bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes of Neuronal Plasticity in Postoperative Cognitive Dysfunction (POCD)
Authors: Zhang Yan
Published: December 2021

Background

Postoperative cognitive dysfunction (POCD) is defined as a prolonged cognitive function impairment that occurs within weeks to months of a surgical procedure. Clinically this is a well‐known risk of the surgical experience in the elderly, having been described as a consequence of anesthesia. The medial prefrontal cortex (mPFC) plays a critical role in remote, recent, and short‐term memories over a broad range of tasks. The effect of POCD on neuronal plasticity in mPFC remains controversial. The present study investigates the impact of laparotomy on cognition and synaptic functions.

Method

Mice were induced with 5% sevoflurane and maintained with 3 ‐ 4% sevoflurane continuously for 30 mins. Under sevoflurane anesthesia, a 2.5 cm longitudinal midline incision was made. Approximately 10 cm of intestine was exteriorized and vigorously rubbed for 2 min and stay outside the abdominal cavity for 1 min. Novel Object Recognition (NOR) test was performed 1hour and 24 hours for the short‐term and long‐term memory seven days after the surgery. Open field test (OFT) and The Elevated Plus Maze test, was performed to exclude motor dysfunction and anxiety. The miniature excitatory postsynaptic currents (mEPSC) and miniature inhibitory postsynaptic currents (mIPSC) were recorded on the 7 or 14 days after surgery.

Result

In the NOR test, mice with undergone laparotomy surgery had worse cognitive performance than the control group. There was no significance between the laparotomy group and the control group in the OFT test and Elevated Plus Maze test. There was no significance in the amplitude of the mEPSC between laparotomy and control group. However, the frequency increased significantly in the laparotomy group than the control group, which can last for 14 days. There was no significance of mIPSC in the amplitude and frequency between the laparotomy group and the control group.

Conclusion

These findings demonstrated that laparotomy surgery under sevoflurane leads to learning and memory impairment in adolescent mice without altering motor dysfunction and anxiety. The increase in the presynapse release ability indicated the glutamatergic neuron abnormalities without altering the GABAergic neuron’s function. Our result suggested that postoperative cognitive dysfunctions may be related to surgical trauma and glutamate neurons abnormalities.
Microglia subtype transcriptomes differ between Alzheimer Disease and control human postmortem brain samples
Authors: Prater Katherine E , Green Kevin J , Chiou Kenneth L , Smith Carole L , Sun Wei , Shojaie Ali , Heath Laura M , Rose Shannon , Keene C. Dirk , Logsdon Benjamin A , Snyder‐Mackler Noah , Blue Elizabeth E , Young Jessica E. , Garden Gwenn A , Jayadev Suman
Published: December 2021

Background

Microglia‐mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer’s Disease (AD). Microglia subtypes are complex, with beneficial and harmful phenotypes. Understanding the gene expression networks which define the spectrum of microglia phenotypes is critical to identifying specific targets for neuroinflammation modulating therapies.

Method

Our study utilized post‐mortem brain tissue from 22 total (7 male) participants; 12 (3 male) had significant AD neuropathic change. Nuclei isolated from prefrontal cortex were sorted for the myeloid marker PU.1 using fluorescence activated nucleus sorting (FANS). The FANS approach yields larger numbers of nuclei annotated as microglia with high quality sequence from each individual. We performed single‐nucleus RNA‐seq using the 10X Genomics Chromium platform.

Results

We isolated more than 120,000 microglia nuclei, facilitating group comparisons based on disease state. Unbiased clustering revealed 10 microglia clusters and improved resolution of microglia heterogeneity compared to standard single‐cell approaches. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles including interferon‐stimulated, endo/lysosomal, neurodegenerative with a “disease‐associated microglia” (DAM) signature, as well as a metabolically active and autophagic cluster. Interestingly, the cluster proportionately enriched for AD individuals’ nuclei is not the DAM cluster but instead one of the clusters in which endo/lysosomal genes are highly upregulated. Furthermore, many of the genes in known AD risk loci are strongly differentially regulated in this AD associated cluster. We also identify a cluster of microglia that is proportionately enriched for control samples with upregulated cell cycle and proliferation genes. Trajectory analysis suggests that the paths AD and control nuclei take from unactivated “homeostatic” to various phenotypic states are also distinct.

Conclusion

Using human AD tissue collected with uniform protocols we characterize the transcriptomic profiles of microglia subtypes in human brain. By enriching for myeloid cells prior to analysis we can resolve microglia subtypes revealing the diversity of microglia which are “inflammatory” as well as other microglia subtypes responding with induction of metabolic and lysosomal pathways. Our data identifies subtypes of microglia that are unique to AD and control individuals. These results support the possibility of pharmacological targeting of specific subtypes of microglia to alter AD progression.
The forceps minor white matter modulates cingulo‐opercular functional connectivity change in subjective cognitive decline
Authors: Ruiz‐Rizzo Adriana L , Viviano Raymond P , Daugherty Ana M. , Finke Kathrin , Müller Hermann J , Damoiseaux Jessica S.
Published: December 2021

Background

The ‘cingulo‐opercular’ network (CON) functional connectivity (FC) decreases in aging and mild cognitive impairment. However, little is known about the cross‐sectional differences or longitudinal changes in CON FC in subjective cognitive decline (SCD). Frontal white‐matter tracts such as the forceps minor exhibit alterations in SCD and, thus, might play a relevant role for CON FC in SCD. Thus, we tested (i) whether baseline SCD predicts CON FC decrease over three years and (ii) whether white matter in the forceps minor modulates that effect.

Method

Sixty‐nine healthy older participants (13 males; 68.33 ± 7.95 years old) underwent resting‐state functional and diffusion‐weighted magnetic resonance imaging. Forty‐nine of those participants were further enrolled in 2 follow‐ups, about 18 months apart each. The degree of SCD was assessed at baseline with the memory functioning questionnaire (MFQ; greater score indicating more SCD). After imaging data preprocessing, we obtained the average CON FC (correlation between 5 regions) for each time point and the neurite density of the forceps minor (‘structural connectivity’, SC), which was then averaged across time points. A latent growth curve model was fit to the longitudinal FC data, setting the intercept at the last time point. The model tested whether baseline MFQ predicted FC after 3 years (latent intercept) and/or its rate of change (latent slope) and whether the interaction between SC and MFQ predicted the latent intercept of FC.

Result

We did not find evidence of baseline MFQ as a predictor of CON FC after 3 years (b = ‐0.19, 95% confidence interval, CI, [‐0.49, 0.11], p = 0.211) or its rate of change (b = ‐0.17, [‐0.37, 0.03], p = 0.093). However, we found that SC (averaged across all time points) modified the relation between MFQ and FC after 3 years (intercept, b = 0.20, [0.03, 0.37], p = 0.020; FIG).

Conclusion

Greater SCD predicts lower CON FC after 3 years in individuals with relatively low neurite density in the forceps minor. This evidence implies that CON FC alterations in SCD are dependent upon the forceps minor’s white matter and that these alterations might be associated with attentional or executive‐function changes in SCD.
Investigating the secretion of small heat shock proteins in reactive astrocytes in Alzheimer’s disease
Authors: Yang Fangjia , Sung Katherine , Sanchez Maria Jimenez
Published: December 2021

Background

Molecular chaperones have protective functions in neurodegeneration by preventing misfolding of aggregation‐prone proteins. These functions have been mostly studied in neurons. However, members of the family of chaperones known as small heat shock proteins (sHSPs), including HSPB1, CRYAB, and HSPB8, are specifically expressed in glial cells rather than in neurons, and their levels increase in astrocytes in human post‐mortem Alzheimer’s disease (AD) brain.

While traditionally considered intracellular proteins, novel extracellular functions have been attributed to chaperones in cancer or the immune system. Interestingly, HSPB1 is also found in senile plaques suggesting these can also be extracellular in the brain. We hypothesize that sHSP can be extracellular and aim to investigate whether sHSPs are secreted from astrocytes in Alzheimer’s disease brain.

Method

We used human post‐mortem brain sections from Alzheimer’s disease patients to investigate changes in extracellular/intracellular localization of HSPB1. To further explore sHSPs secretion, we used primary mouse astrocytes. Reactive astrocytes were induced by TNFα and IL‐1α, mimicking the local environment in the diseased brain. We investigated changes in astrocyte cell lysates and the astrocyte conditioned media by Western blot. To investigate the secretion mechanisms, we also use size exclusion chromatography (SEC) and nanoparticle tracking analysis (NTA)

Result

Although sHSPs are intracellular chaperones, Our analysis of AD patients post‐mortem brain sections suggested that extracellular HSPB1 might increase around astrocytes that are close to amyloid plaques. In primary mouse astrocytes, we also found an increase in sHSPs in the extracellular media when astrocytes become reactive upon treatment with TNFα and IL‐1α. We further investigated their mechanism of secretion by fractionating the astrocyte conditioned media using SEC. NTA and proteinase K protection assays show that the sHSPs were not present in extracellular vesicle fractions, but rather free in the media.

Conclusion

Our study suggests that HSPB1 is secreted from astrocytes near to plaques in AD brain, as well as from reactive astrocytes in culture, and this secretion is not dependent on extracellular vesicles. The mechanisms behind how sHSPs are secreted and their extracellular functions still need to be explored.
Modularity of rsfMRI networks across aging, sexes, and processing speed
Authors: Bustos Nicholas , Nowling Duncan , Warner Graham , Joseph Jane E
Published: December 2021

Background

Functional brain networks shift and adapt with task and environmental demands throughoutneural development and aging, which are both known to have gender specific profiles. The modularity ofthese networks has been shown to decrease with healthy aging but there is debate surrounding sexdifferences in aging and how dimorphisms relate to neurodegenerative pathologies such as Alzheimer’s(AD). This study used resting state functional magnetic resonance imaging(fMRI) to examine sexdifferences in network modularity in mild cognitive impairment (MCI) and healthy control (HC) groups toexplore its potential as a clinical biomarker of a prodromal AD.

Method

Participants included 90 MCI subjects age 55 to 77 (M = 68.19 years), and 127 HC subjects age45 to 84 (M = 66.53 years). Resting state fMRI scans were analyzed using standard preprocessing anddouble regression pipeline in FSL (version 6.0). BOLD time series were extracted from 280 brain regionsusing the Power atlas. Brain Connectivity Toolbox was used to compute the modularity graph theory metric.Generalized linear mixed modeling was used to examine the modularity metric Q as a function of sex andTrails‐A score in HC and MCI.

Result

A significant interaction between sex and Trails‐A score was found (Wald c2=4.7, p=.031) withinthe HC group. Males showed a decrease in modularity with increased processing speed on Trails‐A in linewith previous findings, whereas females showed no association. No significant interactions were found forMCI groups.

Conclusion

These results confirm previous work correlating modularity with task‐specific connectivityand performance. Future analyses should focus on divergences between sexes in brain network modularityto inform differential diagnoses of AD.
TDP‐43 aggregation and inhibition using antibodies targeting RRM2‐CTD domain
Authors: Arias Carlos Quintero , Esposto Josephine C , Martic Sanela
Published: December 2021

Background

TDP‐43 is a highly conserved protein localized to the nucleus. Under pathological conditions, it forms fibrillar aggregates, characteristic of Amyotrophic Lateral Sclerosis (ALS) progression. The exact mechanism of TDP‐43 aggregation and formation into a pathological state has yet to be elucidated, but is an important therapeutic target to consider.

Methods

In vitro full‐length phosphorylated TDP‐43 (pS410)protein was agitated and aged, with and without the presence of TDP‐43 specific antibodies. Immunoblotting was used to confirm the binding of antibodies to TDP‐43. Aggregation was monitored using spectroscopic methods, Thioflavin T (ThT), and turbidity. Transmission electron microscopy (TEM) visualized the formation and structure of phospho‐TDP‐43 aggregates.

Results

The agitation and extensive aging (days) were required to induce aggregation of insoluble phospho‐TDP‐43 aggregates and formation of ThT positive fibrils. When exposed to an antibody specific to the RRM2‐CTD domain on TDP‐43, aggregation was inhibited in a concentration‐dependent manner and fibril formation was reduced.

Conclusions

Inhibition of TDP‐43 aggregation and fibril formation using antibodies demonstrates the potential for epitope‐specific treatment of TDP‐43 proteinopathies.

1) Esposto, J., & Martic‐Milne, S. (2021). Phosphorylated TAR DNA‐binding protein‐43: aggregation and antibody‐based inhibition. Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease, 1867, https://doi.org/10.1016/j.bbadis.2021.166234.
Single cell transcriptomic profiling of neurodegeneration mediated by tau in a novel 3D neuron‐astrocyte coculture model
Authors: Rickner Hannah , Jiang Lulu , Hong Rui , Wolozin Benjamin , Cheng Christine
Published: December 2021

Background

Research into neurodegeneration has been hampered by a lack of systems that rapidly and accurately recapitulate neurodegenerative processes. We report development of a model combining human iPSC derived neurons (hiNCs) and astrocytes (hiACs) in self‐aggregating 3D organoids that reproducibly develop a robust range of tau pathology and neurodegeneration. This system is a scalable and highly manipulatable model of neurodegeneration and critical understudied glial responses. Additionally, the model induces pathology without reliance on genetic overexpression. Our system represents an important technological advance in modeling Alzheimer’s Disease (AD), and is a promising tool for identifying disease modifying treatments.

Methods

The system was developed by combining advances in 3D cell modeling and tau propagation. We perform directed differentiation of wild‐type iPSC to hiNCs and hiACs, and hiNCs are selectively exposed to toxic aggregations to induce pathology. Cells are combined in microwells to induce self‐aggregation, and pathology develops over the course of three weeks. Tau pathogenesis in the model was correlated with human tauopathy progression by immunopathology and single cell transcriptomics, and the application of a selective inhibitor PU‐H71 demonstrated the efficacy of the model to explore disease modifying treatment.

Result

The model consistently displays a robust range of tau pathology within three weeks, including progressive development of hyperphosphorylated tau at positions T181, S262, and S396/404, misfolded tau (MC1, TOMA2), and fibrillar tau (THIOS). Neurodegeneration (FlouroJadeB, LDH) is accompanied by reactive astrogliosis (GFAP), which single cell transcriptomics reveals to be driven by heat shock proteins (HSPs). The observed tau pathology and transcriptional responses were reduced by treatment with PU‐H71, which eliminates dysfunctional HSP epichaperome. Together this evidence demonstrates a rapid and reversible recapitulation of tau pathogenesis.

Conclusion

Our novel model consistently recapitulates tau‐induced neurodegeneration in a human system, and allows for the elucidation of neuronal and astrocytic responses. Additionally, we have demonstrated the power to model the reduction of tau pathology by drug treatment. Continued expansion of the model will include integration of microglia. This novel model represents a technological advance that will allow for the rapid recapitulation of neurodegeneration in a manipulatable system that promises to accelerate drug development for AD.
Mortality in FTD: An Australian perspective
Authors: Loi Samantha M , Chen Ben , Tsoukra Paraskevi , Eratne Dhamidhu , Wibawa Pierre , Farrand Sarah , Kelso Wendy , Evans Andrew H , Walterfang Mark , Velakoulis Dennis
Published: December 2021

THEME: Clinical manifestations

TOPIC: Neuropsychiatry & beh neurology

SUBTOPIC: Neuropsychiatry

Background

Survival duration in frontotemporal dementia (FTD) remains inconsistent, depending on the clinical phenotype with different risk factors identified. Risk factors to mortality include the FTD‐MND presentation, a genetic predisposition (Agarwal S et al. 2019), deficits in neuropsychological tests, imaging changes (Agarwal et al. 2019; Hodges et al. 2003) and non‐tau pathology (Roberson et al. 2005; Hodges et al. 2003). We aimed to identify survival duration and cause of death in this group.

Method

All inpatients admitted to Neuropsychiatry, based at the Royal Melbourne Hospital, in metropolitan Australia from 1992 – 2014, who were diagnosed with probably FTD of any subtype were included. Linkage data was obtained by the Australian Institute of Health and Welfare (AIHW). We reviewed their clinical information including demographics, age of symptom onset, type of presenting symptom, neuroimaging and diagnosis.

Result

Of the 528 individual inpatients identified with a dementia, there were n=100 who had a diagnosis of probable FTD. There were n=76 who had a behavioural‐variant FTD (bv‐FTD), n=14 who had a language‐variant FTD (lang‐FTD) and n=10 who had FTD‐MND. 67% of the group had died. Overall median duration of survival was 10.5 years (95% CI 7.9, 12.2). There were no differences in age of death nor age onset between the three FTD‐subtypes (p=0.479, p=0.289, respectively). As expected, there were significant differences in the median survival duration of the three FTD subtypes, with FTD‐MND having the shortest duration (p=0.004). Causes of death based on ICD‐10 were predominantly dementia‐related (26.3% Other degenerative diseases of nervous system; 17.5% unspecified dementia) but also included acute myocardial infarction (7%) and alcohol‐related (7%). Standardised mortality ratios (SMRs) revealed that compared to population norms, people with FTD had 8x mortality rate.

Conclusion

Not unsurprisingly, FTD‐MND had the shortest duration compared to the other subtypes of FTD. The duration of survival was comparable to other studies. Causes of death revealed that a dementia was identified in almost half of cases. High SMRs suggest that FTD is a particularly “fatal” type of dementia in younger people. Investigation into risk factors to death is required.
Investigating the non‐cell autonomous role of glial chaperones in Alzheimer’s disease
Authors: Sung Katherine , Yang Fangjia , Noble Wendy , Jimenez‐Sanchez Maria
Published: December 2021

Background

Astrocytes are vital in the onset and progression of Alzheimer’s disease (AD). Accumulation of reactive astrocytes, together with tau phosphorylation, correlates very strongly with cognitive decline.

Molecular chaperones are essential for maintaining protein homeostasis. One family of chaperones are the small heat shock proteins (sHSPs), which include HSPB1 and CRYAB. Expression of these sHSPs seems to be restricted to glial cells, and levels are found to increase in those astrocytes found in AD brains. The role that sHSP play in astrocytes in AD is still not known. Emerging evidence suggests vital interplay between different cell types during neurodegenerative diseases. We therefore aim to investigate the non‐cell autonomous role of astrocytic sHSPs in AD.

Method

We are using primary mouse neurons and organotypic brain slice cultures in conjunction with the recombinant adeno‐associated viral system (rAAV). These systems will allow us to replicate the tau pathology found in AD, investigate neuron‐astrocyte interactions and determine whether either can be altered by overexpression of our sHSPs.

Using immunofluorescence, confocal microscopy and western blotting we are characterising expression and localization of sHSPs in post‐mortem human AD brain tissue and brain slice cultures.

Result

Our data shows that HSPB1 is specifically expressed in astrocytes in both human brain tissue and slice cultures. Interestingly, HSPB1 levels in the human brain increase in GFAP‐positive astrocytes surrounding amyloid plaques. When organotypic brain slices are treated with cytokines or Aβ oligomers, reactive astrocytes are induced and levels of HSPB1 and CRYAB are also increased, similar to what we observe in human AD brain.

Conclusion

Our results in human AD brain highlight the importance of astrocytic HSPB1 in AD, and we provide evidence to suggest not only that organotypic brain slices are a good model to replicate and study the function of sHSPs in AD, but that HSPB1 and CRYAB play an important role in the response to AD‐relevant pathology.

Using rAAVs, we aim to manipulate astrocytic sHSPs levels in organotypic brain slices to investigate whether astrocytic sHSPs could modulate neuronal health and tau pathology in a non‐cell autonomous manner.
Astrocytic BMAL1 regulates protein aggregation in mouse models of alpha‐synuclein and tau pathology
Authors: Sheehan Patrick W. , Kanan Michael , Benitez Bruno A. , Harari Oscar , Davis Albert A , Musiek Erik S.
Published: December 2021

Background

The circadian clock regulates inflammatory responses in the peripheral immune system, though its function in neuroinflammation is poorly understood. Deletion of the master circadian clock transcription factor BMAL1 abrogates cellular circadian clock function and can be used to probe cell‐type specific functions of the clock. Our lab has previously shown that Bmal1 deletion induces oxidative stress, astrocyte activation, and increased β‐amyloid plaque deposition in mice. We hypothesized that deletion of Bmal1 would increase pathology in other protein aggregation models.

Methods

We generated global inducible Bmal1 knock out mice expressing human P301S mutant tau. Pathology, aggregation state, and gliosis were quantified at nine months of age. We induced synuclein aggregation in global Bmal1 knock out mice using an alpha‐synuclein preformed fibril injection (PFF) model. Three months post‐PFF injection, mice were analyzed for synuclein pathology and gliosis. To determine a cell‐type specific effect, we generated astrocyte‐ and microglia‐specific Bmal1 knock out mice and used these for PFF injections. Pathology and gliosis were analyzed from these mice three months post‐PFF injection. We then generated astrocyte‐specific Bmal1 knock out mice expressing human P301S mutant tau to test the effect of Bmal1 deletion in astrocytes on tau aggregation.

Results

Global Bmal1 deletion in the P301S model resulted in a significant decrease in aggregated tau and microglia activation. Global Bmal1 knock out mice injected with PFFs had significantly decreased synuclein pathology and a decrease in microgliosis. Bmal1 deletion specifically in astrocytes was sufficient to reduce both tau and synuclein pathology. Using bioinformatics methods, we discovered an astrocytic candidate gene, Bag3, which may play a role in reducing pathology in our models. We used an in vitro PFF uptake assay and found that Bmal1 knockdown resulted in increased PFF uptake, which was reduced to baseline after simultaneous knockdown of Bag3.

Conclusion

Bmal1 deletion in astrocytes is sufficient to reduce tau and synuclein pathologies and attenuate microglia activation. This effect may be driven by the upregulation of the macroautophagy chaperone protein, Bag3. Our data suggests that targeting astrocytic protein degradation machinery may be a therapeutic strategy for reducing intra‐neuronal protein aggregates, such as tau and synuclein.
Meaning from tragedy: exploring attitudes toward dementia patient participation in research
Authors: Bhardwaj Twisha , Santulli Robert B
Published: December 2021

Background

Several prominent bioethics committees currently restrict dementia patient participation in research to projects that are low risk or offer potential benefit to the participant (Bernat). While these barriers were crafted to protect persons living with dementia, they may prevent them from contributing to non‐therapeutic research, a meaningful and rewarding effort that might not improve their own illness but could help future patients. One avenue toward preserving patient autonomy would be a dementia‐specific advance directive which would outline wishes for research participation in the event of cognitive impairment. However, there remains the question of whether it should include options for specific procedures (e.g., MRI, blood tests, lumbar puncture) or merely list broad categories of study risk (e.g., low, moderate, high) to which patients could consent. Before implementing novel legal measures, it is critical to examine attitudes of older individuals toward advance planning for research participation.

Methods

The current project will rely on semi‐structured telephone interviews with cognitively intact seniors to investigate attitudes toward dementia patient participation in research. Broadly, subjects will be prompted to reflect upon (i) their willingness to participate in therapeutic and/or non‐therapeutic research should they develop dementia, (ii) the role of an advance directive and surrogate‐decision maker in the context of research participation, and (iii) the preferred format for a research addendum to a dementia‐specific supplement. Notes will be taken during interviews and analyzed quantitatively and qualitatively for salient themes.

Results

This study has been approved by the Dartmouth Committee for the Protection of Human Subjects. Interviews will begin in the Fall of 2021.

Conclusion

Scientific research is the strongest weapon in the ongoing fight against dementia. Cognitively impaired individuals could be vital members of this effort. By exploring attitudes of older individuals toward advance planning for research participation, this project frames lived experiences within neuroethics and law. Such real‐world opinions will ultimately inform the creation of policy and legal measures to best serve this unique population. Reference: James L. Bernat: Ethical Issues in Neurology, 3rd Philadelphia: Lippincott Williams & Wilkins, 2008, pp. 374‐376.
Applying a deep learning approach focusing on spatiotemporal features in early diagnosis of Alzheimer's disease
Authors: Babatope Eyitomilayo Yemisi , Acosta‐Franco Jesus Alejandro , García‐Vázquez Mireya Saraí , Ramírez‐Acosta Alejandro Álvaro , Citedi‐IPN APIM Laboratory
Published: December 2021

Background

Alzheimer’s disease is a neurodegenerative disorder (Vally & Kathrada, 2019), the most common type of dementia in the elderly population (Kim, 2020) and is a great challenge in the geriatric field. Cognitive impairment is one of the features shown by Alzheimer’s dementia patients, and instrumental activities of daily living (IADL) are predictors of cognitive impairment as proven by several research works. Over the past few years, deep learning has had a tremendous improvement effect on diverse science areas, inclusive of healthcare (Farouk & Rady, 2020). This study aims to explore a non‐invasive and novel approach with the use of deep learning towards the early diagnosis of Alzheimer’s disease.

Method

To measure cognitive impairment, IADL are objectively recorded, capturing data from egocentric videos using wearable cameras that are attached to a glass frame of each participant, mainly focusing on hands use while performing these activities. Obtained images are analyzed based on human‐object interaction and human‐environment interaction. To make precise analysis while performing these activities, we propose the use and relationship of the anatomical planes (coronal, sagittal and transverse planes) and healthy human functional patterns [Martínez‐Velilla, 2018], in a quantitative way using deep learning. In the coronal plane, patterns involving displacement movements and object manipulation were identified with an accuracy of 87%. The information from the sagittal and transverse planes is developed with a deep learning model, which provides the required depth data to link the IADL's quality. By analyzing these planes, we can get more information about the distance of the hand and body motion while performing these activities.

Result

From our work, we obtained an accuracy of 87% recognizing movement patterns of displacement and object manipulation, and a good prediction of the depth of the anatomical planes.

Conclusion

Our model serves as a tool for proactive prediction of Alzheimer’s dementia and support in clinical decision‐making.
Effect of taurine and camel milk on amyloid beta peptide concentration and oxidative stress changes in aluminium chloride‐induced Alzheimer's disease rats
Authors: Abdulkadir Teslim S , Isa Ahmed Sherif , Dawud Fatima A , Ayo Joseph O , Mohammed Mohammed D
Published: December 2021

Background

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by brain accumulation of amyloid‐beta peptide, and oxidative stress (Huang et al., 2016). The study evaluated effects of taurine and camel milk (CM) on amyloid‐beta peptide and malondialdehyde concentrations and haemolysis in AlCl3‐model of Alzheimer’s disease in rats.

Method

Thirty‐five female Wistar rats were divided into seven groups (n=5); Normal saline (0.2 mL/mg body weight); AlCl3 (100 mg/kg); CM (33 mL/kg) (Khatoon et al., 2016); Taurine (50 mg/kg) (Cetiner et al., 2005); AlCl3 (100 mg/kg) + CM (33 mL/kg); AlCl3 (100 mg/kg) + Taurine (50 mg/kg) and AlCl3 (100 mg/kg) + CM (33 mL/kg) + Taurine (50 mg/kg). The administration via oral gavage, lasted for eight weeks. Rats were sacrificed, brain (hippocampal) and blood samples were collected for determination of amyloid‐beta peptide 1‐42 (Aβ) and malondialdehyde concentrations and haemolysis changes.

Result

The concentration of Aβ peptide decreased (P < 0.05) in AD + CM (7.46 ± 0.31 ng/L) and AD + CM + Taurine (9.20 ± 0.43 ng/L), when compared to controls. Malonaldehyde concentration in AD + Taurine decreased (P < 0.05) and superoxide dismutase activity increased (P < 0.05) in AD + CM and AD + CM + Taurine groups compared to controls. At 0.5 % NaCl, percentage haemolysis in AD rats (45.50 ± 1.19 %) was lower (P < 0.05) than in AD + Tau (49.75 ± 3.25 %), AD + CM (51.50 ± 3.00 %) and AD + CM + Tau (52.00 ± 1.70 %) rats. The haemolysis at 0.4 % NaCl was lowest (P < 0.05) in AD (66.00 ± 2.12 %) rats, compared to AD + Tau (71.00 ± 4.40 %), AD + CM (74.25 ± 3.70 %) and AD + CM + Tau (73.50 ± 3.00 %) rats.

Percentage haemolysis at 0.5% NaCl concentration increased (P < 0.05) in AD + CM (53.60 ± 2.96 %) and AD + CM + Taurine (51.20 ± 1.53 %) when compared to the controls.

Conclusion

Taurine and camel milk reduced the accumulation of Aβ peptide and ameliorated the oxidative stress damage by decreasing malondialdehyde concentrations and percentage haemolysis.
Systematic validation of variants of unknown significance in PSEN1
Authors: Burgute Bhagyashri , Renton Alan E. , Ziegemeier Ellen , Cruchaga Carlos , Goate Alison M. , McDade Eric , Llibre‐Guerra Jorge J , Karch Celeste M.
Published: December 2021

Background

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by extracellular amyloid plaques, intracellular neurofibrillary tangles, and progressive cognitive decline. More than 200 mutations in APP, PSEN1, and PSEN2 cause autosomal dominant AD (ADAD). However, common and rare variants also exist within these genes that may be risk factors, protective factors or non‐pathogenic polymorphisms.

Method

To distinguish polymorphisms from pathogenic mutations, we have developed an algorithm for determining ADAD pathogenicity that weighs genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Here, we evaluated 5 novel variants in PSEN1 identified in densely affected AD families in Latin America: p.Val103_Ser104delinsGly, K395I, P264T, A275T and I414T. PSEN1 p.Val103_Ser104delinsGly, K395I, and P264T produced a significant increase in the extracellular A42/40 ratio.

Result

PSEN1 p.Val103_Ser104delinsGly, K395I, and P264T produced a significant increase in the extracellular A42/40 ratio. PSEN1 A275T produced a significant increase in A42 and A40 levels, without altering the ratio. PSEN1 I141I, however, failed to significantly alter A levels in a manner consistent with known pathogenic mutations.

Conclusion

Thus, we propose that PSEN1 I414T is a risk factor or non‐pathogenic polymorphism, and PSEN1 p.Val103_Ser104delinsGly, K395I, and P264T represent novel likely pathogenic mutations.
A Two‐Clone approach to study signaling interactions among neuronal cells in a pre‐clinical Alzheimer’s Disease model
Authors: Yeates Catherine , Sarkar Ankita , Deshpande Prajakta , Kango‐Singh Madhuri , Singh Amit
Published: December 2021

Background

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder with no cure and few treatments. AD causes profound cognitive deficits and memory impairments. Accumulation of the peptide amyloid beta plaque is one of the characteristics of the disease. To understand the progression of Alzheimer’s disease, studies often rely on ectopic expression of amyloid‐beta 42 (Aβ42) throughout an entire tissue. Uniform ectopic expression of Aβ42 may obscure cell‐cell interactions that contribute to the progression of the disease.

Method

We developed a two‐clone system to study the signaling cross talk between GFP‐labeled clones of Aβ42‐expressing neurons and wild‐type neurons simultaneously generated from the same progenitor cell by a single recombination event.

Result

Surprisingly, wild‐type clones are reduced in size as compared with Aβ42‐producing clones. We found that wildtype cells are eliminated by the induction of cell death. Furthermore, aberrant activation of c‐Jun‐N‐terminal kinase (JNK) signaling in Aβ42‐expressing neurons sensitizes neighboring wild‐type cells to undergo progressive neurodegeneration. Blocking JNK signaling in Aβ42‐producing clones restores the size of wildtype clones.

Conclusion

Here we present evidence that JNK signaling between Aβ42‐ expressing cells and adjacent wild‐type cells mediate neurodegeneration.
TSPO and P2X7 discriminate between amyloid‐ and tau‐induced glial responses
Authors: Gomez‐Gutierrez Ruben , Fujita Masahiro , Jankowsky Joanna L
Published: December 2021

Background

Current clinical PET imaging relies on translocator protein (TSPO) to detect neuroinflammation in brain disorders including degenerative conditions such as AD, however this marker lacks cell type‐specificity and offers no information on what type of insult is causing the reaction. An ideal PET tracer would detect both the rise in pro‐inflammatory and loss of anti‐inflammatory glial responses and would discriminate cellular responses to amyloid‐beta from tau. We investigated whether a pair of glial purinergic receptors would provide a better measure of inflammatory status in mouse models of AD than the current standard TSPO.

Method

We studied the expression of P2X7, P2Y12, and TSPO in 5xFAD and PS19 transgenic mice at early and late stages of pathology using quantitative immunohistochemistry. Co‐staining with microglial (Iba1) and astroglial (GFAP) markers was used to identify cell types expressing each receptor.

Result

Expression of P2Y12 decreased significantly with the onset of both Aβ and tau pathology. TSPO increased in 5xFAD mice with amyloid pathology, but not in PS19 mice with tau pathology. We observed the opposite pattern in P2X7 signal, which increased in PS19 mice with tau pathology, but less in 5xFAD mice with amyloid plaques.

Conclusion

Our findings suggest there may be distinct neuroinflammatory responses to Aβ and tau with increased TSPO around amyloid but not tau, and a reciprocal increase in P2X7 around tau but not amyloid. We found that P2Y12 and P2X7 serve as complementary markers reflecting the loss of homeostatic microglia and the rise of a reactive phenotype. Our results support continued investigation of P2Y12 and P2X7 as potential biomarkers of distinct neuroinflammatory responses which may be used in conjunction with TSPO to distinguish AD pathologies in clinical settings.
The chauffeur who banged cars happily: an interesting case of rapidly progressive strategic infarct dementia
Authors: Dubey Shubham , V Ramakrishnan , Dubey Ayush , Mutharasu C
Published: December 2021

Background

Rapidly Progressive Dementias (RPDs) are a subtype of dementia which develop rapidly over few days to weeks or months and lead to varying neuro‐cognitive deficits. There are many causes of RPDs, like autoimmune, degenerative, metabolic, infectious, neoplastic and vascular. Majority of them are treatable if detected timely. We present an interesting case here.

Method

A 41 year old male who worked as a chauffeur for a senior professor was brought to the Neurology department with a rather unusual complaint. The professor said that the chauffeur has been banging his car with other cars and road dividers while driving since 3 days. When enquired, he remained unapologetic about this. Also, he had been keeping mum during conversations. On taking history from wife, it was found that he had been forgetting simple things like names, keys, food and was staying aloof. Also, there had been bouts of over aggressiveness and violent behavior with very less sleep. Examination of the patient revealed fluctuating alertness, inattention and abulia with inability to perform any higher mental function test because of uncooperativeness. There was mild right hemiparesis too. Frontal lobe involvement was ascertained and imaging done.

Result

MRI revealed few patchy areas of acute watershed infarcts in left frontal lobe, corona radiate, centrum semiovale and genu of corpus callosum (Figure 1). It was associated with left ICA thrombosis with significant narrowing. He was started on anti‐platelets and statins with mild improvement. He has been planned for carotid endarterectomy.

Conclusion

Vascular infarcts are an important cause of RPDs. Infarcts in the genu of internal capsule are notorious for causing such presentations and hence also included in ‘Strategic Infarct Dementias’ (SIDs) which are characterized by focal ischemic lesions involving specific sites that are critical for higher cortical functions. Such cases require a careful history and examination along with relevant neuroimaging for proper diagnosis and treatment.

References

1. Geschwind MD, Haman A, Miller BL. Rapidly progressive dementia. Neurol Clin. 2007;25(3):783‐vii. doi:10.1016/j.ncl.2007.04.001

2. Tatemichi TK, Desmond DW, Prohovnik I, et al. Confusion and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome?. Neurology. 1992;42(10):1966‐1979. doi:10.1212/wnl.42.10.1966.
Intestinal microbial dysbiosis induced tau accumulation establishes a gut‐brain correlation for pathology Alzheimer's disease in Drosophila melanogaster
Authors: Srivastav Ankita , Mohideen Sahabudeen Sheik
Published: December 2021

Background

To analyze the concept of whether enteric dysbiosis contributes to the aggravation of tau protein, Drosophila melanogaster was used as a transgenic model organism. To study how the exposure of Pseudomonas sp., a gram‐negative bacteria, influences tau accumulation and neurodegeneration thereby understanding the gut‐brain correlation for the pathology of Alzheimer’s Disease.

Method

The versatile Gal4‐UAS gene expression system was used to express wild‐type tau with the help of pan‐eye specific GMR‐Gal4 in the flies. All the flies were exposed to Pseudomonas sp. to initiate the gut microbial dysbiosis. The extent of neurodegeneration was quantified by automated analysis of the degenerated region in the eye, the number of aggregates, and immunofluorescence quantification in the medulla. To understand the response of glial cells upon bacterial infection in tauopathy‐related dementia, tau was driven by glia‐specific Repo‐GAL4. Similarly, neuroinflammation which is found in tauopathies was studied using an eye‐specific driver line GMR‐GAL4, UAS‐ eiger/CyO.

Result

Upon exposure of Pseudomonas sp. on the wild type tau (tauwt) around the medulla, the degeneration was faster and, there was an increase in the levels of tau as compared to the control. Downregulation of Atg 1 and Atg 18 gene along with significant upregulation of Atg 12 is observed in tau expressing infected flies compared to tau expressing control flies. There was a significant degeneration as well as an increase in the number of aggregates in the medulla of the optic lobe. Similar degeneration was observed in flies expressing tauwt and egr along with an increased accumulation of tau in both retina and medulla.

Conclusion

When the flies expressing tau are subjected to the pathogen, and aggravation in tau accumulation is observed along with neuroinflammation and changes in the homeostasis. Due to its role in maintaining of body’s homeostasis, the gut‐brain correlation can have both detrimental and beneficial effects on the brain and the survival of neurons.
TOMM40, a risk gene for Alzheimer’s disease, is upregulated during proinflammatory response
Authors: Chen Jingchun , Samoylova Natalia G , Cummings Melika G
Published: December 2021

Background

TOMM40 gene has been associated with a risk of Alzheimer’s disease (Brabec et al., 2021). TOMM40 codes for the protein TOM40, which is the main channel forming protein for the translocase of outer membrane (TOM) in mitochondria. TOM40 is required for the efficient pre‐protein transport (Rapaport & Neupert, 1999). A large body of research has been accumulated on the involvement of mitochondria, especially TOM40 pore, in the progression of various diseases, including Alzheimer’s disease (Ahmad, 2019, Gottschalk et al., 2014). Furthermore, TOMM40 is found to be downregulated in brain and blood of patients with Alzheimer’s disease (Lee et al., 2012). As this gene is being explored with increased interest, its mechanisms in microglial responses have not yet been examined directly. In our study, we are attempting to elucidate the role of TOMM40 during microglial pro‐inflammatory responses in a murine and human microglial cell line.

Method

An immortalized murine microglial cell line BV‐2 and human HMC3 cells were used in this study. Microglial inflammation was triggered with proinflammatory agent, lipopolysaccharide (LPS), 10 ng/ml, 100 ng/ml, for 24 hours. During the stimulation, microglial morphology was monitored with phase‐contrast microscope, and TOMM40 gene expression wer measured along with proinflammatory genes (TNF‐α and NLRP3) by Quantitative Real‐Time PCR (qRT‐PCR). In addition, we also used Western blot to check the TOM40 protein expression.

Result

We found that microglia cells were more amoeboid shape with LPS treatment, as compared to original ramified microglia without LPS treatment. qRT‐PCR results showed that TOMM40, TNF‐α, and NLRP3 RNA expression were all upregulated in HMC3 cells when treated with LPS. TOM40 protein was also increased in BV2 cells with Western blot.

Conclusion

Our preliminary data showed that TOMM40 gene expression was upregulated in microglia cells during proinflammatory response, which was consistent with previous findings from Alzheimer’s disease. Our data highlights that we can use the microglial cell lines to study the role of TOMM40 in the progress of Alzheimer’s disease. The project is an undergoing study. Further function and pathway studies in the line will help to design new drugs for Alzheimer’s disease prevention and treatment.
"Seizure and neurodegeneration": Understanding the nature of seizure in patients with cognitive disorder, A chicken and egg situation
Authors: Öz Didem , Keret Ophir , Özbek Yağmur , Yener Gorsev
Published: December 2021

Background

The prevalence of epileptic seizures in dementia is higher than healthy individuals and seizures occur in 10‐22% of individuals with Alzheimer's Disease (AD). This exploratory study investigated the clinicopathological biomarkers and risk factors of individuals with/without active seizures following post‐mortem evaluation.

Method

The study included 1047 subjects with remote and 572 with active seizures. The data was obtained from National Alzheimer’s Coordinating Center(NACC) Dataset. The Chi‐square analysis was performed by using SPSS 26 Package Program with seven variables which consist of 1) major pathological changes (Yes/No/Unknown), 2) Thal phase for amyloid plaques (Phase‐0 to Phase‐5/Unknown), 3) Density of neurocortical plaques (No plaque/Sparse/Moderate/Frequent/Unknown), 4) NIA‐AA AD neuropathological change (No AD/Low‐ADNC/ADNC/Intermediate‐ADNC/High‐ADNC,Unknown), 5)Cerebral amyloid angiopathy (None/Mild/Moderate/Severe/Unknown), 6) AD‐Related genes (Yes/No/Unknown), and 7) Braak stage for neurofibrillary degeneration (Stage‐0 to Stage‐6/Unknown/The presence of tauopathy precludes Braak staging). Post‐hoc comparisons were done by using adjusted residuals.

Result

The chi‐square analysis showed that major pathological changes (χ2=18.107) are more common in patients with active seizures (27.5%) than remote seizures (19.9%). Thal phase for amyloid plaques (χ2=38.771) was significantly different in Stage‐0 and Stage‐1 the percentage of patients with active seizures was higher (5.7%, 4.8%) than remote seizures (1.8%, 1.7%). Braak stage for neurofibrillary degeneration (χ2=81.632) significantly differs among groups. Post‐hoc analysis showed that patients with active seizures (4.4%) had a higher percentage than remote seizures (1.1%) in Stage‐5. Density of neurofibrillary plaques (χ2=36.345) differs in groups showing that frequent plaques are more common in patients with active seizures (11.2%) than remote (6.9%). Cerebral amyloid angiopathy (χ2=51.946) showed a difference indicating mild angiopathy is more common in patients with active seizures (9.6%) than remote (3.9%). (All p<0.001)

Conclusion

These results may indicate that seizures are the result of widespread and severe degeneration in the brain or the degeneration is due to these seizures.