scholarly journals Chronic Seizures Worsen Cognitive Function with Loss of Presenilin 2 Function in a Sex-Related Manner

2021 ◽  
Author(s):  
Kevin M Knox ◽  
Megan Beckman ◽  
Carole L Smith ◽  
Suman Jayadev ◽  
Melissa Barker-Haliski
Keyword(s):  
Cognitive Function ◽  
Clinical Evidence ◽  
Barnes Maze ◽  
Wild Type ◽  
Altered Expression ◽  
Specific Manner ◽  
Early Onset Alzheimer’S Disease ◽  
Presenilin 2 ◽  
Patients With Epilepsy ◽  
The Impact

Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with variants in presenilin 2 (PSEN2). Like patients with epilepsy, untreated seizures may also worsen cognitive function in AD. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p<0.02; females: p<0.02). Chronic seizures more significantly worsened anxiety-like behaviors of female PSEN2 KO mice as measured by percentage of total time exploring the center of an OF. TM performance was significantly worsened in kindled female (p=0.024), but not male, PSEN2 KO mice. Male BM performance was generally worsened by seizures (p=0.038), but not by genotype. Conversely, kindled PSEN2 KO females made the most BM errors (p=0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. This study demonstrates that hippocampus-dependent cognitive function may be only worsened by uncontrolled chronic seizures in female, but not male, PSEN2 KO mice. Our work aligns with clinical evidence of sex-specific worsening of AD burden and supports sex-specific anticonvulsant interventions in AD.

scholarly journals High Dietary Iron Disrupts Iron Homeostasis and Induces Amyloid-β and Phospho-τ Expression in the Hippocampus of Adult Wild-Type and APP/PS1 Transgenic Mice

2019 ◽  
Vol 149 (12) ◽  
pp. 2247-2254 ◽  
Author(s):  
Min Chen ◽  
Jiashuo Zheng ◽  
Guohao Liu ◽  
Chong Zeng ◽  
En Xu ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Transgenic Mice ◽  
Iron Homeostasis ◽  
Iron Concentration ◽  
Amyloid Β ◽  
Dietary Iron ◽  
Wild Type ◽  
Brain Iron ◽  
Sod Activity ◽  
The Impact

ABSTRACT Background Brain iron deposition is a feature of Alzheimer disease and may contribute to its development. However, the relative contribution of dietary iron remains unclear. Objectives We investigated the impact of high dietary iron on brain pathological changes and cognitive function in adult wild-type (WT) mice and amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice. Methods Male WT mice and APP/PS1 mice aged 10 wk were fed either a control diet (66 mg Fe/kg) (WT-Ctrl and APP/PS1-Ctrl) or a high iron diet (14 g Fe/kg) (WT-High Fe and APP/PS1-High Fe) for 20 wk. Iron concentrations in brain regions were measured by atomic absorption spectrophotometry. Brain iron staining and amyloid-β (Aβ) immunostaining were performed. Protein expressions in the hippocampus were determined by immunoblotting. Superoxide dismutase (SOD) activity and malondialdehyde concentration were examined. Cognitive functions were tested with the Morris water maze system. Results In the hippocampus, APP/PS1-High Fe mice had significantly higher iron concentration (2.5-fold) and ferritin (2.0-fold) than APP/PS1-Ctrl mice (P < 0.001), and WT-High Fe mice had significantly higher ferritin (2.0-fold) than WT-Ctrl mice (P < 0.001). Interestingly, APP/PS1 mice had significantly higher iron concentration (2–3-fold) and ferritin (2–2.5-fold) than WT mice fed either diet (P < 0.001). Histological analysis indicated that iron accumulated in the hippocampal dentate gyrus region in APP/PS1 mice, consistent with the pattern of Aβ deposition. For both mouse strains, iron treatment induced Aβ and phospho-τ expression (1.5–3-fold) in the hippocampus, but had little impact on oxidative stress and cognitive function. Furthermore, APP/PS1 mice had significantly lower SOD activity and higher malondialdehyde concentration than WT mice in the hippocampus (P < 0.0001), paralleled by apparent cognitive dysfunction. Conclusions Dietary iron overload induces iron disorder and Aβ and phospho-τ expression in the hippocampus of adult WT and APP/PS1 transgenic mice.

scholarly journals WS635 Attenuates the Anesthesia/Surgery-Induced Cognitive Impairment in Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Jiefu Lin ◽  
Fuyi Shen ◽  
Jing Lu ◽  
Feng Liang ◽  
Yiying Zhang ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Abdominal Surgery ◽  
Neurocognitive Disorder ◽  
Barnes Maze ◽  
Wild Type ◽  
Isoflurane Anesthesia ◽  
Before And After ◽  
Mice Brain ◽  
Different Doses

Anesthesia/surgery has been reported to be associated with perioperative neurocognitive disorder (PND) in patients and induces cognitive impairment in mice. Previous studies demonstrate cyclosporine A (CsA) attenuates the anesthesia/surgery-induced cognitive impairment in mice. However, CsA has immunosuppressive effects and may not be routinely used to prevent or treat PND in patients. WS635 is a nonimmunosuppressive CsA analog. We, therefore, set out to determine whether WS635 could mitigate the anesthesia/surgery-induced cognitive impairment in mice. We performed abdominal surgery under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h in 9 month-old wild-type (WT) mice. We treated the mice with CsA (10 mg/kg) or different doses (13.2 mg/kg, 26.4 mg/kg and 52.8 mg/kg) of WS635 before and after the anesthesia/surgery. Barnes maze and fear conditioning system (FCS) were employed to evaluate the cognitive function in mice. We measured the amounts of postsynaptic density (PSD)-95, synaptophysin, and ATP in the hippocampus and cortex of the mice using western blot and ATP Colorimetric/Fluorometric Assay, respectively. We found that the treatment with 52.8 mg/kg, but not 13.2 mg/kg or 26.4 mg/kg, of WS635 attenuated the anesthesia/surgery-induced cognitive impairment in mice and the reductions in the amounts of PSD-95, synaptophysin, and ATP in the mice brain tissues. These results have established a system to study WS635 further and suggest that we need to perform more experiments to determine whether WS635 can ultimately be used as one of the interventions for PND in patients.

Subtle Impact of Akt1 and Akt3 on Exploratory Behavior in Gene Targeted Mice

2015 ◽  
Vol 223 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Christina Leibrock ◽  
Michael Hierlmeier ◽  
Undine E. Lang ◽  
Florian Lang
Keyword(s):  
Forced Swimming Test ◽  
Open Field Test ◽  
Wild Type ◽  
Average Speed ◽  
Closed Area ◽  
Light Area ◽  
Swimming Test ◽  
The Impact ◽  
Center Area ◽  
Dark Transition

Abstract. The present study explored the impact of Akt1 and Akt3 on behavior. Akt1 (akt1-/-) and Akt3 (akt3-/-) knockout mice were compared to wild type (wt) mice. The akt1-/- mice, akt3-/- mice, and wt mice were similar in most parameters of the open-field test. However, the distance traveled in the center area was slightly but significantly less in akt3-/- mice than in wt mice. In the light/dark transition test akt1-/- mice had significantly lower values than wt mice and akt3-/- mice for distance traveled, number of rearings, rearing time in the light area, as well as time spent and distance traveled in the entrance area. They were significantly different from akt3-/- mice in the distance traveled, visits, number of rearings, rearing time in the light area, as well as time spent, distance traveled, number of rearings, and rearing time in the entrance area. In the O-maze the time spent, and the visits to open arms, as well as the number of protected and unprotected headdips were significantly less in akt1-/- mice than in wt mice, whereas the time spent in closed arms was significantly more in akt1-/- mice than in wt mice. Protected and unprotected headdips were significantly less in akt3-/- mice than in wt mice. In closed area, akt3-/- mice traveled a significantly larger distance at larger average speed than akt1-/- mice. No differences were observed between akt1-/- mice, akt3-/- mice and wt-type mice in the time of floating during the forced swimming test. In conclusion, akt1-/- mice and less so akt3-/ mice display subtle changes in behavior.

The Oxford Handbook of Adult Cognitive Disorders

2019 ◽  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Neurodevelopmental Disorders ◽  
Brain Aging ◽  
Cognitive Disorders ◽  
Diverse Range ◽  
Medical Specialties ◽  
Psychiatric Illnesses ◽  
Medical Disorders ◽  
The Impact

The prevalence of cognitive impairment caused by neurodegenerative diseases and other neurologic disorders associated with aging is expected to rise dramatically between now and year 2050, when the population of Americans aged 65 or older will nearly double. Cognitive impairment also commonly occurs in other neurologic conditions, as well as in non-neurologic medical disorders (and their treatments), idiopathic psychiatric illnesses, and adult neurodevelopmental disorders. Cognitive impairment can thus infiltrate all aspects of healthcare, making it necessary for clinicians and clinical researchers to have an integrated knowledge of the spectrum of adult cognitive disorders. The Oxford Handbook of Adult Cognitive Disorders is meant to serve as an up-to-date, scholarly, and comprehensive volume covering most diseases, conditions, and injuries resulting in impairments in cognitive function in adults. Topics covered include normal cognitive and brain aging, the impact of medical disorders (e.g., cardiovascular, liver, pulmonary) and psychiatric illnesses (e.g., depression and bipolar disorder) on cognitive function, adult neurodevelopmental disorders (e.g., Down Syndrome, Attention Deficit/Hyperactivity Disorder), as well as the various neurological conditions (e.g., Alzheimer’s disease, chronic traumatic encephalopathy, concussion). A section of the Handbook is also dedicated to unique perspectives and special considerations for the clinicians and clinical researchers, covering topics such as cognitive reserve, genetics, diversity, and neuroethics. The target audience of this Handbook includes: (1) clinicians, particularly psychologists, neuropsychologists, neurologists (including behavioral and cognitive neurologists), geriatricians, and psychiatrists (including neuropsychiatrists), who provide clinical care and management for adults with a diverse range of cognitive disorders; (2) clinical researchers who investigate cognitive outcomes and functioning in adult populations; and (3) graduate level students and post-doctoral trainees studying psychology, clinical neuroscience, and various medical specialties.

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals Effect of the Information Support Robot on the Daily Activity of Older People Living Alone in Actual Living Environment

2021 ◽  
Vol 18 (5) ◽  
pp. 2498
Author(s):  
Jumpei Mizuno ◽  
Daisuke Saito ◽  
Ken Sadohara ◽  
Misato Nihei ◽  
Shinichi Ohnaka ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Older People ◽  
Daily Activity ◽  
Living Environment ◽  
Living Alone ◽  
Information Support ◽  
Sleep Patterns ◽  
High Cognitive Function ◽  
Environment Study ◽  
The Impact

Information support robots (ISRs) have the potential to assist older people living alone to have an independent life. However, the effects of ISRs on the daily activity, especially the sleep patterns, of older people have not been clarified; moreover, it is unclear whether the effects of ISRs depend on the levels of cognitive function. To investigate these effects, we introduced an ISR into the actual living environment and then quantified induced changes according to the levels of cognitive function. Older people who maintained their cognitive function demonstrated the following behavioral changes after using the ISR: faster wake-up times, reduced sleep duration, and increased amount of activity in the daytime (p < 0.05, r = 0.77; p < 0.05, r = 0.89, and p < 0.1, r = 0.70, respectively). The results suggest that the ISR is beneficial in supporting the independence of older people living alone since living alone is associated with disturbed sleep patterns and low physical activity. The impact of the ISR on daily activity was more remarkable in the subjects with high cognitive function than in those with low cognitive function. These findings suggest that cognitive function is useful information in the ISR adaptation process. The present study has more solid external validity than that of a controlled environment study since it was done in a personal residential space.

scholarly journals Titanium Dioxide Presents a Different Profile in Dextran Sodium Sulphate-Induced Experimental Colitis in Mice Lacking the IBD Risk Gene Ptpn2 in Myeloid Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 772
Author(s):  
Javier Conde ◽  
Marlene Schwarzfischer ◽  
Egle Katkeviciute ◽  
Janine Häfliger ◽  
Anna Niechcial ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Titanium Dioxide ◽  
Genetic Risk ◽  
Intestinal Inflammation ◽  
Sodium Sulphate ◽  
Food Additive ◽  
Wild Type ◽  
Dextran Sodium Sulphate ◽  
Risk Gene ◽  
The Impact

Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO2) might play a causative role in the disease. Therefore, in the present study we aimed to explore the interaction between the food additive TiO2 and the well-characterized IBD risk gene protein tyrosine phosphatase non-receptor type 2 (Ptpn2) and their role in the development of intestinal inflammation. Dextran sodium sulphate (DSS)-induced acute colitis was performed in mice lacking the expression of Ptpn2 in myeloid cells (Ptpn2LysMCre) or their wild type littermates (Ptpn2fl/fl) and exposed to the microparticle TiO2. The impact of Ptpn2 on TiO2 signalling pathways and TiO2-induced IL-1β and IL-10 levels were studied using bone marrow-derived macrophages (BMDMs). Ptpn2LysMCre exposed to TiO2 exhibited more severe intestinal inflammation than their wild type counterparts. This effect was likely due to the impact of TiO2 on the differentiation of intestinal macrophages, suppressing the number of anti-inflammatory macrophages in Ptpn2 deficient mice. Moreover, we also found that TiO2 was able to induce the secretion of IL-1β via mitogen-activated proteins kinases (MAPKs) and to repress the expression of IL-10 in bone marrow-derived macrophages via MAPK-independent pathways. This is the first evidence of the cooperation between the genetic risk factor Ptpn2 and the environmental factor TiO2 in the regulation of intestinal inflammation. The results presented here suggest that the ingestion of certain industrial compounds should be taken into account, especially in individuals with increased genetic risk

scholarly journals Risk of Nursing Home Use Among Older Americans: The Impact of Psychiatric History and Trajectories of Cognitive Function

2021 ◽  
Author(s):  
Maria T Brown ◽  
Miriam Mutambudzi
Keyword(s):  
Nursing Home ◽  
Cognitive Function ◽  
Latent Class ◽  
Study Data ◽  
Psychiatric Training ◽  
Psychiatric History ◽  
Term Care ◽  
Increased Risk ◽  
Course Variables ◽  
The Impact

Abstract Objectives Mental illness and cognitive functioning may be independently associated with nursing home use. We investigated the strength of the association between baseline (1998) psychiatric history, 8-year cognitive function trajectories, and prospective incidence of nursing home use over a 10-year period while accounting for relevant covariates in U.S. adults aged 65 and older. We hypothesized that self-reported baseline history of psychiatric, emotional, or nervous problems would be associated with a greater risk of nursing home use and that cognition trajectories with the greatest decline would be associated with a subsequent higher risk of nursing home use. Methods We used 8 waves (1998–2016) of Health and Retirement Study data for adults aged 65 years and older. Latent class mixture modeling identified 4 distinct cognitive function trajectory classes (1998–2006): low-declining, medium-declining, medium-stable, and high-declining. Participants from the 1998 wave (N = 5,628) were classified into these 4 classes. Competing risks regression analysis modeled the subhazard ratio of nursing home use between 2006 and 2016 as a function of baseline psychiatric history and cognitive function trajectories. Results Psychiatric history was independently associated with greater risk of nursing home use (subhazard ratio [SHR] 1.26, 95% confidence interval [CI] 1.06–1.51, p &lt; .01), net the effects of life course variables. Furthermore, “low-declining” (SHR 2.255, 95% CI 1.70–2.99, p &lt; .001) and “medium-declining” (2.103, 95% CI 1.69–2.61, p &lt; .001) trajectories predicted increased risk of nursing home use. Discussion Evidence of these associations can be used to educate policymakers and providers about the need for appropriate psychiatric training for staff in community-based and residential long-term care programs.

scholarly journals Antimicrobial Use in COVID-19 Patients in the First Phase of the SARS-CoV-2 Pandemic: A Scoping Review

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 745
Author(s):  
Wenjuan Cong ◽  
Ak Narayan Poudel ◽  
Nour Alhusein ◽  
Hexing Wang ◽  
Guiqing Yao ◽  
...  
Keyword(s):  
Critical Illness ◽  
Scoping Review ◽  
Clinical Evidence ◽  
Length Of Hospital Stay ◽  
Severity Of Illness ◽  
Antibiotic Prescribing ◽  
Antimicrobial Use ◽  
Clinical Scenarios ◽  
Scoping Reviews ◽  
The Impact

This scoping review provides new evidence on the prevalence and patterns of global antimicrobial use in the treatment of COVID-19 patients; identifies the most commonly used antibiotics and clinical scenarios associated with antibiotic prescribing in the first phase of the pandemic; and explores the impact of documented antibiotic prescribing on treatment outcomes in COVID-19 patients. The review complies with PRISMA guidelines for Scoping Reviews and the protocol is registered with the Open Science Framework. In the first six months of the pandemic, there was a similar mean antibiotic prescribing rate between patients with severe or critical illness (75.4%) and patients with mild or moderate illness (75.1%). The proportion of patients prescribed antibiotics without clinical justification was 51.5% vs. 41.9% for patients with mild or moderate illness and those with severe or critical illness. Comparison of patients who were provided antibiotics with a clinical justification with those who were given antibiotics without clinical justification showed lower mortality rates (9.5% vs. 13.1%), higher discharge rates (80.9% vs. 69.3%), and shorter length of hospital stay (9.3 days vs. 12.2 days). In the first 6 months of the pandemic, antibiotics were prescribed for COVID-19 patients regardless of severity of illness. A large proportion of antibiotic prescribing for mild and moderate COVID-19 patients did not have clinical evidence of a bacterial co-infection. Antibiotics may not be beneficial to COVID-19 patients without clinical evidence of a bacterial co-infection.

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