of Alzheimer’s disease clinical trials? A post‐hoc analysis of phase 3 solanezumab trials
Authors: Ezzati Ali , Davatzikos Christos , Wolk David A. , Aisen Paul S. , Lipton Richard B.
Published: December 2020

Background

The ideal participants for Alzheimer’s disease (AD) clinical trials would show cognitive decline in the absence of treatment (i.e. placebo arm) and would also respond to the therapeutic intervention. However, up to 50% of placebo treated participants enrolled in the AD clinical trials do not show cognitive or functional decline during the timeframe of trials. One strategy to boost the power of trials is to exclude individuals who are not likely to progress using data‐driven predictive models. In this study, we aimed to investigate if using machine learning (ML) predictive models can be an effective tool for enriching enrollment in AD trials.

Method

We used data from 769 patients from the placebo arm of two phase 3, double‐blind trials of EXPEDITION (N=367) and EXPEDITION2 (N=402). Patients had 18 months of follow‐up. Ensemble linear discriminant ML models were developed using EXPEDITION data to classify participants as 1) cognitive decliners, change of >0 from baseline in the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS‐cog) score, versus stable cognition, change of £0 from baseline ADAS‐cog score; or 2) functional decliners, change of <0 from baseline in the Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) versus stable function, change of ≥0 from baseline ADCS‐ADL, at both 15 and 18 months of follow‐up. Data from EXPEDITION2 were used to validate models. Features used in ML models included baseline demographics, Apo4 genotype, neuropsychological scores, functional scores and volumetric MRI.

Result

In EXPEDITION and EXPEDITION2 trials, 45.2% and 42.0% of participants in the placebo arm did not show cognitive decline, respectively (Table 1). Models had high sensitivity and modest specificity in both the training (EXPEDITION) and (EXPEDITION2) samples for detecting the stable group. Positive predictive value of models was higher than the base prevalence of cognitive or functional decline, and negative predictive value of models were higher than the base rate of participants who had stable cognition or function (Tables 2 and 3).

Conclusion

Predictive models may boost the power of AD trials through selective inclusion of participants expected to decline and exclusion of those expected to remain stable.
Understanding meaningful symptoms and challenges in people with Down syndrome and dementia: A qualitative study of caregivers’ perspectives
Authors: Knox Kari , Stanley Justin , Hendrix James A , Hillerstrom Hampus , Achenbach Jillian , Chicoine Brian , Lai Florence , Lott Ira T , Rockwood Kenneth
Published: December 2020

Background

People with Down syndrome are at an increased risk of developing Alzheimer’s Disease. As many more individuals with Down syndrome are now living into older adulthood, the prevalence of Alzheimer’s disease has risen significantly in this group. Identifying dementia symptoms in this setting can be daunting due to heterogeneous baseline function, cognition, and behaviour. Here, we interviewed caregivers to elicit their impressions of the most meaningful symptoms and challenges for people with Down Syndrome and dementia.

Method

Initially, a dementia symptom menu was adapted for Down syndrome by four expert clinicians. We then recruited 10 caregivers of people with Down syndrome and dementia. Semi‐structured interviews began with open‐ended discussion of symptoms and challenges, followed by an in‐depth menu review. Interviews were facilitated by a research nurse, audio recorded and transcribed verbatim. Transcripts were reviewed by two researchers who coded quotes independently. Codes were discussed to identify emergent themes.

Result

Caregivers ranged from 54‐77 years of age (median 65). Most were female (9/10) with ≥15 years of education (10/10). The person they cared for was 52‐61 years (median 58) with Down syndrome and a formal diagnosis (6/10) or clinical suspicion (4/10) of dementia. Chiefly, two themes were identified: caregiver burden and healthcare difficulties. Caregiver burden was expressed in many ways such as increased responsibilities, financial impact and emotional toll. Caregivers also described challenges with medical professionals who were not well‐equipped for these patients (“One [physician] was very honest with me and said ‘I have to tell you; I have no clinical experience with this’”). This was particularly noted by caregivers in rural areas. When asked to list their five most meaningful symptoms, caregivers reported behavioural changes (13/50, e.g. irritability/frustration) followed by cognitive decline (12/50, e.g. verbal repetition) and physical manifestations (11/50, e.g. incontinence).

Conclusion

In eliciting views about the most meaningful symptoms and challenges, semi‐structured interviews identified two main themes: caregiver burden and healthcare difficulties. Although in people without Down syndrome cognitive decline is the hallmark of dementia, here caregivers interviewed frequently reported changes in behaviour and physical manifestations as most meaningful.
Dynactin 6 deficiency enhances tubular ER‐associated dystrophic neurites formation
Authors: Sharoar Md. Golam , Yan Riqiang
Published: December 2020

Background

The formation of dystrophic neurites (DNs) is a contributing factor to synaptic dysfunction in Alzheimer’s disease (AD) patients’ brains. We have shown that tubular endoplasmic reticulum (ER) shaping proteins reticulon 3 (RTN3), REEP2 and REEP5 are participated in the formation DNs, named as RTN3 immunoreactive DNs or RIDNs. RIDNs are appeared as clustered or dispersed forms in AD and aging mouse brain, respectively. Ultrastructural investigation showed that RIDNs are constitute with abnormal clustering of tubular ER. The over expression of RTN3 accelerates aging associated disperse RIDNs formation in Tg‐RTN3 mouse brain hippocampus. To determine a molecule that may cause RTN3 mediated abnormal tubular ER clustering, we aimed to identify RTN3 interacting proteins and to elucidate its functional roles in tabular ER accumulation and RIDNs formation in aging and AD brain.

Methods

Yeast two‐hybrid system, co‐immunoprecipitation, domain mapping and immune‐confocal studies to identify RTN3 interacting proteins. WB was performed to measure the protein level. Formation of RIDNs in mouse brains were detected using immuno‐confocal study. AAV9‐RTN3‐mCherry and AAV9‐DCTN‐GFP were injected at hippocampus of wild type mice to over expressed RTN3 and DCTN6.

Results

We have identified that N‐terminal domain of RTN3 interacts with dynactin 6 (DCTN6), a protein component that involved in dynein‐mediated retrograde transport of cargo vesicles. Our immune‐confocal studies on DCTN6 and RTN3 over expressed cells and primary cultured neuron indicate that RTN3‐DCTN6 interaction likely mediates the tubular ER trafficking. The DCTN6 protein level decreases during aging and it reduces in hippocampus compared to cortical samples of the same age mice. To understand the functional roles of DCTN6 in RIDNs formation during aging and beta‐amyloid plaque deposition, DCTN6 deficient Tg‐RTN3 and 5xFAD mice were generated. Tg‐RTN3; DCTN6+/‐ showed reduced DCTN6 protein level and enhanced hippocampus specific RINDs formation compare to Tg‐RTN3; DCTN6+/+ mouse. We are investigating whether RIDNs formation are increases in DCTN6 deficient 5xFAD mice and whether AAV9‐DCTN6 overexpression reduces RIDNs formation in AAV9‐RTN3 overexpressed mouse brain.

Conclusion

RTN3‐DCTN6 interaction likely mediates the tubular ER transport in axons and the DCTN6 deficiency is a contributing factor for tubular ER accumulation, RIDNs formation in AD and aging brain.
3D‐chemocentric target deconvolution of unprecedented anti‐inflammatory drug scaffolds
Authors: Kim Mi‐hyun , Dhorma Lama Prema , Teli Mahesh Kumar , Venkanna Arramshetti
Published: December 2020

Background

A typical hit‐to‐lead flow focuses on a well‐established molecular target. However, imperfect pathological backgrounds of the diseases can bring out low confidence on the chosen target. Therefore, despite unclear targets, the regulation of neuroinflammation is an important approach of early stage drug discovery in AD and neurological disorders. The potential targets of anti‐inflammatory agents are enormous but don't be clear investigated with their atomic level mechanism.

Method

ChOS (Chemistry‐oriented synthesis), a kind of inverse drug design, suggests target deconvolution of unprecedented anti‐inflammatory agents (in‐house compounds) through 3D‐chemocentric approach.

Result

The inverse approach identified an in‐house anti‐inflammatory agent, as the first‐in‐class small molecule antagonist for non‐histaminergic neurons, investigated a new therapeutic indication of a known target, and provided pharmacological profile of in‐house anti‐inflammatory agents.

Conclusion

The inverse drug discovery approach of in‐house anti‐inflammatory agents, ChOS, can be a compensatory alternative for neurological disorders and the results wait for AD & dementia collaboration.
Transcriptomic correlates of neurite degeneration due to human brain‐derived Aβ and protection by clinical anti‐Aβ antibodies
Authors: Stern Andrew , Liu Wen , Jin Ming , Walsh Dominic M. , Selkoe Dennis J.
Published: December 2020

Background

The proximate cause of dementia in Alzheimer disease (AD) is the dystrophy and loss of synapses and neurites, and the eventual death of neurons. Upstream events include hyperphosphorylation and aggregation of tau, and further upstream is the formation of soluble oligomers of Aβ. The molecular details which link these three and other events within the “amyloid cascade” remain murky, but elucidating them will likely reveal new therapeutic targets.

Method

To dissect early steps in the Aβ oligomer‐driven neuritotoxicity, we recently developed an in vitro system in which human brain‐derived soluble Aβ is applied to iPSC‐derived human neurons (iNs) to induce neurite degeneration (Jin et al, Nat Commun. 2018; 9(1):2676). Soluble extracts from AD brain were either immunodepleted of Aβ with a polyclonal antiserum or mock‐immunodepleted with rabbit IgG, then applied at 21 DIV to iPSC‐derived neurons that had been induced by Neurogenin‐2 expression. Neurite integrity was tracked using the NeuroTrack module of the IncuCyte ZOOM system for live‐cell analysis. Various humanized anti‐Aβ antibodies were added at concentrations from 0.5 to 3 ug/mL along with the control antibody bevacizumab (Avastin).

Result

Immunodepletion with the polyclonal antibody resulted in efficient removal of Aβ. Mock‐immunodepleted, but not immunodepleted, human soluble brain extracts caused quantifiable neuritotoxicity using this unbiased, automated imaging system. These effects were rescued to different degrees by different anti‐Aβ antibodies but not by Avastin.

Conclusion

Human AD brain‐derived soluble extracts cause neuritotoxicity to human neurons in an Aβ oligomer‐dependent manner. This effect can be decreased by anti‐Aβ antibodies currently in clinical trials, including aducanumab and BAN2401. We are now performing unbiased transcriptomic and proteomic profiling of the iNs after treatment with human‐derived soluble Aβ oligomers to determine the immediate molecular events that precede and accompany Aβ‐dependent neuritotoxicity. These results will be compared with recently‐published single‐cell transcriptomic data from AD brain to identify potential therapeutic targets.
Navigation ability before and after menopause
Authors: Chapin Benjamin Albert , Khondoker Mizanur , Coughlan Gillian , Spiers Hugo , Hornberger Michael
Published: December 2020

Background

Cognitive decline is a common complaint in menopause. Alzheimer disease(AD) has higher incidence in women and early menopause increases risk for AD. Studies of cognitive change at menopause have had mixed results. Navigational ability declines early in the course of AD. No studies have looked at changes in navigational ability around menopause. Objective: Determine the effect of menopause on navigation.

Method

Participants were 200,999 persons aged 35‐65 who downloaded the Sea Hero Quest app and completed enough levels to analyze navigation. Measures of navigation examined included distance traveled and time spent to complete levels as well as accuracy in determining one’s starting point after completing a maze. These scores were normalized based on early, simple levels in order to control for video game ability. Each measure was analyzed by splitting male and female participants into ages 35‐45 and ages 55‐65 in order to look at persons before and after menopause. Groups were analyzed using a 2‐way ANOVA with gender and age as independent variables. Additionally, piecewise linear modeling was applied to the entire population aged 35 to 65 to test whether there was a significant change in the slope of decline in navigational ability at age 51, the average age of menopause.

Result

Female gender and advancing age were both predictive of worse performance on all measures. ANOVA found significant(p<0.001) but small effect sizes for an age by gender interaction with partial eta2 for distance = 0.002, duration < 0.001 and flare accuracy <0.001. Piecewise linear modeling found small but significant (p<0.001) changes in slope of worsening scores in distance, duration and flare accuracy at age 51. The increased rate of worsening performance was actually greater in men than women.

Conclusion

While men had better navigational performance than women at all ages, there is not a substantial change in this gap following menopause. Additionally, the relative rate of decline in female performance actually decreased relative to males at the typical age of menopause. This study suggests that natural menopause is unlikely to have a significant negative effect on navigational ability.
Throughput optimized immuno‐infrared‐assay for Alzheimer’s disease diagnosis
Authors: Budde Brian , Mann Marvin , Woitzik Nathalie , Güldenhaupt Jörn , Kötting Carsten , Gerwert Klaus Bernhard
Published: December 2020

Background

It is believed, that one of the first events in the progression of Alzheimer’s Disease is the misfolding of the Amyloid Beta (Aβ) Peptide. This event takes place up to 20 years before the clinical onset of the disease. Therefore, biosensors detecting the misfolding of Aβ are especially useful for the early and specific detection of Alzheimer’s Disease. In recent studies, our biosensor based on ATR‐FTIR spectroscopy performed with an overall accuracy of 86% [1,2,3]. This system is robust and reliable but the user input required is very high because each sensor can only be used once. To overcome these issues and increase the automation capacity, a regenerative system is urgently needed.

Method

To achieve higher throughput of this system, we introduced immunoglobulin binding proteins (Protein A and Protein G) as capture for antibody immobilization. Protein A and Protein G are able to recognize and bind the constant region of different IgG antibodies in a non‐covlant manner. This allows multiple measurements within the same system by performing multiple binding and elution cycles.

Result

Protein A and Protein G can be attached covalently to the sensor without losing its ability to bind IgG antibodies [4]. The antibody binding and elution is monitored by ATR‐FTIR spectroscopy and validated using fluorescence spectroscopy. It is possible to perform at least 35 cycles of antibody binding and elution over 7 days without loss in diagnostic accuracy. The sensor is still able to extract different biomarkers like Aβ and the Tau Protein from CSF with highly comparable results compared to the recently used system.

Conclusion

The development of a regenerative immuno‐infrared‐sensor is crucial to reduce the user input and to increase the throughput of this method. Compared to assays where the capture antibody is covalently immobilized, the regenerative system has a factor 6 increased thoughput. References: (1) Nabers, A. et al. (2016) J. Biophotonics, 9. 224‐234. (2) Nabers, A. et al. (2018) EMBO Mol. Med. 10, e8763. (3) Nabers, A et al. (2019) Alzheimer’s Dement. Diagnosis, Assess. Dis. Monit., 11, 257‐263. (4) Budde, B. et al. (2019) ACS Sens. 4, 1851‐1856.
A cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from subjective cognitive decline
Authors: Yang Dong Won , Hong Yun Jeong , Ho Seong Hee , Jeong Jee Hyang , Park Kee Hyung , Kim Sang Yun , Wang Minjung , Choi Seong Hye , Han SeungHyun , Kang Seung Wan
Published: December 2020

Background

Subjective cognitive decline(SCD) has been considered as at risk state to progress to mild cognitive impairment(MCI) or Alzheimer's disease(AD) dementia. The purpose of this study is to set up cohort and to identify risk factors for the progression to MCI or dementia from amnestic SCD

Method

We enrolled subjects aged 60 years or older complaining of persistent cognitive decline. To include higher risk SCD patients with rapidly progression, subjects needs to have 7% to 50% of the verbal memory and over 7% of the rest subtests of comprehensive neuropsychological battery. We named this state of SCD as an amnestic SCD. Brain magnetic resonance imaging (MRI) volumetry, visual and standardized uptake value ratio (SUVR) analysis of 18F‐Florbetaben brain amyloid‐beta Positron Emission Tomography (PET) were. Blood amyloid oligomerization was measured by the Multimer Detection System‐Oligomeric Aβ (MDS‐OAβ) method. Quantitative EEG were also analyzed. Sleep time and physical activity were collected with wearable device (Fitbit alta). Gait speed, body mass index, and muscle strength were measured.

Result

We analyzed 120 SCD subjects (male 53, female 67). Mean age and education were 70.9 and 11.2 years. 25 (20.8%) showed amyloid positive PET and 26(21.6%) had APOE ε4 allele. Positive amyloid PET SCD had higher frequency of APOE ε4 (48%) compared to amyloid negative SCD (14%). Positive amyloid PET SCD also had lower delayed verbal memory score and lower frontal inferior, anterior, medial and lateral temporal and lateral parietal regional brain volume ratio. Power spectral analysis of EEG showed increased relative theta /alpha ratio in the bilateral frontal regions. sLORETA showed increased theta spectrum in the left superior temporal, transverse temporal and fusiform area in amyloid positive SCD. MDS‐OAβ was positive in 55.1% which was not associated with SUVR value of amyloid PET.

Conclusion

Amnestic SCD with amyloid PET positive showed higher APOE ε4 allele, lower regional brain volume in AD related areas, lower verbal memory score and higher relative theta/alpha ratio in the frontal area. Longitudinal follow‐up for the next 3 years will identify risk factors for the progression to MCI or dementia and clinical significance of blood MDS‐OAβ value.
Distinctive roles of estrone and estradiol in shaping verbal memory circuitry in postmenopausal women
Authors: Schroeder Rachel A , Thurston Rebecca C , Wu Minjie , Aizenstein Howard J , Derby Carol A , Maki Pauline M
Published: December 2020

Background

Declining levels of estrogen have been implicated as a key mechanism contributing to declines in verbal memory that occur with menopause and as a potential factor contributing to risk of AD in women. We examined the association of two estrogens in postmenopausal women ‐ estradiol (E2), secreted by the ovary, and estrone (E1), secreted by peripheral tissues and the dominant estrogen in postmenopause – with functional connectivity during performance of verbal encoding and recognition tasks. We hypothesized that higher estrogen would be associated with greater functional connectivity between the hippocampus and prefrontal cortex (PFC) and between the left and right hippocampus.

Method

Participants were enrolled in MsBrain, a cross sectional investigation of postmenopausal women (n=98, mean age 59.2 +/‐ 4.2 years, 78.6% White). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Verbal memory was assessed using the California Verbal Learning Test (CVLT) and a functional MRI verbal memory task using a block design with two phases: encoding and recognition. A generalized psychophysiological interaction (gPPI) analysis estimated task‐based hippocampal‐whole brain functional connectivity using SPM12. Principal time series of the seed region (left or right hippocampus), task conditions (novel words, familiar words), interaction variables (seed times series × task condition), and motion parameters were included in the design matrix.

Result

E1 was positively associated with connectivity between the hippocampus and rostral anterior cingulate cortex (ACC), mid cingulate, dorsal ACC, and left insula during verbal encoding. E2 was positively associated with connectivity with rostral ACC/medial PFC and left orbital inferior frontal cortex during encoding and connectivity with rostral ACC, bilateral orbital PFC, bilateral middle temporal cortex, precuneus and posterior cingulate cortex during retrieval. All results survived multiple comparison at corrected p < 0.05. No associations were found between estrogen levels and verbal memory performance.

Conclusion

Estrogen levels in postmenopause may play a significant role in functional connections between the hippocampus and key nodes of the salience network via E1 and cognitive control network via E2. Results suggest that estrogens enhance the ability to attend to stimuli and engage neural resources required for encoding and recognizing verbal information.
Success of referring participants to the Generation program and lessons learned for future enrollment into Alzheimer’s disease prevention trials
Authors: Gordon David , Salata Hayley , Walsh Trisha L. , High Nellie M. , Kettenhoven Cassandra L. , Reiman Eric M. , Tariot Pierre N. , Langbaum Jessica B.
Published: December 2020

Background

We developed GeneMatch in 2015 to assist enrollment into Alzheimer’s disease (AD) prevention studies by enriching referrals based in part on APOE4 genotype. The API Generation Program, which enrolled cognitively unimpaired (CU) APOE4 carriers ages 60‐75 was the first multisite clinical trial to use GeneMatch as a recruitment source.

Method

GeneMatch is a US‐based, trial‐independent recruitment program of the Alzheimer’s Prevention Registry (APR), conducting APOE testing in CU individuals aged 55‐75. GeneMatch does not disclose APOE results to participants directly, however, results are used to match participants to enrolling studies in a manner that does not inadvertently disclose genotype. Participants are notified by email when they have been invited to a study. A reminder email is sent 7 days later, a letter is mailed to the participant’s home 2mo after if no response is received. Once a participant accepts his/her invitation, their contact information is shared with their preferred study site through an online portal. In July 2016, GeneMatch began inviting participants to the Generation Program.

Result

To date, >90,000 people have joined GeneMatch, > 30% are APOE4 carriers. Recruitment in the Generation Program and treatment with umibecestat was terminated in July 2019 after an early signal of mild worsening in some measures of cognitive function. At that time, 16,521 GeneMatch participants had been invited to the Generation Program, 33% (5,461) of whom accepted their invitations. Of those who accepted, 2,202 consented to the Generation Program (randomization data not yet available), 292 were scheduled for screening, 511 were awaiting scheduling for screening, 242 were waiting to be contacted by their selected study site, 1,209 were found to be ineligible after a phone screen by sites, 695 were no longer interested, and 310 were lost to follow‐up.

Conclusion

The Generation Program was on track to complete enrollment in 2019 and GeneMatch was a successful program in helping to recruit APOE4 carriers. Lessons learned include the importance for GeneMatch to coordinate with study sites to ensure they are prepared to receive referrals Future analyses will examine success of GeneMatch (vs. other recruitment sources) for randomization.
Public libraries' involvement in creating a dementia friendly society
Authors: Jensen Anders Møller , Gregersen Rikke
Published: December 2020

Background

The WHO recommendations on creating dementia friendly society that helps combat stigma, and improve quality of life for people with dementia, has many parties involved. Over the years the free public libraries in the Scandinavian welfare model has developed interventions towards groups with special needs, but little is known about the needs and wishes of people with dementia. In collaboration, three libraries in Denmark has explored how they can contributed to fulfilling the national goal of creating a dementia friendly society. The aim was to investigate how special programmes towards people with dementia, and their relatives, were received by the target group, and employees at the libraries.

Method

Three public libraries in Denmark developed activities based on oral text‐reading supported by pictures and/or visits to relevant museums, in order to create stimulating cultural input covering different literary genres. Between five and nine group activity’s were performed at the libraries, having 15 persons with dementia – some with the assistance of relatives – participated in the program. The sessions lasted one and a half hour. The participants lived at home with support primarily from their spouse. The participants were interviewed no later than one week after the last activity about their experiences participating in the program, and recommendation for the library sectors involvement in creating a dementia friendly society. In addition, staff involved in the activities were interviewed to document their experiences of working with people with dementia. The interviews were recorded, transcribed verbatim, and analysed using thematic analyses.

Result

The programs activities were well received and dropout rate was low. The activities helped the persons with dementia re‐experience the joy of literature, and stimulated them culturally, as well as intellectually. The staff was supportive of the library sectors involvement in creating a dementia friendly society, but pointed out that knowledge about dementia and the organisation in small groups were barriers for further deployment of the program.

Conclusion

The results showed promising results regarding public libraries involvement in creating a dementia friendly society.
Disruption of concordance among spontaneous measures of intrinsic brain connectivity in Alzheimer’s disease
Authors: Chen Xiangliang , Dronse Julian , Richter Nils , Fassbender Ronja V. , Reutern Boris , Dillen Kim , Jacobs Heidi I. L. , Fink Gereon R. , Kukolja Juraj , Onur Oezguer A.
Published: December 2020

Background

In the last years, several voxel‐wise data‐driven metrics gained attention to study resting‐state connectivity in healthy aging and various pathological states. More recently, a new measure assessing the interaction between the commonly used metrics has been proposed and made widely available via the DPABI toolbox: the so‐called concordance index (CI). This index reflects the coupling of different metrics. The value of this new measure in Alzheimer's disease (AD) research is yet unclear.

Method

Healthy young controls (YC, n=26), healthy senior controls (SC, n=29), and patients diagnosed with AD (n=35) underwent 3T resting‐state fMRI. First, the fractional amplitude of low frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated. Next, the CI among these measures was determined for each time window and each brain voxel across time by using Kendall's W. Differences in the CI between groups were examined on a whole brain, voxel‐wise, and network‐level using masks of seven of the most prominent intrinsic brain networks, with age, sex, head motion and gray matter volume as covariates.

Result

The whole‐brain CI was significantly lower in AD patients as compared to YC and SC, which is in line with results from analyzing the single metrics. Reductions of the CI in AD was consistently observed in all networks investigated except for the limbic network. In SC compared to YC, no network‐level CI differences were detectable. On the voxel level, AD patients compared to SC showed lower CI in the right middle temporal gyrus, and SC compared to YC revealed lower CI in the left middle frontal gyrus. Analyzing the single metrics for their own, we observed a lower fALFF in the right angular gyrus in AD compared to SC, but no differences were detected for ReHo and DC.

Conclusion

The newly proposed CI based on resting‐state connectivity may serve as a more sensitive imaging marker in AD than single metrics. The data suggest that this index distinguishes well between neurodegeneration and healthy aging.