bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of sex and diet in hypothalamic disturbances in wild‐type mice and the 3xTg‐AD mouse model of familial Alzheimer’s disease
Authors: Robison Lisa S , Gannon Olivia J , Salinero Abigail E , Thomas Melissa A , Zuloaga Kristen L
Published: December 2020

Background

Hypothalamic dysfunction occurs early in the clinical course of Alzheimer’s disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observable years prior to the onset of cognitive symptoms. Late‐life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high fat diet and metabolic disease (e.g. obesity, type 2 diabetes), particularly in mid‐life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two‐thirds of AD patients, we sought to determine whether these relationships may vary by sex.

Methods

WT and 3xTg‐AD male and female mice were fed a control (10% fat) or high fat (HF; 60% diet) diet from ∼3‐7 months of age, then tested for metabolic and hypothalamic disturbances.

Results

On control diet, male 3xTg‐AD mice displayed increased expression of genes indicative of inflammation in the hypothalamus, including Iba1 (+34%), GFAP (+53%), TNF‐α (+46%) and IL‐1β (∼6‐fold increase) compared to WT. Male 3xTg‐AD mice on control diet also model what is seen clinically in AD in terms of metabolic disturbances (decreased body weight, reduced fat mass, hypoleptinemia). In contrast, female 3xTg‐AD mice on control diet displayed metabolic disturbances opposite that of 3xTg‐AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin), though HF diet alone did not alter hypothalamic expression of inflammatory markers in WT mice, nor did it exacerbate hypothalamic inflammation in 3xTg‐AD males. HF diet resulted in the greatest metabolic disturbances in 3xTg‐AD females, in addition to markedly increased hypothalamic expression of GFAP and IL‐1β (+99% and ∼5‐fold increase, respectively, vs. WT control females).

Conclusions

These findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg‐AD mouse model appears to be dependent on both sex and diet.
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

Background

Mounting 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.

Method

Using 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).

Result

The 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).

Conclusion

Caregiving 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

Background

In 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.

Methods

In 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.

Results

We 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.

Conclusions

These 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

Background

Our 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.

Method

We 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.

Result

Screening 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.

Conclusion

Work 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

Background

Traumatic 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.

Method

To 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.

Result

Phospho‐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.

Conclusion

Repeated 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

Background

There 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.

Method

We 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.

Result

In 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.

Conclusion

Collectively, 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

Background

Alzheimer’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.

Methods

We 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.

Results

TTESA 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.

Conclusions

Based 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

Background

Primary 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.

Methods

We 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).

Result

Twenty 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.

Conclusion

Our 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

Background

People 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.

Methods

A 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.

Results

A 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.

Conclusions

The 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

Background

Multiple 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.

Method

We 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.

Result

27 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.

Conclusion

Plasma 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

Background

AXS‐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.

Method

The 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.

Result

366 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.

Conclusion

In 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.
A study based on the embodied emotion approach: The recognition of whole‐body social emotions and postural control in Alzheimer's disease dementia, Parkinson's disease and healthy control
Authors: Martínez‐Pernía David , Rivera‐Rei Álvaro , Forno Gonzalo , Troncoso Alejandro , Aravena Oliver , Vergara Mayte , Silva Victoria , Carrera Valentina , Calderón Jorge , Cea Ignacio , Henriquez Fernando , Lillo Patricia , Villagra Roque , Slachevsky Andrea
Published: December 2020

Background

Alzheimer's disease dementia (ADD) and Parkinson's disease (PD) have a significant impairment in social emotion recognition. Most of these studies assess emotional perception as the ability to identify others' facial emotions (Ekman faces). Nevertheless, emotional recognition with information that integrates whole‐body and postural control responses has not been investigated in ADD or PD.

Method

66 participants were recruited (ADD, PD, healthy controls (HC)). Subjects were diagnosed following NINCDS‐ADRDA criteria for ADD, and the United Kingdom Parkinson's Disease Society Brain Bank criteria for PD. Inclusion criteria considered older than 60 years and non‐other neuropsychiatric comorbidity. All participants were assessed in global cognition (ACE‐III), executive function (IFS, FAS), memory (FCRST), and social cognition (Minisea (Faux Pas (FP), Ekman faces (EF)). Three videos were elaborated with persons practicing risk sports (neutral, pleasant, unpleasant); and another unpleasant condition that did not show a human body (car accidents). Videos were previously validated by their emotional properties (120 subjects) following the Self‐assessment Manikin. Participants stood up at a force platform while videos (60 seconds) were presented at a TV screen (40 inches) at face height and 1 meter to the front. Postural control data to compute center of pressure (COP) were collected at a sample rate of 125Hz. At the end of each video, participants had to rate (1‐9) valence, intensity, and control. COP parameters included velocity, area, and frequency decomposition. Statistical analysis was performed on the first principal component (PC1) on those parameters. Emotional recognition was analyzed by ANOVA (3*3) (group*self‐perception), and postural data by Repeated‐Measures ANOVA (3*4) (group*emotional condition).

Result

Participants with ADD(n=25) show significant impairment in all cognitive domains assessed even when FP was adjusted for control questions, compared to PD(n=14) and HC(n=27). ADD showed significant differences in the recognition of whole‐body negative emotions (6,04+2,752), compared to PD (3,71+2,585) and HC (4,19+2,286). When postural control responses were analyzed, the pleasant condition showed significantly bigger displacements (PC1) than the other emotional conditions.

Conclusion

ADD participants have problems recognizing negative social emotions that involve whole‐body. Emotional stimuli produce changes similar in postural control among groups, which depend on emotional conditions. These results suggest studying the emotion beyond facial emotion.
Longitudinal network connectivity measurements in medial temporal lobe subregions discriminate preclinical Alzheimer’s from amyloid‐β negative controls
Authors: Khandelwal Pulkit , Xie Long , Bassett Danielle S , de Flores Robin , Wolk David A , Yushkevich Paul A , Das Sandhitsu R
Published: December 2020

Background

Finding sensitive outcome measures for disease progression in clinical trials of preclinical Alzheimer’s disease (AD) remains challenging. We hypothesize that longitudinal network connectivity measurements of the medial temporal lobe (MTL) subregions, sites of earliest tau pathology, are more sensitive to progression at early stages than annualized subregional atrophy rates, thus, increasing power to detect a significant effect in a shorter timeframe.

Method

Longitudinal T1‐weighted MRI scans of 229 amyloid‐β negative (Aβ‐) controls and preclinical AD (Aβ+ controls) from ADNI were included (Table 1). Anterior/posterior hippocampus, entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36, and parahippocampal cortex (PHC) were segmented in baseline MRI (Figure 1, Xie et al. 2019). Deformation‐based morphometry was used to obtain follow‐up volume measurements, which were subsequently entered in a linear regression to estimate an annualized atrophy rate for each subregion. The network measurements of strength, clustering coefficient, and local efficiency (Soto et al. 2016) were obtained from an adjacency matrix (Figure 1) whose elements represented inter‐regional covariance in volume measurements over time. At least three time points were used for each subject. The preclinical AD group was compared to the Aβ‐ controls with ANCOVA and Bonferroni correction, using age as a nuisance covariate. We compared the discriminative power of the network measurements against the atrophy rates for follow‐up MRI scans within 4, 2 and 1.5 years from baseline.

Result

Discriminative ability of both atrophy rates and network measurements diminishes with decreasing number of follow‐up scans. However, at least one network measurement was still significantly stronger, in absolute terms, than atrophy rates for all three follow‐up scan time periods (Tables 2,3,4, Figure 2). Even with short follow‐up (<1.5 years), a number of network measures were significant while atrophy rate was not (Table 4).

Conclusion

The longitudinal network measurements of the MTL subregions are sensitive to disease progression in preclinical AD to a greater extent than longitudinal atrophy rates, perhaps because they account for inter‐region interactions in the network which may capture covariance patterns relevant to the neurodegenerative process. As a result, they may serve as efficient outcome measures in clinical trials, potentially allowing treatment effects to be detected earlier.
Sensitive biomarkers to Alzheimer's disease progression in longitudinal MRI from deep learning
Authors: Dong Mengjin , Xie Long , Wang Jiancong , Das Sandhitsu R , Wolk David A , Yushkevich Paul
Published: December 2020

Background

In clinical trials of disease‐modifying treatments of Alzheimer’s disease (AD), the measure of hippocampus volume change from longitudinal MRI is a well‐studied biomarker of disease progression. However, even the most sensitive longitudinal MRI measures can be confounded by the presence of motion and susceptibility artifacts. We hypothesize that deep learning can be used to differentiate MRI changes due to biological factors (tissue loss) from changes due to artifact and other non‐biological factors, leading to novel biomarkers that are more sensitive to longitudinal change that can accurately evaluate disease progression.

Method

357 subjects (142 training, 215 test) with 3‐8 longitudinal T1‐weighted MRI scans (0.5 to 5.5 years) were selected from ADNI2/GO (Table 1), including cognitively normal (CN), amyloid negative (A‐) older adults, preclinical AD (A+ controls), and A+ patients with early and late mild cognitive impairment (eMCI, lMCI). For each subject, pairs of scans were rigidly registered and trimmed around the hippocampal region. A 3D convolutional neural network (CNN3D) (He et al., 2015) was trained to detect the correct temporal order of arbitrarily ordered input pairs from the same subject and for two pairs of same‐subject images as input, to detect which pair had a longer interscan interval (Figure 1). The successful detection of the temporal order of scans would suggest that the network can capture only time‐induced biological change and ignore non‐biological factors that are independent of time. The results were compared to ALOHA, a deformation‐based morphometry algorithm for quantifying hippocampal change (Das et al., 2012).

Result

CNN3D extracted the temporal order of MRI scans much more accurately than ALOHA (Table 2, 3) and the CNN3D‐derived longitudinal change measure was more sensitive than ALOHA in differentiating healthy aging (A‐ CN) and preclinical AD (A+ CN) (Figure 2). CNN3D can also detect change in a shorter period of time (Figure 3).

Conclusion

CNN3D inferred the temporal order of longitudinal MRI scans, suggesting its ability to pinpoint true biological changes that correlate with time better than registration‐based approaches. Deep‐learning‐based MRI change detection may emerge as a more powerful disease progression biomarker for disease‐modifying clinical trials in AD.
Lycium barbarum extracts preserve retinal function by rescuing synaptic loss in 3XTG mouse model of Alzheimer’s disease
Authors: Liu Jinfeng , Xiong Guoying , Lin Youhong , Chang Raymond Chuen‐Chung , So Kwok‐Fai , Chiu Kin
Published: December 2020

Background

Ocular abnormalities were reported in patients with Alzheimer’s disease (AD). The Lycium barbarum extracts (LBE) have been demonstrated to be neuroprotective. The current study aim to investigate the effect of oral feeding LBE on structural and functional changes of retina in the 3xTg AD mouse model.

Method

6 months old 3xTg‐AD and C57/6J mice were treated by gavage with low (200mg/kg) or high (2g/kg) doses of LBE daily for 3 months, while water treatment was used as a placebo control. Retinal function was evaluated by electroretinogram (ERG). Mice were sacrificed after 3 months of treatment, and the eyes were harvested. Morphological changes of the retina were analyzed in cross‐sections. Expressions of synaptophysin, PSD95, 8‐OHG, Calpain2, and Calpain5 were detected by Immunohistochemical staining.

Result

ERG results showed that the scotopic retinal response of 3xTg‐AD mice started to decline at 4–6 months of age, followed by a rapid decrease at 6–8 months of age. In this study, one month high doses LBE gavage group showed a significant increase of b‐wave in scotopic ERG. The same tendency of b‐wave preservation was observed at two months post high doses LBE feeding without statistical significance and vanished at three months (9 months of age). In 9 months old AD mice, no significant changes were observed in inner nuclear layer (INL) thickness and outer nuclear layer (ONL) thickness compared to age‐matched C57 mice. Accordingly, there were no significant differences in retinal ganglion cell and bipolar cell numbers between AD mice and C57 mice. However, presynaptic density in INL but not ONL was decreased in AD mice. This synapse loss could be rescued by LBE feeding with significance in high dose. IHC staining revealed highly expressed 8‐OHG, Calpain2 and Calpain5 in AD mice, which were downregulated by LBE feeding in a dose dependent manner.

Conclusion

Our results indicated that at early‐ and mid‐stage of AD, presynaptic changes in IPL contributed to b‐wave decline and LBE gavage could rescue the retinal functional deterioration in 3xTg AD mice by preventing the synapse loss in IPL through inhibiting oxidative stress and lowering Ca2+ in retinas.
Raising our voices: The impact of a dementia choir on well‐being and quality of life
Authors: Sheets Debra J , Smith Andre P , MacDonald Stuart
Published: December 2020

Background

The benefits of non‐pharmacological interventions for PwAD that maintain or improve function in ADLs, cognition and reduce behavioural symptoms have been well‐documented (Sampath, Forbes, Barton, & Blake, 2015).4 Strategies to slow the progression of AD (protective factors) have emphasized healthy diet, aerobic exercise, active social life, and cognitive stimulation (Wong, Gilmour & Ramage‐Mori, 2016)). Arts‐based approaches to dementia prevention are unique in shifting the attention from disease‐related declines and losses toward innovation and creative action. Examples include sensory stimulation such as music therapy (McDermott, Crellin, Ridder, Orrell, 2013; Keeler, et al., 2015; Harris & Caporella, 2014), art therapy including movement/dance and painting, cognitive engagement and physical activities (Williams, Plassman, Burke, Benjamin, 2010), and psychosocial interventions such as one‐on‐one socializing. Stigma represents one of the biggest barriers to living well with dementia following diagnosis (Alzheimer’s Association, 2019). Social isolation is common as roles, friendships and opportunities to participate in the broader community disappear. An intergenerational dementia choir that focuses on strengths rather than losses and offers opportunities for learning, friendships and purposeful engagement towards common goals (e.g., regular social engagement, public concerts at season’s end).

Method

Persons with dementia (n = 32), in partnership with their family caregivers (n=32) and local high school students (n=29), sang in a professionally conducted choir for as many as three seasons (∼ 12 weeks long) spanning up to 18 months of follow‐up. Assessments of psychosocial, physiological, and cognitive function were completed every four to six weeks as part of an intensive repeated measures design.

Result

Findings indicate that this novel lifestyle intervention offers an effective non‐pharmacological alternative approach for older adults with dementia. Choir participation has important and significant impacts on psychosocial well‐being and quality of life. Both caregivers and PwD experienced reductions in health risks and improvements in quality of life. Students’ understanding of dementia became more positive over time and new friendships developed.

Conclusion

The discussion focuses on policy implications and the need for meaningful and inclusive community‐based programs for PwD and their caregivers.
Utility of MRI in the identification of hippocampal sclerosis of aging
Authors: Woodworth Davis C. , Nguyen Hannah L. , Khan Zainab , Kawas Claudia H. , Corrada María M. , Sajjadi S. Ahmad
Published: December 2020

Introduction

Hippocampal sclerosis of aging (HS) is a common pathology often misdiagnosed as Alzheimer's disease. We tested the hypothesis that participants with HS would have a magnetic resonance imaging (MRI)‐detectable hippocampal pattern of atrophy distinct from participants without HS, both with and without Alzheimer's disease neuropathology (ADNP).

Methods

Query of the National Alzheimer's Coordinating Center database identified 198 participants with MRI and autopsy. Hippocampal subfields were segmented with FreeSurfer v6. Analysis of covariance for subfield volumes compared HS+ participants to those without HS, both with ADNP (HS–/ADNP+) and without (HS–/ADNP–).

Results

HS+ participants (N = 27, 14%) showed atrophied cornu ammonis 1 (CA1; leftP < .001, ηp2 = 0.14; rightP = .001, ηp2 = 0.09) and subiculum (leftP < .001, ηp2 = 0.139; rightP = .001, ηp2 = 0.085) compared to HS–/ADNP+ (N = 100, 51%). Compared to HS–/ADNP– (N = 71, 36%), HS+ also had atrophy in subiculum (leftP < .001, ηp2 = 0.235; rightP = .002, ηp2 = 0.137) and CA1 (leftP < .001, ηp2 = 0.137; rightP = .006, ηp2 = 0.070).

Discussion

Subiculum and CA1 atrophy from clinical MRI may be a promising in vivo biomarker for HS.
Quantitative Mapping of Glutathione within Intracranial Tumors through Interlocked MRI Signals of a Responsive Nanoprobe
Authors: Zhang Peisen , Zeng Jianfeng , Li Yingying , Yang Chen , Meng Junli , Hou Yi , Gao Mingyuan
Published: December 2020

Studies reveal that malignant tumors feature uneven distributions of some key biomarkers across the entire tumorous region. Nevertheless, only very limited progress has been made towards non‐invasive and quantitative detection of tumor‐specific biomarkers in vivo, especially with clinically compatible imaging modalities. Reported here is an Fe3O4 nanoparticle‐based glutathione (GSH) responsive magnetic resonance imaging (MRI) probe that can form particle aggregates within tumors in vivo to give rise to strong GSH concentration dependent interlocked relaxivities. A quantitative correlation between the interlocked MRI signals and local GSH concentration was established, and further applied for mapping the heterogeneous distribution of GSH within an intracranial tumor (2.4 mm × 1.6 mm) in vivo. This methodology will offer a practical route for quantitatively mapping tumor‐specific biomarkers in vivo with unlimited detection depth, which largely challenges optical‐imaging‐based approaches.
Influence of PTFE as a solid lubricant on the mechanical, electrical, and tribological properties of CF‐reinforced PC composites
Authors: Shamsuddin Muhamad Syukri Mohamed , Othman Ainur Hanim , Nasir Ramdziah Md , Hassan Aziz , Senawi Rozaimi , Thirmizir Mohd Zharif Ahmad , Ishak Zainal Arifin Mohd
Published: December 2020

The objective of this research was to study the effects of polytetrafluoroethylene (PTFE) as a solid lubricant on the mechanical, electrical, and tribological properties of carbon fiber (CF)‐reinforced polycarbonate (PC) composites. Samples were prepared by means of single‐screw extrusion and injection molding processes. The mechanical tests included tensile, flexural, and failing weight impact tests, while the electrical tests consisted of surface and volume resistivity tests. The tribological testing was conducted under dry sliding conditions using pin‐on‐disk configuration. The results showed that the addition of CF managed to significantly reduce the electrical resistivity as the CF loading approached 10–15 wt%. The addition of PTFE managed to reduce the resistivity of the composite, that is, from 4.51 to 0.53 × 10 (Ωcm). The incorporation of 15 wt%. CF resulted with an increase of 45% in tensile strength and 51.5% in flexural strength, while the addition of PTFE had a negative impact on both properties. It was shown that PTFE was able to reduce the friction coefficient, μ and wear rate, K up to 0.257 and 6.35 × 106 (mm3/Nm), respectively, which can be attributed to the excellent abilities of PTFE to form transfer film. The composite consisting of 15 wt% CF and 10 wt%. PTFE showed highest improvement in term of electrical resistivity, and is deemed the most suitable composition for this study. Scanning electron microscopy was also carried out to further elucidate the fracture and wear mechanism of the PC/CF/PTFE composites.
Functionalized graphene nanoplatelets as a barrier enhancing filler in organic photovoltaic encapsulant
Authors: Yuwawech Kitti , Wootthikanokkhan Jatuphorn , Tanpichai Supachok
Published: December 2020

This research work has concerned the development of polymer films, reinforced with graphene nanoplatelets (GNP) for use as encapsulating films for organic photovoltaic (OPV) cells. The aim of this work was to investigate the effects of concentrations and orientations of GNP on mechanical, optical, and barrier properties of polymer composite films. In this regard, the neat GNP was modified with Fe3O4 prior to mixing with acrylate‐based monomers. The mixture was then cured by photo‐polymerization with and without the application of magnetic fields. Changes in orientation of the functionalized GNP with the direction of applied magnetic fields were analyzed by optical microscopy, scanning electron microscopy, and transmission electron microscopy. From the results, it was found that by inducing the orientation of functionalized GNP to the horizontal direction (with respect to the OPV cell), the great enhancement in tensile and barrier properties of the polymer composite films was achieved. This led to the longer performance of the OPV cell encapsulated with the nanocomposite film with 0.1 phr of the horizontally oriented GNP in comparison with the OPV cell encapsulated with the film reinforced with randomly oriented GNP at the same content.
Assessing the value of reviewing all fetal death records for birth defects surveillance, compared to only those with maternal anomaly codes
Authors: Tessarolo Ashley , Ramirez Glenda M. , Contreras Dianna
Published: December 2020

Background

The Arizona Birth Defects Monitoring Program (ABDMP) creates case‐finding lists of potential birth defects. As part of this, ABDMP includes all fetal death records, in addition to records for mothers and infants with an associated birth defect code. This project aims to understand the value of including all fetal deaths in case‐finding, and to assess the impact on the rate of birth defects if all fetal death cases are not reviewed.

Methods

We assessed 2016–2017 fetal death records based on case‐finding source and ICD‐10 CM codes. We categorized cases by whether they had a hospital discharge ICD‐10 CM code indicating a maternal diagnosis for a fetal anomaly (i.e., “O35” code), and compared them to cases reported only by a stillbirth code, meaning that a baby was born deceased, with no reference to birth defects. Positive and negative predictive values were calculated (PPV, NPV, respectively).

Results

For 2016–2017, fetal deaths make up 6% (n = 89) of all confirmed birth defects (n = 1,416), and fetal deaths with no O35 code make up 4% (n = 54) of all confirmed birth defects cases in Arizona. Had cases without an O35 code not been included, 4% (n = 54) of confirmed birth defect cases in Arizona for 2016–2017 would have been missed. The PPV was 68.6%.

Conclusion

The work involved in reviewing the additional 1,000 records per year is warranted by the value noted. It is evident that by including all fetal deaths we capture a more accurate picture of the occurrence of birth defects in Arizona.
Niels Bohr's Diplomatic Mission during and after World War Two
Authors: Aaserud Finn
Published: December 2020

The Danish physicist Niels Bohr is best known for two major achievements: first, his model of the quantum atom, published in 1913, for which he received the Nobel Prize in 1922; and second, the “Copenhagen interpretation” of quantum mechanics developed together with colleagues at his institute in the latter half of the twenties. Having turned his institute toward nuclear physics, making it a pioneer institution in this emerging field, Bohr escaped from Nazi‐occupied Denmark in 1943. Learning in England about the advanced state of the secret project to develop an atomic bomb, which Bohr had so far considered impracticable in a foreseeable future, he agreed to join the project. Bohr decided instantly that the prospect of such a weapon of mass destruction would require what he came to call an “open world” among nations, and he worked conscientiously toward this end until he died in 1962. In the process, statesmen, including Winston Churchill and Franklin D. Roosevelt, as well as diplomats from several countries, came to encounter Bohr and his political mission. Although not as successful as his scientific achievements, his mission was considered by Bohr himself as equally important. Yet it constitutes a hitherto relatively neglected part of Bohr's career.1