bluuebunny/crossref_metadata_2025 huggingface dataset:
HOPE4MCI trial: First trial targeting reduction of hippocampal overactivity to treat mild cognitive impairment due to Alzheimer’s disease with AGB101
Authors: Rosenzweig‐Lipson Sharon , Barton Russell , Gallagher Michela , Mohs Richard
Published: December 2021

Background

AD pathophysiological pathways involving both amyloid and tau have been functionally linked to excessive neural activity, with heightened neural activity causing dysfunction and progressive spread of pathology in the disease from an origin in the medial temporal lobe/hippocampus. Like hippocampal overactivity, recent evidence has demonstrated an association of amyloid and p‐tau 217 in early AD, with progressive elevation of p‐tau217 as the disease progresses. Substantial clinical evidence also indicates that hippocampal overactivity longitudinally predicts subsequent cognitive decline/conversion to dementia due to AD. AGB101 (low dose levetiracetam) demonstrates efficacy on a range of AD‐related molecular, synaptic, electrophysiological, functional and behavioral endpoints across models and species. Clinical proof of concept for this therapeutic hypothesis was demonstrated with AGB101 in a Phase 2A study that showed a reduction in hippocampal overactivity resulted in improvement in task related memory performance. To further examine this hypothesis, the HOPE4MCI trial is investigating the effects of AGB101 (low dose levetiracetam, 220 mg extended release) in a 78‐week protocol using tau biomarkers ([11C]MK 6420 pet imaging and p‐tau 217 plasma) alongside CDR‐SB (sole primary endpoint) for clinical/cognitive efficacy in MCI due to AD.

Methods

This is a multicenter, randomized, double‐blind, placebo‐controlled, 78‐week, fixed‐dose study evaluating AGB101 versus placebo as a treatment for slowing the progression of MCI due to AD. Inclusion criteria: Subjects must meet the following inclusion criteria at screening:

1) Subjects between 55 and 85 years old 2) Have MCI due to AD consistent with the NIA‐AA criteria: MMSE (24‐30); CDR (0.5); Impaired delayed recall on the ISLT; essentially preserved ADLs 3) Evidence of an amyloid‐positive PET scan.

Results

The HOPE4MCI trial has completed enrollment with 164 subjects randomized. Baseline data for CDR‐SB and MMSE are consistent with recently enrolled MCI due to AD (prodromal AD) studies. Subject demographics, screen failure information, safety and dropout information will be presented at the meeting.

Conclusions

HOPE4MCI represents the first and only Phase 3 clinical trial targeting the reduction of hippocampal overactivity for slowing the progression of MCI due to AD. The HOPE4MCI trial is supported, in part, by R01AG061091 to RM and R01AG048349 to MG.
Multimodal neuroimaging biomarkers of Alzheimer’s disease in older adults with depression: Preliminary findings from a pilot cohort
Authors: Mayblyum Danielle V. , Premnath Pranitha Y , Rubinstein Zoe B. , Sanchez Justin S , Thibault Emma G. , Farrell Michelle E. , Quiroz Yakeel T. , Amariglio Rebecca E. , Vannini Patrizia , Rentz Dorene M , Sperling Reisa A. , Johnson Keith A. , Blacker Deborah , Marshall Gad A , Gatchel Jennifer R
Published: December 2021

Background

Subclinical depressive symptoms in older adults have been linked to AD pathology and cognitive decline. However, it’s unclear how these findings translate to the spectrum of clinically significant late life depressive symptoms. To explore this, we examined cross‐sectional associations between depressive symptoms and neuroimaging biomarkers of AD (ATN) in a pilot cohort of older adults with moderate‐to‐severe depressive symptoms and compared these participants to non‐depressed older adults.

Method

Seventeen community‐dwelling clinically‐normal (CN) older adults meeting DSM5 criteria for major depression (73.4±4.7 y.o., 58.8% female) underwent MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET and completed a clinical battery including the 30‐item Geriatric Depression Scale (GDS) and Preclinical Alzheimer’s Cognitive Composite (PACC). A comparison group of non‐depressed older adults (no history of depression, GDS≤5; 73.0±5.5 y.o., 63.2% female) derived from existing observational studies at our site with similar clinical‐neuroimaging batteries were matched using nearest neighbor propensity score to depressed participants by age, sex, and APOE‐ε4 carrier status in a 4:1 ratio (Table 1). We examined cortical amyloid and regional tau and atrophy in a priori regions of interest (ROI) previously implicated in AD and mood (medial temporal lobe, amygdala, frontal cortex). We utilized t‐tests to explore group differences and linear regressions adjusted for age to investigate associations between depressive symptoms and ATN biomarkers.

Result

In the depressed group, depressive symptoms were significantly associated with elevated FTP in all ROI and with lower hippocampal volume, but not with cortical PiB (Table 2, Fig. 1). There were no significant group differences compared to non‐depressed controls in cortical PiB, regional FTP, or volume measures; however, participants with depression had worse cognitive performance on the PACC than non‐depressed participants (t=‐2.04, p=0.050).

Conclusion

Preliminary findings in this pilot sample suggest that moderate‐to‐severe depressive symptoms in older adults may be more closely associated cross‐sectionally with tau and hippocampal volume than cortical amyloid. Future work in a larger depressed cohort and with longitudinal follow‐up is needed to characterize risk in older adults with depression and consider opportunities for AD prevention.
Plasma NfL trajectory during ICU‐treatment of COVID‐19 patients: A prospective cohort study
Authors: Smeele Patrick , Vermunt Lisa , Duitman Jan‐Willem , Heunks Leo , Blok Siebe , Horn Janneke , Boogaard Harm‐Jan , Nossent Esther , Teunissen Charlotte E. ,   COVID‐19 Biobank Amsterdam
Published: December 2021

Background

COVID‐19 is a respiratory disease where neurological sequelae are frequently reported. Neurofilament light (NfL) in plasma is a validated biomarker for neuronal damage. We assessed the trajectory of NfL levels in intensive care unit (ICU) patients diagnosed with COVID‐19, and studied its relationship to clinical outcomes and markers of hypothesized pathophysiological mechanisms.

Method

As part of the Art‐Deco study and Amsterdam UMC COVID‐biobank, longitudinal samples and clinical data were collected weekly from a cohort of 31 prospectively admitted ICU patients with a minimum of 7 days of ventilation. The mean±sd age was 63±11 years. Admission duration ranged from 14‐35 days and 156 samples were collected. We evaluated the NfL trajectory over time, and whether this trajectory differed by 90‐day mortality outcome. Due to the non‐linear trajectory of NfL, we applied linear mixed models including cubic splines for the time variable. Secondly, we tested whether baseline or peak NfL levels predicted mortality (n=7/31), delirium incidence after detubation (n=18/22), and duration of delirium (6±6 days). Third, we assessed if disease severity (day 7 Sequential Organ Failure Assessment [SOFA] score) and baseline hypoxemia (pAO2 before intubation), inflammation (IL1‐b, IL‐6, IL‐8, TNF‐α), and coagulopathy (d‐dimer, presence of pulmonary embolism) were predictive of the NfL trajectory. For the latter models, we included an interaction term for the pathophysiological markers in the linear mixed models. All models were adjusted for age.

Result

NfL increased during ICU admission (p<001), and persisted longer in the non‐survivors (p<0.05;Figure 1). Baseline or maximum NfL was not predictive of mortality or delirium incidence. However, maximum NfL correlated to the duration of delirium (r=0.5;p=0.02). From the pathophysiological markers, SOFA scores (p<0.05) and baseline TNF‐α (p<0.05) were related to a stronger increase of NfL over time.

Conclusion

NfL levels increased over time and plateaued after 2‐3 weeks in most COVID‐19 patients at the ICU. Peak levels of NfL were predictive of delirium persistence. Repeated NfL levels may provide a future method for monitoring neurological outcomes in sedated ICU patients. Disease severity and specific inflammatory components appear important predictors of the NfL trajectory reflecting axonal damage in severe COVID‐19 patients.
Home care becoming essential during pandemic
Authors: Hogan Lakelyn
Published: December 2021

Background

Prior to COVID‐19, the home care industry was not seen as an extension of the healthcare system. However, the pandemic revealed that keeping older adults and individuals living with dementia at home and out of the hospital was essential. Just like the rest of the LTC industry, home care had to quickly adapt to keep individuals safe while still providing person centered care. Join this session to learn important lessons learned for the home care industry and best practices for moving forward.
ALTOIDA‐iADL for the diagnosis of Mild Cognitive Impairment and early Alzheimer's disease
Authors: Tort‐Merino Adrià , Tarnanas Ioannis , Bügler Maximilian , Harms Robbert , Fernandez‐Villullas Guadalupe , Juncà‐Parella Jordi , Bosch Beatriz , Lladó Albert , Sanchez‐Valle Raquel , Balasa Mircea
Published: December 2021

Background

Diagnostic accuracy for the early detection of mild cognitive impairment (MCI) is critical both in the clinical and research settings. Our aim was to evaluate the diagnostic performance of the ALTOIDA‐iADL test in subjects with non‐degenerative MCI and prodromal (pAD) and mild (mAD) Alzheimer's disease.

Methods

ALTOIDA‐iADL is a 10‐minute administrable cognitive test, which assesses activities of daily living in the form of an augmented virtual reality game. The task consists of placing and finding virtual objects in a real environment and provides a final score (the NeuroMotor Index; NMI). The NMI is obtained by weighting multi‐modal information such as hands’ micromovements, walking bouts and speed, reaction time and navigation trajectory (among others), and represents the overall outcome of the individual task performance. Fifty‐one participants were included and classified according to cerebrospinal fluid (CSF) AD biomarkers: MCI (n = 22; age: 68.2; MMSE: 26.5), pAD (n = 15; age: 69.4; MMSE: 24.0) and mAD (n = 14; age: 70.6; MMSE: 20.7).

Results

The NMI allowed differentiating between subjects with absence (Aβ‐) and presence (Aβ+) of abnormalities in the amyloid biomarker (p < 0.01). Also, differences were found between the MCI group and the pAD (p < 0.01) and mAD (p < 0.01) groups (Fig. 1). ROC curves showed good diagnostic accuracy of the NMI in the discrimination between the Aβ‐ and Aβ+ (AUC = 0.777; p < 0.01), MCI and pAD (AUC = 0.781; p < 0.01) and MCI and mAD (AUC = 0.772; p < 0.01). The NMI did not discriminate between the pAD and mAD (AUC = 0.557; p = 0.61) groups (Fig. 2). The NMI correlated with CSF NfL levels (r = ‐.456; p < 0.05) and the MMSE score (r = .432; p < 0.01), showing an association with the degree of cognitive impairment.

Conclusions

ALTOIDA‐iADL is useful in the differential diagnosis between patients with non‐degenerative MCI and prodromal and mild Alzheimer's disease. Its performance is related to the degree of impairment in cognitive screening tests and with biomarkers of axonal damage/neurodegeneration.
Pathogenic tauR406W induced neurodegeneration and memory deficits rescued by HDAC6 null mutation in Drosophila melanogaster
Authors: Sarkar Arkajyoti , Mohideen Sahabudeen Sheik
Published: December 2021

Background

Genetic screening was performed by Drosophila melanogaster to observe how different variants of HDAC6 regulate tauR406W mediated neurodegeneration.

Method

The versatile Gal4‐UAS gene expression system was used to express variants of HDAC6 and tauR406W with the help of pan‐eye specific GMR‐Gal4, and pan‐neuronal elav‐Gal4 in the flies. The extent of neurodegeneration was quantified by automated analysis of degenerated tissues, the number of aggregates, immunofluorescence, and also with the help of various behavioral and memory assays. Live imaging was performed on the wing with GCamP6f to study the role of HDAC6 on axonal transport.

Result

On expressing the HDAC6 mutants (H237A, H664A) the levels of total tau were increased followed by a decrease in acetylated α‐tubulin levels. We have also noticed a reduction in mRNA levels of Atg1, Atg8, and Atg12. On analyzing the various regions of the eye, there was a significant surface degeneration as well as an increase in the number of aggregates. The wings of flies expressing a GCamp6f and eb1‐eGFP displayed a defective axonal transport as well as damaged neuronal morphology. Upon expressing HDAC6[KO], there was amelioration in memory deficits, neurodegeneration and the flies regained a better retinal surface morphology.

Conclusion

HDAC6 can interact with tau mutations outside the microtubule‐binding region (MTBR) and can cause memory deficits, behavioral anomalies. Inhibition of HDAC6 via gene therapy can be an effective therapy to treat Alzheimer’s disease and other associated dementias.
ReMember‐Me system: Developing a new, remote digital tool for detecting and preventing cognitive decline
Authors: Moza Sotiria , Polycarpou Marina , Hadjicosta Andria , Sampanai Romina , Tziannarou Antonia
Published: December 2021

Background

The COVID19 pandemic and social distancing measures imposed have intensified the need for tools allowing the remote and early assessment of cognitive decline, in order to prevent undiagnosed neurocognitive disorder cases among older adults. The goal of the ReMember‐Me project (Image 1), funded by the EC and AAL Programme, is to create a remote, digital system for detecting, preventing and addressing cognitive decline early on. The first system prototype released includes the ReMember‐Me Cognitive Assessment Scale (RMCAS), a new digital instrument to detect cognitive difficulties, as well as, measures of physical, psychoemotional and motor status, sleep quality and serious games. The RMCAS includes 19 tasks assessing orientation, verbal, visual and prospective memory, calculation, attention, executive function, language and abstract thinking.

Method

The system is being, currently, pilot‐tested with 14 healthy and cognitively fit older adults (M=74.50, SD=4.14, 77.8% females) in a pre‐post intervention study. Participants completed a baseline assessment with the ReMember‐Me system and other standardized tools and will be tested again after two months to explore any intervention effects.

Result

The preliminary results showed that RMCAS has good fidelity and homogeneity (Table 1), individual items can yield results comparable to the Mini Mental State Examination (Table 2) while the digital administration of RMCAS did not seem to have any effect on performance compared to the traditional, hard copy administration (F=2.319, p>.05)

Conclusion

The preliminary results of the study indicate that the RMCAS may be a promising new digital instrument for the remote assessment of cognitive decline. Further testing is planned with 350 people in total, including participants with neurocognitive disorder, in total, to draw more concrete conclusions regarding its validity and reliability.
Analysis of brain‐derived blood exosomes for diagnostics of synucleinopathies
Authors: Dutta Suman , Hornung Simon , Kruayatidee Adira , Maina Katherine M , del Rosario Irish , Paul Kimberly , Poon Wayne W. , Fogel Brent L. , Bronstein Jeff M. , Ritz Beate , Bitan Gal
Published: December 2021

Background

Synucleinopathies are diseases characterized by aggregation and deposition of α‐synuclein in different brain cells. Diagnosis of these neurological disorders is challenging due to overlapping complex clinical symptoms. Developing reliable biomarkers that can distinguish among the synucleinopathies is an urgent public health need. Recently, α‐synuclein was shown to transfer via exosomes between different brain cells suggesting that measuring α‐synuclein in brain‐derived exosomes could serve as a potential biomarker for synucleinopathies.

Method

In this study, we used antibody‐coated magnetic beads to immunochemically isolate specific exosomes released by neurons or oligodendrocytes from serum/plasma of healthy individuals and patients with Parkinson’s disease and Multiple System Atrophy and measured biomarker concentration in them by a sensitive electro‐chemiluminescence ELISA. Oligodendroglial and neuronal exosomes were isolated from serum of 101 patients with MSA, 104 patients with PD and 100 healthy controls.

Result

Significantly higher concentrations of α‐synuclein were found in both neuronal and oligodendroglial exosomes from patients than in controls. The absolute values of α‐synuclein in neuronal and oligodendroglial exosomes provided moderate separation between the MSA and PD groups, yet the ratio between the two cell types allowed separating the two disease groups with 90.0% sensitivity and 90.0% specificity.

Conclusion

α‐Synuclein in brain‐derived blood exosomes provides a sensitive biomarker for distinguishing patients with MSA from healthy controls and from patients with PD using a blood test and suggest that the method can be expanded further for other neurodegenerative diseases.
Sports Post‐Concussion Syndrome (PCS) Model in Drosophila melanogaster
Authors: English Elizabeth A , Chazot Paul L
Published: December 2021

Background

Scientific and societal interest is growing in understanding links between sports concussion and neurodegeneration. When multiple symptoms, such as memory loss, anxiety and headaches, persist after head impact(s), this is defined as post‐concussion syndrome (PCS). Aetiology of PCS is poorly understood and there is no specific pharmacological cure. This study aimed to generate a novel sports PCS model in
Drosophila melanogaster
to facilitate further understanding of the syndrome.

Methods

The HIT device was constructed as per prior methods1, but with protractor added and impact forces measured with a pancake load cell for repeatable trauma application to fly subgroups at 0° (control), 30°, 45° or 60° release angles, measured as 0N, 1.1N, 1.8N and 2.1N respectively. Hits were repeated five times with 48‐72 hour intervals to model multiple traumas contact‐sports players experience during their careers. To evaluate effects of impacts, motor ability, survival and reactive oxygen nitrogen species (RONS) levels were measured. Motor ability was reported as a percentage of the number of flies that climbed above 5.5cm in 5.5 seconds. Flies were frozen at 21‐22 days post‐eclosure (middle‐age), heads and bodies separated and homogenised, then post‐centrifugation supernatant was assayed with DCF‐DA: condensed into highly fluorescent DCF in the presence of RONS, quantified by fluorescence spectroscopy.

Results

As with most human mild head trauma cases, fly motor ability was not significantly different acutely or long‐term following HIT device impacts. Similarly, with 1.8N impacts, lifespan was not significantly different compared to non‐trauma controls. Meanwhile, RONS levels increased in both fly heads (brains) and bodies (periphery) with five 1.8N impacts, representative of physiological stress in contact sportspeople with PCS.

Conclusions

Five 1.8N hits (at 45° release angle) produced the most suitable Drosophila sports PCS model. This novel model offers a rapid, inexpensive drug screening approach for prospective PCS treatments, and shows promise in investigating the oxidative stress mechanisms underlying PCS. Additional analyses, including neurodegeneration biomarker quantification and behavioural monitoring, are currently being explored to validate this model.

Reference: 1 Katzenberger RJ et al. (2013) PNAS 110, 4152‐4159.
Chronic Microglial Activation and Ageing Reduces the Numbers of Medial Septal Cholinergic Cells and Alters Their Morphology
Authors: Gamage Rashmi Vasundhara , Gyengesi Erika
Published: December 2021

Background

Pathological ageing is associated with brain inflammation that increases the risk of neurodegenerative disease like Alzheimer’s disease (AD). Chronic activation of microglia, the resident immune cells of the central nervous system (CNS), lead to “neuroinflammation” and result in gradual neurodegeneration. Pro‐inflammatory cytokine interleukin‐6 (IL‐6) is a common early inflammatory marker in AD. Medial septum (MS) of the basal forebrain (BF) provides most of the cholinergic innervations into the hippocampus and the cortex. While BF cholinergic cell loss and reduced cortical choline acetyltransferase (ChAT) activity is associated with cognitive decline, the underlying mechanism leading to cholinergic cell loss is still unknown.

Method

Aged, 12 (n=5) and 24 (n=5) months GFAP‐IL6 (presenting continuous IL‐6 expression under the control of GFAP promoter, contributing to chronic microglia activation), and aged, 12 (n=5) and 24 (n=5) months ChATBAC‐eGFP (GFP tagged cholinergic neurones to represent the effect of healthy ageing) mice were used. Immunohistochemistry combined with unbiased stereology and 3D morphology analysis were used to estimate the number and morphology of Iba1+ microglia and ChAT+ cholinergic cells, in the MS.

Result

Stereological estimation of MS microglia number displayed a significant 25% increase GFAP‐IL6 (12M) mice compared to control ChATBAC‐eGFP (12M) mice. A significant 30% increase was obtained for GFAP‐IL6 (24M) mice compared to control (24M) mice. Furthermore, a significant 23% increase in microglia was obtained for GFAP‐IL6 (24M) mice compared to the GFAP‐IL6 (12M) mice. Meanwhile, Cholinergic cell number displayed a significant 31% decrease in GFAP‐IL6 (12M) mice compared to control (12M) mice. While a significant 30% decrease was displayed in GFAP‐IL6 (24M) mice compared to control (24M) mice. There was a tendency for the cholinergic cell number to decrease with ageing among control and GFAP‐IL6 cohorts. A significant change in microglial morphology was also observed with ageing and neuroinflammation, that resembled reactive microglial morphology. Cholinergic cell morphology displayed visible effects of ageing and neuroinflammation with GFAP‐IL‐6 cohorts displaying patterns like neuronal degeneration.

Conclusion

These findings demonstrate a potential direct effect of chronic microglia activation on cholinergic cell number in the MS which can exacerbate throughout ageing leading to neurodegenerative impairments.
"Multi‐domain interventions for dementia prevention – A Systematic Review"
Authors: Castro Carolina B , Costa Lais , Dias Cintia B , Chen Juliana , Loo Ruey , Sohrabi Hamid R , Brown Belinda M , Martins Ralph N
Published: December 2021

Background

The increase in the ageing population is accompanied by increased rates of cognitive decline and dementia, which has a profound impact on both morbidity and mortality and a significant care‐related stress and financial burden. In the new global economy, dementia has become a central issue for public health in Australia. Dementia is the second greatest cause of death in Australia and about 60% of all dementia cases are due to Alzheimer’s disease (AD). In AD, damage starts occurring in the brain 20 to 30 years prior to any cognitive symptom. There is currently no cure for AD. However, the year between the start of its development and the appearance of symptoms represent a window of opportunity for implementing strategies to delay or prevent the progression of the disease through lifestyle interventions.

Method

The study will be conduct in two parts:

1) A systematic review based on multidomain interventions.

2) AU ARROW Intervention.

A comprehensive search of electronic databases (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus) will be performed to retrieve publications and alerts were set to identify publications until 31 august 2021.

Results

An expected positive outcome would give more evidence that lifestyle changes and if a single nutrient itself or a whole pattern as MIND DIET that are relatively easy to adopt, can help to prevent or delay brain function decline and dementia, such as Alzheimer’s disease dementia in an Australian population

Conclusion

a multidomain intervention focused on cognitive training, and nutritional and physical activity counselling seems decrease cognitive decline in older adults.
Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient‐derived pluripotent cell models
Authors: Minaya Miguel , Martinez Rita , Eteleeb Abdallah , Cruchaga Carlos , Harari Oscar , Karch Celeste M.
Published: December 2021

Background

Mutations in the microtubule‐associated protein tau (MAPT) cause heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD‐tau). Yet the pathogenic events linked to disease remain poorly understood. This study aimed to identify genes and pathways that lead to FTLD‐tau.

Method

To identify the earliest genes and pathways that are dysregulated in FTLD‐tau, we identified differentially expressed genes in RNA‐seq data generated from induced pluripotent stem cell (iPSC)–derived cortical neurons carrying MAPT R406W, MAPT P301L, and MAPT IVS10+16 and isogenic, controls and brain tissue samples from progressive supranuclear palsy (PSP) and control brains. We then identified pathological pathways and drug targets that were enriched among the differentially expressed genes.

Results

We identified 275 genes that were differentially expressed in iPSC–derived cortical neurons from MAPT R406W carriers compared to isogenic controls, MAPT IVS10+16 carriers compared to isogenic controls, and MAPT P301L carriers compared with isogenic controls. These commonly dysregulated genes were enriched for pathways involving synaptic function, neuronal development, and endolysosomal function. A subset of these genes were also changed in brains from human subjects with PSP compared to normal control brains. Finally, a subset of genes, enriched in glutamate receptor signaling, were altered across the mutant neurons and significantly changed with tau accumulation in a mouse model of tauopathy (Tau‐P301L mice).

Conclusion

The results from this study demonstrate that iPSC‐derived neurons capture molecular processes that occur in human brains and can be used to model disease and point to common molecular pathways driven by 3 distinct MAPT mutations
Investigating inflammatory responses in a corticosterone‐induced model of depression
Authors: Dunnett Sophie Louise , Chang Raymond Chuen‐Chung
Published: December 2021

Background

Major depressive disorder (MDD) is a prevalent neuropsychiatric condition, affecting approximately 264 million people worldwide. While various hypotheses have been proposed for MDD, the full extent of the neuropathology underlying depression has not yet been elucidated. Nonetheless, evidence suggests that inflammation is a key pathological feature underlying depression, and that inflammation can predispose individuals to developing depression. In this study, we utilised a corticosterone (CORT)‐induced model of depression in rats, since elevated glucocorticoids are an important feature of MDD. Using this model, we investigated the inflammatory changes that occur both systemically and in various brain regions, focusing on inflammatory cytokines and various markers of innate immune pathways. Additionally, we administered CORT for different durations to assess how the inflammatory status changes depending on the length of elevated CORT levels.

Methods

CORT or vehicle (sesame oil) is administered daily via subcutaneous injections to Sprague‐Dawley (SD) rats for 14, 21 or 28 days. Afterwards, various tissues samples including liver, kidney, frontal cortex, hippocampus, striatum, thalamus and hypothalamus are collected and processed for qPCR analysis. Additionally, tissue samples from the brain are collected and processed for immunofluorescence staining of GFAP and Iba1.

Results

Following 14 days of CORT administration, there are alterations to some of the inflammatory cytokines and markers of the innate immune system assessed in the liver, with no alterations to inflammatory markers in the brain. However, at 21 days there are increases in many of the inflammatory cytokines and innate immune markers assessed in both the liver and the kidney. Additionally, in the brain there are elevated levels of cytokines TNFa and Il1b in the striatum, IL1b in the thalamus and TNFa in the hypothalamus. At 28 days, many of the markers that were altered at 21 days return to baseline in the liver and kidney, though TNFa and IL1b in the kidney and IL1b in the liver remain elevated. Additionally, TNFa is elevated in the frontal cortex and striatum following CORT administration.

Conclusion

CORT administration impacts inflammation both in the periphery and in the brain. However, the alterations that occur depend on the duration of CORT administration and the tissue.
Evaluation of the effect of Donepezil hydrochloride on Ethanol‐induced hippocampal damage
Authors: Okhuevbie Daniel Ohiokhai , Awolaja Simbiat , Balogun Zainab
Published: December 2021

Background

Alcohol consumption has long been associated with brain damage. In particular, ethanol has direct effect on nerve cells and has been implicated in the progression of neurodegenerative diseases such as Alzheimer’s disease. Due to its high level of plasticity, the hippocampus is one of the most susceptible sites to neurotoxicity. The aim of this study was to evaluate the effect of a named cholinesterase inhibitor on ethanol‐induced brain damage

Method

Twenty‐one Wistar rats were placed into seven groups and housed in cages. They were fed with standard rat chow and water ad libitum. Six groups (groups A, B, C, D, E and F) were treatment groups and received ethanol while group G served as the control. Groups D, E and F received Donepezil hydrochloride after a week of ethanol administration while the first three groups continue to receive ethanol. After three weeks, the rats were dissected and the brain tissue were preserved in 10% formol saline. Histological examination was carried out on the hippocampus section using Haematoxylin and Eosin (H & E) staining procedure.

Result

The hippocampus was cut into sections and placed in a cassette. Findings revealed general degenerative changes in the treatment groups while the capillaries of the control group appeared without any form of congestion and microangiopathy. Group A specifically experienced autolysis while group F underwent glial cell vacuolation in response to neuronal cell injury induced by ethanol.

Conclusion

This study shows it is possible to ameliorate and probably reverse the neurotoxic effect of ethanol on the brain.
Auditory processing in AD: An EEG study
Authors: Georgalli Christina
Published: December 2021

Background

Alzheimer's disease is a progressive neurodegenerative disorder, which is associated with cognitive impairment, behavioral disorders and memory loss, among others (Andrade, Cortes, Guzman‐Martinez and Maccioni, 2017; Cortés, Andrade and Maccioni, 2018; Tarawneh and Holtzman, 2012). By 2050, nearly 14 million (13.8 million) Americans over age 65 could be living with the disease (Hebert, Weuve, Scherr and Evans, 2013), a fact that highlights the importance of identifying and discriminating biomarkers; the reason why the study is mainly conducted: to indicate whether or not auditory deficits occur in patients with Alzheimer's disease (AD) and memory deficits and hence to identify potential biomarkers.

Method

The study aims to compare measurements of amplitude for three different latencies which are between 0 and 50 ms, between 50 and 100ms and between 100 and 200ms for three different events such as new event, old event and difference between new and old event, using EEG data gathered from a specific memory task. Data have been collected from 136 participants based on two groups such as 73 participants belonged to the control group while 63 belonged to the patient group. The data were reliable and normal therefore analyzed with the help of t‐test.

Result

The results indicate that there is no significant difference between the control and patient groups at 0 to 50 amplitude latency. However, the study concluded a statistically significant difference between control and patient group at 50 to 100 and 100 to 200 ms amplitude latency.

Conclusion

EEGs with reduced levels of maladaptation reveal the presence of hidden neurodegenerative disorders and resistance to memory or psychiatric complaints such as depression and Alzheimer’s disease. The importance of EEG in diagnosing differences in common causes of dementia depends on specific clinical issues. The results of this study allow us to claim that such differences in amplitude latencies might contribute to our knowledge about auditory processing in AD and such knowledge could be beneficial as a diagnostic criterion of the disease in the future.
Targeted and untargeted mass spectrometry reveals impact of high fat diet on peripheral amino acid regulation in a mouse model of Alzheimer's disease
Authors: Taylor Amelia L , Davis Don E , Codreanu Simona G , Harrison Fiona E. , Sherrod Stacy D , McLean John A
Published: December 2021

Background

Mass spectrometry‐based metabolomics analyses were performed to examine metabolic changes under diet‐induced obesity in Alzheimer's Disease (AD) and assess whether these changes are reversible with diet modification. Specifically, amino acid metabolism was investigated because amino acid levels are related to obesity/diabetes and elevated levels have been shown to induce many of the pathophysiological hallmarks of AD.

Method

Targeted hydrophilic interaction liquid chromatography‐triple quadrupole mass spectrometry (HILIC‐MS/MS) and untargeted reversed‐phase liquid chromatography‐high resolution tandem mass spectrometry (RPLC‐HRMS/MS) assays were developed to analyze the metabolic changes that occur in AD and obesity. Frozen liver samples were obtained from a previously defined study, in which APPSwe/PS1ΔE9 (APP/PSEN1) transgenic mice (to represent familial or early‐onset AD) and wild‐type litter mater controls were fed either a high‐fat diet (HFD, 60% kcal from lard), low‐fat diet (LFD, 10% kcal from lard), or reversal diet (REV, high‐fat for 7.5 months followed by low‐fat for 2.5 months). Liver samples were collected after sacrifice and were prepared through homogenization and an established protein precipitation protocol.

Result

Multiple amino acids (including alanine, glutamic acid, leucine, isoleucine, and phenylalanine), carnitines, and members of the fatty acid oxidation pathway were significantly increased in APP/PSEN1 mice on HFD compared to LFD. More substantial effects and changes were observed in the APP/PSEN1 mice than WT mice, suggesting that they were more sensitive to a HFD. These dysregulated peripheral pathways include numerous amino acid pathways and fatty acid beta oxidation and suggest that obesity combined with AD further enhances cognitive impairment. These dysregulated peripheral pathways include pathways directly linked to the TCA cycle and mitochondrial dysfunction, which suggest that the HFD may contribute to AD pathogenesis by further contributing to this mitochondrial dysfunction. Furthermore, partial reversibility of many altered pathways was observed, which highlights that diet change can mitigate metabolic effects of AD. The same trends in individual amino acids were observed in both strategies, highlighting the biological validity of the results.

Conclusion

Our targeted and untargeted metabolomics results suggest that numerous peripheral pathways, specifically amino acid metabolism and fatty acid metabolism, were significantly affected in a combinatorial fashion by AD genotype and diet.
Role of tau protein on the photophysical properties of fluorescent carbon dots
Authors: Camilus Nayomi S , Lucas Sarah , Wu Colin , Naccache Rafik , Martic Sanela
Published: December 2021

Background

Globally, a number of individuals who live with Alzheimer’s disease (AD), an incurable and debilitating disease, is increasing. Tau protein has a structural role, maintains integrity of microtubules and is one of the underlying causes of the tauopathies [1]. It is unfolded and highly soluble under physiological conditions. However, tau protein undergoes post‐translational modifications like phosphorylation and aggregates causing cell death and spreading. In vitro, tau aggregation is typically evaluated using spectroscopic and microscopic methods.

Methods

Herein, we propose to evaluate the use of carbon dots, an important type of fluorescent nanoparticles, as potential probes for tau protein aggregation. Dual fluorescent carbon dots were used in combination with tau protein, prior and post aggregation. Aggregation of the longest isoform of tau441 was induced using heparin. The fluorescence spectroscopy was used to analyze photophysical properties of carbon dots as a function of monomeric and aggregated tau.

Results

The fluorescence quenching was observed for all protein containing samples, and was dependent on the aging time used for aggregation. The performance of carbon dots was compared to the standard Thioflavin T assay.

Conclusion

Data indicate that nanomaterials may be useful platforms for sensing application targeting biomarkers of neurodegenerative diseases.

References:

[1] a. Andronesi, O. C., Bergen, M. V., Biernat, J., Seidel, K., Griesinger, C., Mandelkow, E., & Baldus, M. (2008). Characterization of Alzheimer’s‐like paired helical filaments from the core domain of tau protein using solid‐state NMR spectroscopy. Journal of the American Chemical Society, 130(18), 5922‐5928.; b. Jeganathan, S., Hascher, A., Chinnathambi, S., Biernat, J., Mandelkow, E. M., & Mandelkow, E. (2008). Proline‐directed pseudo‐phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC‐1) conformation. Journal of Biological Chemistry, 283(46), 32066‐32076.
Association of pulmonary function with mild cognitive impairment and brain pathologies: a community‐based cohort study
Authors: Wang Jiao , Dove Abigail , Song Ruixue , Qi Xiuying , Ma Jun , Bennett David A. , Xu Weili
Published: December 2021

Background

The association of pulmonary function (PF) with mild cognitive impairment (MCI) and its underlying mechanisms remain unclear. We examined the association of PF with MCI and brain pathologies.

Method

Within the Rush Memory and Aging Project, the 1025 no cognitive impairment (NCI) participants (mean age: 79.41±7.77 years) were followed for up to 21 years to detect incident MCI. PF was assessed with a composite score based on forced vital capacity, forced expiratory volume in 1s, and peak expiratory flow measured at baseline, and further divided into tertiles (i.e., lowest, middle, and highest). MCI was diagnosed following standard criteria. During the follow‐up, 396 participants died and underwent autopsies for neuropathological assessment (including Alzheimer’s disease [AD], and vascular brain pathologies). Data were analyzed using Cox regression, Laplace regression, and Logistic regression.

Result

During the follow‐up (median 7 years, interquartile range 4‐10 years), 461 participants developed MCI. Compared to the highest PF, the multi‐adjusted HR (95% CI) was 2.07 (1.55‐2.78) for MCI. The median time from NCI to MCI development was 4.05 (95% CI: 2.78‐5.31) years shorter in people with the lowest PF than those with the highest PF. In the pathological data analysis, the lowest PF was significantly related to higher AD pathology (odds ratio [OR]: 1.45, 95% CI: 1.29‐1.62) and vascular brain pathologies (OR: 3.47, 95% CI: 1.50‐8.03) compared to the highest PF.

Conclusion

The lowest PF is associated with a 2‐fold risk of MCI and accelerates progression from NCI to MCI by more than 4 years. Both neurodegenerative and vascular mechanisms may underlie this association.
Preclinical modelling in the mouse of altered neuroinflammation in Alzheimer’s disease – Down syndrome
Authors: Mumford Paige , Noy Suzanna , Tybulewicz Victor L , Fisher Elizabeth , Hong Soyon , Wiseman Frances K
Published: December 2021

Background

People with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology, amyloid plaques and neurofibrillary tangles, by age 40 and the majority will develop dementia, due to having three copies of the chromosome 21 (Hsa21) gene APP leading to raised Aβ. How trisomy of the other Hsa21 protein‐encoding genes affects AD is unclear (1). People with DS have a perturbed immune system, with elevated pro‐inflammatory cytokines and an over‐activated interferon response (2,3). Several genes on Hsa21 have been implicated in inflammation differences in DS but how these genes modify neuroinflammation, an important aspect of AD, in AD‐DS is unknown. We are investigating how an extra copy of five Hsa21 candidate genes (RUNX1, IFNAR1, IFNAR2, IFNGR2, and IL10RB) modify neuroinflammation.

Method

Mouse models used had three copies of Hsa21 orthologous genes in the mouse, including our five candidate genes; the Dp2Tyb strain (three copies of ∼33 genes) and Dp1Tyb strain (three copies of ∼148 genes). Techniques used were qPCR, immunohistochemistry, and MSD immunoassay.

Result

The Dp1Tyb and Dp2Tyb brain has increased expression of Hsa21 candidate genes. The Dp1Tyb model has increased microglia number in the hippocampus, elevated levels of IL‐1β, and elevated Oas2, C3, and C1qa expression (n=11 wild‐type, n=10 Dp1Tyb). The Dp2Tyb model has elevated levels of interferon‐γ in the cortex but few changes to interferon‐stimulated genes (n=12 wild‐type, n=12 Dp2Tyb).

Conclusion

The Dp1Tyb and Dp2Tyb models have neuroinflammatory changes that reflect those seen in people with DS, though the phenotypes of the Dp1Tyb are more pronounced. The increased microglial number, IL‐1β levels, and neuroinflammatory genes found in the Dp1Tyb were not seen in the Dp2Tyb, suggesting these changes are due to gene(s) which are in three‐copies in the Dp1Tyb but not the Dp2Tyb. One such candidate gene is USP25, which was recently found to exacerbate neuroinflammation in a mouse model of amyloid pathology (4).

References: 1. Wiseman FK et al. Nat Rev Neurosci. 2015;16(9):564‐574. doi:10.1038/nrn3983 2. Sullivan KD et al. Elife. 2016;5:e16220. doi:10.7554/eLife.16220 3. Sullivan KD et al. Sci Rep. 2017;7(1):14818. doi:10.1038/s41598‐017‐13858‐3 4. Zheng Q et al. Sci Adv. 2021;7(1):eabe1340. doi:10.1126/sciadv.abe1340
Characterisation of the biophysical and cellular properties of Tau35, a disease‐associated tau fragment
Authors: Lyu Chen
Published: December 2021

Background

Tauopathies are characterised by the accumulation of intracellular tau aggregates in the brain. Tau inclusions contain various of truncated tau species, but the potential detrimental effects of these tau fragments are not well established. Tau35 is a C‐terminal fragment of wild‐type human tau, identified in tauopathy brain. We showed that minimal expression of Tau35 in transgenic mice recapitulates key features of tauopathy, including cognitive and motor dysfunction.

Method

We used small angle X‐ray scattering (SAXS), circular dichroism (CD), and transmission electron microscopy (TEM) to characterise the conformations of recombinant or aggregated Tau35 and full‐length (2N4R) tau. Tau assembly kinetics was monitored using Thioflavin T (ThT) and quantified. To assess cellular effects of tau, differentiated SH‐SY5Y cells (dSH) and mouse primary cortical neurons were exposed to Cy5‐labelled oligomeric tau and examined by immunofluorescence, western blots and live dead assay.

Result

SAXS analysis showed that both Tau35 and 2N4R tau display characteristics of intrinsically disordered monomeric proteins, with Tau35 exhibiting more restricted motions. ThT kinetics indicated that Tau35 is more prone to beta‐sheet formation and this was confirmed by CD and TEM analysis. Rapid uptake of aggregated Tau35 and 2N4R tau was observed by both dSH and mouse neurons. Internalised tau accumulates with time. However no significant cell death were observed with dSH.

Conclusion

Our results demonstrate that Tau35, a fragment associated with human tauopathy, exhibits increased aggregation and rapid uptake into neuronal cells, which likely impacts on tau propagation.
An investigative study to demonstrate the link between combined intake of marijuana and codeine in Alzheimer’s disease pathology
Authors: Memudu Adejoke Elizabeth , Waziri Ruth Joan
Published: December 2021

Background

Assessment of the contributory role of combined ingestion of codeine and Marijuana to the pathogenesis of Alzheimer’s disease which is the most common cause of dementia among older adults; by studying changes in spatial memory, astrocytic proliferation, Nissl bodies, lipid peroxidation and antioxidant enzyme status.

Method

Twenty (20) adult male Wistar rats used for this study were divided into four groups (n=5): the control, codeine, marijuana and a group given both codeine and marijuana. The animals were exposed to the drug treatment for ten (10) days. Behavioral tests for memory using Y maze was conducted. The animals were euthanized and brain tissues fixed in 4% PFA and processed for Cresyl fast Violet stain for Nissl bodies, glial fibrillary acidic protein (GFAP) immunohistochemistry for astrocytes with focus on prefronto‐hippocampus cortex. Serum antioxidant activity of superoxide dismutase (SOD), glucose‐6‐phosphodehydrogenase (G6PDH), Lactate dehydrogenase (LDH) activity and lipid peroxidation enzyme marker –Malondialdehyde (MDA) were accessed.

Result

The prefronto‐hippocampal cortex of rats exposed to Codeine, Marijuana (B and C) and those give both drugs (D) were characterized with loss of neurons, necrosis, chromatolysis and proliferation of astrocytes as compared with the control. However, combined drug use has more severity in the loss of loss of spatial memory, reduced number of arm entries and increased immobility time as compared with the control, codeine and Marijuana only groups. Group D, had severe decline in SOD and G6PDH serum activity and an elevation in lipid peroxidation as compared with B and C.

Conclusion

the combine use of codeine and marijuana has more deleterious effects on neuron cell integrity, memory, cognition and antioxidant enzymes because it induces severe oxidative stress that predisposes to the development of Alzheimer’s disease in an individual.
Openness and age influence the progression of mild cognitive impairment
Authors: Merlin Silvia Stahl , de Oliveira Maira Okada , Cassimiro Luciana , Avolio Isabella B , Brucki Sonia Maria Dozzi
Published: December 2021

Background

The characterization of risk factors for dementia and protective factors for the maintenance of healthy aging remains a relevant area for research. For this reason, the way people interact with the world around them and, therefore, some psychological and personality characteristics of individuals, seem to determine behavioral patterns that are associated with better health throughout life and, consequently, prevent the progression of early cognitive changes to dementia.

Method

One hundred and two volunteers were evaluated clinically and for personality characteristics and neuropsychological testing. Of these, 25 subjects were classified as cognitively normal (CN), 25 as subjective cognitive decline (SCD), 28 as non‐amnestic mild cognitive impairment (naMCI), and 24 as amnestic mild cognitive impairment (amMCI). Follow‐up occurred over two years from the initial assessment, and participants' cognitive categories were re‐analyzed every six months to observe variation in the same.

Result

Of the 102 subjects, 65 remained at follow‐up. The sample followed up longitudinally was composed predominantly of women (65%), white (74%), with a mean age of 78 (±7.5) years and 12 (±4.8) years of education. Throughout the process, 23% of CN, 15% of DCS, and 27% of CCLNA individuals worsened cognitively. In the same period, 15% of the CCLAM and 31% of the CCLNA improved in cognitive ratings. Using the contingency table to study associations of variables, it was observed that older ages present greater cognitive worsening (p=0.05), and that very low or high indices of the personality trait Openness present associations with cognitive worsening (p=0.005). Probably because the Open extremes are a product of the improper functioning of the Standard Mode Network.

Conclusion

The factors most associated with cognitive change in this group of elderly were age and the intensity of the Openness aspects of the personality.