bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of acculturation on psychological distress in Latino and Asian caregivers
Authors: Nguyen Julia Phuong , Hoang Diane , Zhou Kieran , Harvey Danielle J , Meyer Oanh L 
Published: December 2020

AbstractBackgroundMounting demands for caregiving and an increasingly diverse caregiver population have prompted several studies examining the role of cultural factors in caregiver outcomes. Little is known about how caregiving interacts with acculturation processes to affect mental health. We investigate the role of caregiving and acculturation factors on psychological distress among a diverse sample of adults.MethodUsing data from the 2009 California Health Interview Survey, the largest statewide survey in the nation, we examined whether acculturation [i.e., generational status (1st, 2nd, or 3rd) and language of interview (English or Spanish/Asian language)] and caregiving status were related to psychological distress (N = 14,189).ResultThe sample was 58.4% Latino, 34.5%Asian, and 7.1% Multiracial. Regression analyses indicated that first generation caregivers had significantly more distress than 1st generation individuals who were not caregivers (β=0.93, 95% CI: (0.20, 1.66), p=0.01); moreover, the difference in distress level between caregivers and non‐caregivers was smaller in the 3rd generation than in the 1st generation (β=‐1.06, 95% CI: (‐2.06, ‐0.07), p=0.04). Among non‐caregivers, those in the 3rd generation had more distress than those in the 1st generation (β=0.69, 95% CI: (0.15, 1.24), p=0.01). Additionally, caregivers had much higher levels of distress than non‐caregivers among those interviewed in a language other than English relative to those tested in English (β=1.14, 95% CI: (0.11, 2.18), p=0.03). The difference in distress was not quite significant between caregivers and non‐caregivers who were interviewed in English (β=0.42, 95% CI: (‐0.07, 0.91), p =0.09).ConclusionCaregiving status in first generation Latinos and Asians is associated with higher psychological distress. Differences in distress levels between caregivers and non‐caregivers was larger among first generation immigrants suggesting that being less acculturated further exacerbates caregiver distress. These results were further supported by acculturation as measured by language of interview. Results have significant implications for assessment and intervention in immigrant caregiver groups.
Diesel exposure and ApoE genotype interact to induce hippocampus‐dependent cognitive behavior deficits in a humanized mouse model
Authors: Mommer Brett C , Abel Glen , Storm Daniel , Xia Zhengui 
Published: December 2020

AbstractBackgroundIn humans the ApoE gene, particularly the ApoE4 allele, is the major risk factor for the development of Alzheimer’s Disease (AD) dementia. The allele’s incomplete penetrance indicates that environmental factors play an important part in disease development and, indeed, environmental exposures such as high doses of heavy metals have been shown to interact with ApoE in animal models, exacerbating AD‐typical cognitive decline. Epidemiological evidence suggests that other exposures, such as industrial and traffic‐related air pollution (TRAP) that human populations are commonly exposed to, is associated with cognitive decline and AD pathology in humans. Recent studies in mice show that exposure to diesel exhaust, a simulation of TRAP exposure, perturbs hippocampal gene expression, inhibits adult hippocampal neurogenesis, and impairs the formation of hippocampus‐dependent memory.MethodsIn this study we investigated, in male and female humanized ApoE‐KI mice, whether diesel exposure (DE) at a modest, human‐relevant concentration of particulate matter (PM2.5 under 200ug/m3) was sufficient to induce a deficit in the formation of hippocampus‐dependent short‐term spatial working memory in both the Novel Object Location (NOL) and Cued‐Contextual Fear tests, and whether ApoE genotype altered the timing or severity of the deficit.ResultsWe found that exposure leads to a deficit in both the hippocampus‐dependent NOL and contextual fear tests but not in the hippocampus‐independent, amygdala‐dependent cued fear test, and the onset and severity of the deficits depended on ApoE genotype. ApoE4 mice developed a DE‐induced deficit earlier than ApoE3 mice. Further, we found that ApoE2 mice experienced a DE‐induced deficit later than ApoE3 mice, supporting a protective role of ApoE2. The gene‐by‐environment interaction (GxE) also depended on sex, with the detrimental effect of ApoE4 most pronounced in males and the protective effect of ApoE2 most pronounced in females.ConclusionsThese findings, presented here first, suggest that the prevalence among human populations of widespread particulate matter exposures found to affect laboratory animals’ hippocampal function, coupled with human population‐level heterogeneity of ApoE alleles, could underlie a GxE between diesel and ApoE on the development of AD dementia.
Inhibition of the MSUT2: RNA interaction for the treatment of tauopathies
Authors: Baker Jeremy D , Kraemer Brian C 
Published: December 2020

AbstractBackgroundOur previous work revealed RNA binding protein MSUT2 drives tau‐mediated neurodegeneration and cognitive decline in mouse models of tauopathy. Therefore, we hypothesized that MSUT2 inhibitors could be therapeutic for tauopathy disorders. Here we have designed a drug‐discovery workflow for the identification of MSUT2 inhibitors to be used as tool compounds, potential therapeutic compounds, and to be used for probing the underlying MSUT2 mechanism of pathology.MethodWe employed a drug repurposing screening strategy for the identification of MSUT2 modifying compounds. We developed both fluorescent polarization and alpha assay screens for small molecule discovery from a well validated drug repurposing library. Our workflow included validation of hits by dose response analysis, specificity testing against MSUT2 binding partner PABPN1, orthogonal assays of activity, as well as testing for cytotoxicity.ResultScreening of a 700 compound drug repurposing library against MSUT2 activity resulted in a 1.7% hit rate for significant MSUT2 inhibitors. Subsequent validation studies presented narrowed these hits to 3 potential tool compounds with dose responsive activity and selectivity against MSUT2 with relatively low cytotoxic characteristics.ConclusionWork here serves as proof of principle strategy for finding inhibitors of the RNA‐binding protein MSUT2 for the treatment of tauopathies.
Persistent upregulation of brain phospho‐tau is accompanied by elevated hippocampal synaptic excitability and altered Ca2+ handling, following single or repeated closed‐head concussive impacts
Authors: McDaid John 
Published: December 2020

AbstractBackgroundTraumatic brain injury (TBI) is of widespread clinical concern and a significant risk factor for Alzheimer’s‐like dementia (AD). Notably, repeated concussions, vs. single concussions, have been shown to result in worsened and sustained neurological symptoms, including impaired cognition and histopathology similar to that observed in AD.MethodTo assess and compare the long‐term effects of single or repeated concussive impacts on phospho‐tau, an established marker of neurodegeneration, along with mediators of memory encoding such as synaptic transmission and plasticity, and cellular Ca2+ signaling, we utilized a closed‐head controlled cortical impact (CCI) approach which closely replicates the mode of injury in clinical cases. We examined rats 30 days post‐CCI to measure persistent injury effects. Groups received either a sham procedure, a single impact, or three successive impacts at 48 hour intervals. After 30 days, hippocampal slices were fixed and immunostained for phospho‐tau species, or prepared for 2‐photon Ca2+ imaging and electrophysiological recordings.ResultPhospho‐tau staining was elevated in the repeated concussion group, an effect which was accompanied by a decreased ryanodine receptor‐mediated Ca2+ response. In both concussion groups, hippocampal circuits showed increased synaptic responsivity upon Schaffer collateral stimulation compared to sham animals, indicating sustained hyperexcitability in hippocampal circuitry. This synaptic potentiation was not accompanied by LTP deficits, but basal Ca2+ and voltage‐gated Ca2+ signals were elevated in both concussion groups.ConclusionRepeated concussion may lead to a similarly persistent upregulation of phospho‐tau, along with upregulation of select excitatory hippocampal synapses, possibly through changes in postsynaptic Ca2+ signaling/regulation, which, along with the aberrant histopathology observed, may form a basis for the detrimental long‐term cognitive symptoms and conversion to AD.
A novel extract of Nerium oleander ameliorates neuroinflammation and amyloid plaques in the transgenic mouse model of Alzheimer’s disease
Authors: Lee Hyoung‐gon 
Published: December 2020

AbstractBackgroundThere have been numerous efforts for the development of the therapy for Alzheimer’s disease (AD) although effective treatment is not still available. Previous studies demonstrated the protective effect of PBI‐05204, a novel botanical extract of Nerium oleander, on oxidative damage and neuronal cell death. Both oleanolic acid and triterpenoids, the main constituent of both extracts, have been shown to modulate multiple cellular pathways including oxidative stress, inflammation, proliferation and apoptosis. Give that these neurotoxic mechanisms are pathologically linked with AD, the treatment of PBI‐05204 may be an effective therapy for AD. Thus, in this study, we examined its therapeutic effect on AD‐related pathological changes in the transgenic mouse model of AD to evaluate the therapeutic effect of PBI‐05204 on the pathological changes linked to AD.MethodWe treated the APP/PSEN1dE9 transgenic mice with PBI‐05204 for four months (4‐8 months of age) and examined neuropathological changes such as Aβ accumulation and neuroinflammation using immunohistochemistry and immunoblot assay.ResultIn our analysis, we found that Aβ plaques were significantly reduced by the treatment of PBI‐05204 compared to the control group. Furthermore, the treatment with PBI‐05204 significantly reduced neuroinflammation, which is evidenced by the reduced activation of microglia and astrocytes.ConclusionCollectively, our data clearly indicate that the treatment of PBI‐05204 reduces Aβ pathology and neuroinflammation in APP/PSEN1dE9 transgenic mouse model, suggesting the therapeutic potential of PBI‐05204 for the treatment of AD.
Disruptions in transposable elements and gene networks occur before the onset of tauopathy in a humanized mouse model of AD
Authors: de Evsikova Caralina Marin , Evsikov Alexei 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) is an age‐related neurodegenerative disorder culminating in dementia with additional non‐cognitive behavioral and metabolic symptomatology such as hyperactivity and altered sleep/wake patterns, which promote weight loss. In demented patients weight loss is associated with adverse outcomes, including accelerated AD progression and higher institutionalization. Mouse models of tau deposition, such as Tg4510 mice, also have negative energy balance. Tg4510 mice, which express a P301L mutant variant of human tau, develop both cognitive and non‐cognitive symptoms. To identify early pre‐symptomatic factors affecting AD, we analyzed RNA‐seq data from young, pre‐tauopathic Tg4510 mice to identify gene and transposable elements (TE) expression changes that may initiate the behavioral and metabolic derangements in AD.MethodsWe analyzed RNA‐seq from hippocampi of 2 month old Tg4510 mice (n=5) vs. controls (n=6). Using our established TTESA pipeline, reads were aligned to reference genome and measured gene expression or TEs with featureCounts. Pathway enrichment analysis using Visual Annotation Display was used to discover common functional themes using Gene Ontology and Mammalian Phenotype Ontology.ResultsTTESA results detected the majority of significantly differentially expressed TEs were retrotransposons (68%), which consisted mainly of long terminal repeats (LTRs; 70%) and some LINE retroelements (30%) in young transgenic mice. VLaD pathway analysis revealed several biological processes upregulated in transgenic mice, including defense, inflammation, and immune system processes and related categories of myeloid leukocyte activation and aggregation, cytokine production, T cell activation, B cell activation, regulation of natural killer cells, regulation of IL‐6 and TNF production, and TLR3 signaling. Likewise, genes invoked in the defense response to virus, were significantly increased. Notably, downregulation of genes associated with brain developmental processes, such as synaptic signaling, regulation of long‐term synaptic depression, chemical synaptic transmission, and neuronal structures, such as neuronal projections, proximal dendrites, and presynaptic membranes. Lastly, non‐cognitive behavioral pathways were downregulated, such as the regulation of circadian sleep/wake cycle.ConclusionsBased on our data, we conclude that early dysregulation of TEs may act as initial trigger altering neural gene expression networks underlying neuronal development, behavioral, cellular defense mechanisms and immune responses to viruses in this humanized mouse model of AD.
Personalized repetitive transcranial magnetic stimulation for non‐fluent and semantic variants of primary progressive aphasia
Authors: Pytel Vanesa , Cabrera‐Martín María Nieves , Delgado‐Álvarez Alfonso , Ayala José Luis , Balugo Paloma , Fuertes Miguel Yus , Carreras María Teresa , Moreno‐Ramos Teresa , Carreras José Luis , Matias‐Guiu Jorge , Matias‐Guiu Jordi A 
Published: December 2020

AbstractBackgroundPrimary progressive aphasia (PPA) is a neurodegenerative syndrome characterized by the neurodegeneration of language brain regions and networks. As in many other neurodegenerative disorders, effective treatments are lacking or have limited efficacy. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a potential treatment for many neurological and psychiatric disorders, and lately also for neurodegenerative disorders. We aimed to assess the effect of rTMS, on language, global cognition, neuropsychiatric symptoms, and brain metabolism in patients with PPA using a personalized target.MethodsWe conducted a randomized, double‐blind, pilot study of patients with PPA receiving rTMS. Simple randomization was used to separate patients into 2 groups with a 3:2 ratio: i) active‐site rTMS therapy only (n = 12); ii) a cross‐over group (n = 8). In the latter group, subjects were randomly allocated 1:1 to receive therapeutic rTMS followed by control‐site rTMS, or vice versa. Fifteen sessions of neuronavigated rTMS with personalized targeting were delivered. The primary outcome was changes in spontaneous speech (word count using a story description task). Secondary outcomes included changes in other language tasks (object naming, story reading task, repetition), global cognition (Addenbrooke’s Cognitive Examination), global impression of change (patient and caregiver), neuropsychiatric symptoms (Neuropsychiatric Inventory), and brain metabolism (FDG‐PET).ResultTwenty patients with PPA were enrolled (14 with nonfluent and 6 with semantic variant PPA). Compared to the control group, the group receiving active‐site rTMS showed improvements in spontaneous speech, other language tasks, patient and caregiver global impression of change, apathy, and depression. This group also showed improvement or stabilization of results obtained in the baseline examination. Increased metabolism was observed in several brain regions after the therapy, particularly in the left frontal and parieto‐temporal lobes and in the precuneus and posterior cingulate bilaterally.ConclusionOur findings suggest that high‐frequency rTMS with personalized targeting improves language, patient and caregiver perception of change, apathy, and depression. The finding of increased regional brain metabolism suggests enhancement of synaptic activity with the treatment. This study provides a rationale and supports the consideration for conducting a phase III randomized clinical trial using rTMS in PPA.
Connecting patients and families by a tablet on wheels during the time of COVID‐19 pandemic
Authors: Hung Lillian 
Published: December 2020

AbstractBackgroundPeople staying in hospitals need more support to cope with the lock down and visitor restriction during the COVID‐19 pandemic, especially for older people with cognitive or physical impairment. Everyday technology such as a touchscreen tablet has great potential to support person‐centred care. Aims: We aimed to support the adoption of tablets for hospitalized people with dementia to connect with families and friends.MethodsA patient‐oriented research approach was employed to co‐produce the toolkit. We are a transdisciplinary team, including a medical student, physicians, nurses, patients, and family partners. We facilitated staff focus groups (n = 3), and conducted stakeholders' interviews (n = 4) to gain a more comprehensive understanding of users' needs. The sample included ten patients, ten family members, 40 staff members, nurses, care workers, physicians, and unit clerks (n = 40). The Consolidated Framework for Implementation Research (CFIR) guided the research design and qualitative analysis.ResultsA toolkit was developed based on participants’ perspectives on what needs to be in place to support successful adoption. We developed a mobile tablet with one mechanical arm and one leg on wheels. Participants reported impacts: (a) it puts a smile on the patient’s face, (b) it alleviates anxiety and worries on both sides, and (c) it reduces responsive behaviours.ConclusionsThe conceptual framework CFIR provides helpful guidance in identifying barriers to implementation. Working with users including patient and family partners to explore possible solutions was key to our success. Future research should engage patient and family partners to seek proactive strategies to address obstacles to advance the science of technology implementation.
Quantification of neurological blood‐based biomarkers in critically ill patients with COVID‐19
Authors: Cooper Jennifer , Stukas Sophie K , Hoiland Ryan , Thiara Sonny , Foster Denise , Mitra Anish , Panenka William J , Sekhon Mypinder S , Wellington Cheryl L 
Published: December 2020

AbstractBackgroundMultiple neurological manifestations of COVID‐19 have been reported such as headache, anosmia, ischemic stroke, and cerebral hemorrhages. Objective characterization of the acute neurological damage in critically ill patients with COVID‐19 has not yet been reported.MethodWe performed a prospective observational study of plasma brain biomarkers in critically ill patients with respiratory failure that were diagnosed with (COVID‐19) or without (ICU control) COVID‐19. Demographics, co‐morbidities, daily clinical physiologic and laboratory data were collected. Plasma samples were drawn for measurement of neurofilament‐light chain (NF‐L), total tau (t‐tau), ubiquitin carboxy‐terminal hydrolase L1 (UCH‐L1), and glial fibrillary acidic protein (GFAP). The primary neurological outcome was delirium as defined by the intensive care delirium screening checklist (ICDSC, scale 1 ‐ 8). Associations between brain biomarkers and markers of respiratory failure of COVID‐19 were analyzed.Result27 patients with COVID‐19 and 19 ICU controls were enrolled. The concentration of plasma GFAP, UCH‐L1 and NF‐L levels was higher in both groups compared to healthy controls. Compared to ICU controls, patients with COVID‐19 had significantly higher GFAP (272 [150‐555] pg/ml vs 118 [78.5‐168] pg/ml, p=0.0009). In patients with COVID‐19, GFAP (rho=0.5115, p=0.0064), UCH‐L1 (rho=0.4056, p=0.0358) and NF‐L (rho=0.6223, p=0.0005) were positively correlated with the ICDSC score and were higher in patients diagnosed with delirium (ICDSC ≥4) in the COVID‐19 group but not ICU controls. There were no associations between PaO2/FiO2 or diagnosis of ARDS and plasma concentration of GFAP, t‐tau, UCH‐L1, or NF‐L in patients with COVID‐19.ConclusionPlasma GFAP is 2‐fold higher in critically ill patients with COVID‐19 compared to ICU controls, and higher concentrations of GFAP, UCH‐L1 and NF‐L are associated with delirium specifically in patients with COVID‐19.
Efficacy and safety of AXS‐05, a novel, oral, NMDA‐receptor antagonist with multimodal activity, in agitation associated with Alzheimer’s disease: Results from ADVANCE‐1, a phase 2/3, double‐blind, active and placebo‐controlled trial
Authors: O'Gorman Cedric , Jones Amanda , Cummings Jeffrey L. , Tabuteau Herriot 
Published: December 2020

AbstractBackgroundAXS‐05 (dextromethorphan/bupropion modulated delivery tablet) is a novel, oral, non‐competitive NMDA receptor antagonist with activity on other neurotransmitter systems (sigma‐1, serotonin, norepinephrine, and dopamine) which have been implicated in the cognitive and behavioral abnormalities of Alzheimer’s disease (AD). Up to 70% of patients with AD experience agitation. AD agitation is associated with accelerated cognitive decline, early institutionalization, increased mortality, and increased caregiver burden. There are no approved pharmacological treatments for AD agitation.MethodThe ADVANCE‐1 trial was a Phase 2/3, randomized, double‐blind, controlled, 5‐week study of AXS‐05 in AD agitation. Patients were randomized to treatment with AXS‐05, placebo, or bupropion. The primary endpoint was the change from baseline in the Cohen Mansfield Agitation Inventory (CMAI). The modified Alzheimer’s Disease Cooperative Study‐Clinical Global Impression of Change for Agitation (mADCS‐CGIC) was a key secondary endpoint.Result366 AD patients with clinically significant agitation were randomized to AXS‐05 (n = 159), bupropion (n = 49), and placebo (n = 158). On the primary endpoint, AXS‐05 significantly relieved agitation, demonstrating a change from baseline in the CMAI total score of 15.4 compared to 11.5 for placebo (p = 0.010) and 10.0 for bupropion (p<0.001). These results represent a mean percentage reduction from baseline of 48% for AXS‐05 versus 38% for placebo. AXS‐05 was numerically superior to placebo starting at Week 2, achieving statistical significance at Week 3 (p = 0.007) only one week after full dosing with AXS‐05. AXS‐05 demonstrated clinical response (≥30% improvement on the CMAI) in 73% of patients compared to 57% for placebo (p = 0.005). AXS‐05 demonstrated statistically significant improvements in agitation as compared to placebo on the mADCS‐CGIC (p = 0.036). The most commonly reported AEs with AXS‐05 were somnolence (8.2% AXS‐05, 4.1% bupropion, 3.2% placebo), dizziness (6.3%, 10.2%, 3.2%, respectively), and diarrhea (4.4%, 6.1%, 4.4%, respectively). There was no evidence of cognitive decline or sedation with AXS‐05.ConclusionIn the ADVANCE‐1 Phase 2/3 trial, AXS‐05 rapidly, substantially, and significantly improved agitation in patients with AD as compared to placebo. AXS‐05 was well tolerated and not associated with cognitive decline or sedation.