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PSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

ABSTRACT: Although more patients survive sepsis and are increasingly discharged from the hospital, they often experience long-term cognitive and psychological impairment with significant socioeconomic impact. However, the pathophysiological mechanisms have not been fully elucidated. In the present study, we showed that LPS induced long-term neurobehavioral abnormities, as reflected by significantly decreased freezing time to context and sucrose preference. Using a high-throughput quantitative proteomic screen, we showed that phosphorylation of synaptic GTPase-activating protein 1 (pSynGAP1) was identified as the hub of synaptic plasticity and was significantly decreased following LPS exposure. This decreased pSynGAP was associated with significantly lower theta and gamma oscillations in the CA1 of the hippocampus. Notably, restoration of pSynGAP1 by roscovitine was able to reverse most of these abnormities. Taken together, our study suggested that pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might play a critical role in long-term neurobehavioral abnormities of sepsis survivors.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7746391 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

Wang Yong Y Wei Hua H Tong Jianhua J Ji Muhuo M Yang Jianjun J

Aging 20201116 22

Although more patients survive sepsis and are increasingly discharged from the hospital, they often experience long-term cognitive and psychological impairment with significant socioeconomic impact. However, the pathophysiological mechanisms have not been fully elucidated. In the present study, we showed that LPS induced long-term neurobehavioral abnormities, as reflected by significantly decreased freezing time to context and sucrose preference. Using a high-throughput quantitative proteomic sc ...[more]

PMID: 33203791

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Project description:Cognitive impairment and functional disability are major determinants of caregiving needs and societal health care costs. Although the incidence of severe sepsis is high and increasing, the magnitude of patients' long-term cognitive and functional limitations after sepsis is unknown.To determine the change in cognitive impairment and physical functioning among patients who survive severe sepsis, controlling for their presepsis functioning.A prospective cohort involving 1194 patients with 1520 hospitalizations for severe sepsis drawn from the Health and Retirement Study, a nationally representative survey of US residents (1998-2006). A total of 9223 respondents had a baseline cognitive and functional assessment and had linked Medicare claims; 516 survived severe sepsis and 4517 survived a nonsepsis hospitalization to at least 1 follow-up survey and are included in the analysis.Personal interviews were conducted with respondents or proxies using validated surveys to assess the presence of cognitive impairment and to determine the number of activities of daily living (ADLs) and instrumental ADLs (IADLs) for which patients needed assistance.Survivors' mean age at hospitalization was 76.9 years. The prevalence of moderate to severe cognitive impairment increased 10.6 percentage points among patients who survived severe sepsis, an odds ratio (OR) of 3.34 (95% confidence interval [CI], 1.53-7.25) in multivariable regression. Likewise, a high rate of new functional limitations was seen following sepsis: in those with no limits before sepsis, a mean 1.57 new limitations (95% CI, 0.99-2.15); and for those with mild to moderate limitations before sepsis, a mean of 1.50 new limitations (95% CI, 0.87-2.12). In contrast, nonsepsis general hospitalizations were associated with no change in moderate to severe cognitive impairment (OR, 1.15; 95% CI, 0.80-1.67; P for difference vs sepsis = .01) and with the development of fewer new limitations (mean among those with no limits before hospitalization, 0.48; 95% CI, 0.39-0.57; P for difference vs sepsis <.001 and mean among those with mild to moderate limits, 0.43; 95% CI, 0.23-0.63; P for difference = .001). The declines in cognitive and physical function persisted for at least 8 years.Severe sepsis in this older population was independently associated with substantial and persistent new cognitive impairment and functional disability among survivors. The magnitude of these new deficits was large, likely resulting in a pivotal downturn in patients' ability to live independently.

Project description:BackgroundIn addition to poor survival rates, individuals with glioblastoma (GBM) are at risk of neurocognitive impairment due to multiple factors. This study aimed to characterize neurocognitive impairment, neurobehavioral symptoms, fatigue, sleep disturbance, and depressive symptoms in newly diagnosed GBM patients; and to examine whether neurobehavioral symptoms, fatigue, sleep, and depressive symptoms influence neurocognitive performance.MethodsThis study was part of a prospective, inception cohort, single-arm exercise intervention in which GBM patients underwent a neuropsychological assessment shortly after diagnosis (median 4 weeks; ie, baseline) and 3, 6, 12, and 18 months later, or until tumor progression. Here, we present baseline data. Forty-five GBM patients (mean age = 55 years) completed objective neurocognitive tests, and self-report measures of neurobehavioral symptoms, fatigue, sleep disturbance, and depressive symptoms.ResultsCompared to normative samples, GBM patients scored significantly lower on all neurocognitive tests, with 34 (76%) patients exhibiting neurocognitive impairment. Specifically, 53% exhibited impairment in memory retention, 51% in executive function, 42% in immediate recall, 41% in verbal fluency, and 24% in attention. There were high rates of clinically elevated sleep disturbance (70%), fatigue (57%), depressive symptoms (16%), and neurobehavioral symptoms (27%). A multivariate regression analysis revealed that depressive symptoms are significantly associated with neurocognitive impairment.ConclusionsGBM patients are vulnerable to adverse outcomes including neurocognitive impairment, neurobehavioral symptoms, fatigue, sleep disturbance, and depressive symptoms shortly after diagnosis, prior to completing chemoradiation. Those with increased depressive symptoms are more likely to demonstrate neurocognitive impairment, highlighting the need for early identification and treatment of depression in this population.

Project description:BackgroundThe purpose was to prospectively examine the effects of sedentary behaviors on subjective memory impairment in breast cancer survivors (BCS) and the extent to which sleep disturbances mediated this pathway.MethodsBCS (N = 380; Mage = 57.38 ± 9.25 years) completed questionnaires assessing demographics, health history, sitting behaviors, sleep disturbance, subjective memory impairment, and moderate-to-vigorous physical activity (MVPA) at baseline and 6-month follow-up. A subsample (N = 300) wore an accelerometer to objectively estimate sedentary time and MVPA. Structural equation modeling was used to test direct and indirect effects of self-reported and objectively estimated sedentary behaviors on memory impairment (through sleep disturbance) across time. Models were adjusted for demographic, clinical, and MVPA covariates.ResultsAt baseline, more total daily sitting (γ = 0.23), occupational sitting (γ = 0.11), television viewing (γ = 0.15), and computer use (γ = 0.22) were associated with greater sleep disturbance, which was associated with greater memory impairment (γ = -0.22). Indirect effects of self-reported sitting on memory were significant. At follow-up, increased total daily sitting (γ = 0.08) and computer use (γ = 0.14) predicted increased sleep disturbance, which predicted increased memory impairment (γ = -0.09). The indirect path from increased computer use to memory impairment was significant (β = -0.01). In the accelerometer subsample, greater daily sedentary time at baseline was associated with less sleep disturbance (γ = -0.14) and memory impairment (indirect effect: β = 0.03).ConclusionsFindings provide early evidence that sedentary contexts may differentially influence sleep disturbance and memory impairment in BCS. Computer use and television viewing may pose the strongest risks to cognitive health. Disparate findings between objective and subjective sedentary measures warrant further research.

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PSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

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pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

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