bluuebunny/crossref_metadata_2025_split 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

AbstractBackgroundAD 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.MethodsThis 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.ResultsThe 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.ConclusionsHOPE4MCI 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

AbstractBackgroundSubclinical 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.MethodSeventeen 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.ResultIn 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).ConclusionPreliminary 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

AbstractBackgroundCOVID‐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.MethodAs 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.ResultNfL 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.ConclusionNfL 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

AbstractBackgroundPrior 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

AbstractBackgroundDiagnostic 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.MethodsALTOIDA‐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).ResultsThe 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.ConclusionsALTOIDA‐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

AbstractBackgroundGenetic screening was performed by Drosophila melanogaster to observe how different variants of HDAC6 regulate tauR406W mediated neurodegeneration.MethodThe 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.ResultOn 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.ConclusionHDAC6 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

AbstractBackgroundThe 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.MethodThe 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.ResultThe 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)ConclusionThe 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

AbstractBackgroundSynucleinopathies 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.MethodIn 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.ResultSignificantly 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.Conclusionα‐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

AbstractBackgroundScientific 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.MethodsThe 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.ResultsAs 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.ConclusionsFive 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

AbstractBackgroundPathological 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.MethodAged, 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.ResultStereological 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.ConclusionThese 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

AbstractBackgroundThe 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.MethodThe 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.ResultsAn 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 populationConclusiona multidomain intervention focused on cognitive training, and nutritional and physical activity counselling seems decrease cognitive decline in older adults.