Showing papers on "Cognitive decline published in 2020"

Diagnosis and Treatment of Parkinson Disease: A Review

Abstract: Importance Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease–like movement problems such as rigidity, slowness, and tremor. More than 6 million individuals worldwide have Parkinson disease. Observations Diagnosis of Parkinson disease is based on history and examination. History can include prodromal features (eg, rapid eye movement sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (eg, tremor, stiffness, slowness), and psychological or cognitive problems (eg, cognitive decline, depression, anxiety). Examination typically demonstrates bradykinesia with tremor, rigidity, or both. Dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain. Parkinson disease has multiple disease variants with different prognoses. Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression. Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (eg, carbidopa-levodopa, dopamine agonists), and slower disease progression. Other individuals have an intermediate subtype. For all patients with Parkinson disease, treatment is symptomatic, focused on improvement in motor (eg, tremor, rigidity, bradykinesia) and nonmotor (eg, constipation, cognition, mood, sleep) signs and symptoms. No disease-modifying pharmacologic treatments are available. Dopamine-based therapies typically help initial motor symptoms. Nonmotor symptoms require nondopaminergic approaches (eg, selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition). Rehabilitative therapy and exercise complement pharmacologic treatments. Individuals experiencing complications, such as worsening symptoms and functional impairment when a medication dose wears off (“off periods”), medication-resistant tremor, and dyskinesias, benefit from advanced treatments such as therapy with levodopa-carbidopa enteral suspension or deep brain stimulation. Palliative care is part of Parkinson disease management. Conclusions and Relevance Parkinson disease is a heterogeneous disease with rapidly and slowly progressive forms. Treatment involves pharmacologic approaches (typically with levodopa preparations prescribed with or without other medications) and nonpharmacologic approaches (such as exercise and physical, occupational, and speech therapies). Approaches such as deep brain stimulation and treatment with levodopa-carbidopa enteral suspension can help individuals with medication-resistant tremor, worsening symptoms when the medication wears off, and dyskinesias.

APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline

Abstract: Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the e3/e4 or e4/e4 alleles) are distinguished from those without APOE4 (e3/e3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.

Abstract: Summary Background CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy. Methods We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63–69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses. Findings We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p Interpretation Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease. Funding Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.

The characterisation of subjective cognitive decline

Abstract: A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases.

Immediate and long-term consequences of COVID-19 infections for the development of neurological disease.

Abstract: Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. While these symptoms arise acutely during the course of infection, less is known about the possible long-term consequences for the brain. Severely affected COVID-19 cases experience high levels of proinflammatory cytokines and acute respiratory dysfunction and often require assisted ventilation. All these factors have been suggested to cause cognitive decline. Pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. This article summarizes the current understanding of neurological symptoms of COVID-19 and hypothesizes that affected patients may be at higher risk of developing cognitive decline after overcoming the primary COVID-19 infection. A structured prospective evaluation should analyze the likelihood, time course, and severity of cognitive impairment following the COVID-19 pandemic.

Consequences of physical inactivity in older adults: A systematic review of reviews and meta-analyses.

Abstract: Background Globally, populations are ageing. Typically, physical activity levels decline and health worsens as we age; however, estimates of the impact of physical inactivity for population health often fail to specifically focus on older adults. Methods Multiple databases were searched for systematic reviews and/or meta-analyses of longitudinal observational studies, investigating the relationship between physical activity and any physical or mental health outcome in adults aged ≥60 years. Quality of included reviews was assessed using AMSTAR. Results Twenty-four systematic reviews and meta-analyses were included. The majority of reviews were of moderate or high methodological quality. Physically active older adults (≥60 years) are at a reduced risk of all-cause and cardiovascular mortality, breast and prostate cancer, fractures, recurrent falls, ADL disability and functional limitation and cognitive decline, dementia, Alzheimer's disease, and depression. They also experience healthier ageing trajectories, better quality of life and improved cognitive functioning. Conclusion This review of reviews provides a comprehensive and systematic overview of epidemiological evidence from previously conducted research to assess the associations of physical activity with physical and mental health outcomes in older adults.

Education and Cognitive Functioning Across the Life Span.

Abstract: Cognitive abilities are important predictors of educational and occupational performance, socioeconomic attainment, health, and longevity. Declines in cognitive abilities are linked to impairments in older adults' everyday functions, but people differ from one another in their rates of cognitive decline over the course of adulthood and old age. Hence, identifying factors that protect against compromised late-life cognition is of great societal interest. The number of years of formal education completed by individuals is positively correlated with their cognitive function throughout adulthood and predicts lower risk of dementia late in life. These observations have led to the propositions that prolonging education might (a) affect cognitive ability and (b) attenuate aging-associated declines in cognition. We evaluate these propositions by reviewing the literature on educational attainment and cognitive aging, including recent analyses of data harmonized across multiple longitudinal cohort studies and related meta-analyses. In line with the first proposition, the evidence indicates that educational attainment has positive effects on cognitive function. We also find evidence that cognitive abilities are associated with selection into longer durations of education and that there are common factors (e.g., parental socioeconomic resources) that affect both educational attainment and cognitive development. There is likely reciprocal interplay among these factors, and among cognitive abilities, during development. Education-cognitive ability associations are apparent across the entire adult life span and across the full range of education levels, including (to some degree) tertiary education. However, contrary to the second proposition, we find that associations between education and aging-associated cognitive declines are negligible and that a threshold model of dementia can account for the association between educational attainment and late-life dementia risk. We conclude that educational attainment exerts its influences on late-life cognitive function primarily by contributing to individual differences in cognitive skills that emerge in early adulthood but persist into older age. We also note that the widespread absence of educational influences on rates of cognitive decline puts constraints on theoretical notions of cognitive aging, such as the concepts of cognitive reserve and brain maintenance. Improving the conditions that shape development during the first decades of life carries great potential for improving cognitive ability in early adulthood and for reducing public-health burdens related to cognitive aging and dementia.

Neurobiology of COVID-19.

Abstract: Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19 who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic "NeuroCovid" classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the long-term sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson's disease, or Alzheimer's disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.

How the COVID-19 pandemic is focusing attention on loneliness and social isolation.

Abstract: The effects of the coronavirus disease 2019 (COVID-19) pandemic upon human health, economic activity and social engagement have been swift and far reaching Emerging evidence shows that the pandemic has had dramatic mental health impacts, bringing about increased anxiety and greater social isolation due to the physical distancing policies introduced to control the disease In this context, it is possible to more deeply appreciate the health consequences of loneliness and social isolation, which researchers have argued are enduring experiences for many people and under-recognised contributors to public health In this paper, we examine the social and psychological consequences of the COVID-19 pandemic, with a focus on what this has revealed about the need to better understand and respond to social isolation and loneliness as public health priorities Social isolation and loneliness are understood to be distinct conditions, yet each has been found to predict premature mortality, depression, cardiovascular disease and cognitive decline Estimates of the prevalence and distribution of social isolation and loneliness vary, possibly ranging from one-in-six to one-in-four people, and the lack of knowledge about the extent of these conditions indicates the need for population monitoring using standardised methods and validated measures Reviews of the evidence relating to social isolation and loneliness interventions have found that befriending schemes, individual and group therapies, various shared activity programs, social prescription by healthcare providers, and diverse strategies using information and communication technologies have been tried There remains uncertainty about what is effective for different population groups, particularly for prevention and for addressing the more complex condition of loneliness In Australia, a national coalition - Ending Loneliness Together - has been established to bring together researchers and service providers to facilitate evidence gathering and the mobilisation of knowledge into practice Research-practice partnerships and cross-disciplinary collaborations of this sort are essential for overcoming the public health problems of loneliness and social isolation that have pre-existed and will endure beyond the COVID-19 pandemic

Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment

Abstract: Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.

Cognitive impairment in multiple sclerosis: clinical management, MRI, and therapeutic avenues.

Abstract: Multiple sclerosis is a chronic, demyelinating disease of the CNS. Cognitive impairment is a sometimes neglected, yet common, sign and symptom with a profound effect on instrumental activities of daily living. The prevalence of cognitive impairment in multiple sclerosis varies across the lifespan and might be difficult to distinguish from other causes in older age. MRI studies show that widespread changes to brain networks contribute to cognitive dysfunction, and grey matter atrophy is an early sign of potential future cognitive decline. Neuropsychological research suggests that cognitive processing speed and episodic memory are the most frequently affected cognitive domains. Narrowing evaluation to these core areas permits brief, routine assessment in the clinical setting. Owing to its brevity, reliability, and sensitivity, the Symbol Digit Modalities Test, or its computer-based analogues, can be used to monitor episodes of acute disease activity. The Symbol Digit Modalities Test can also be used in clinical trials, and data increasingly show that cognitive processing speed and memory are amenable to cognitive training interventions.

Association of Blood Pressure Lowering With Incident Dementia or Cognitive Impairment: A Systematic Review and Meta-analysis.

Abstract: Importance The benefit of blood pressure lowering for the prevention of dementia or cognitive impairment is unclear. Objective To determine the association of blood pressure lowering with dementia or cognitive impairment. Data Sources and Study Selection Search of PubMed, EMBASE, and CENTRAL for randomized clinical trials published from database inception through December 31, 2019, that evaluated the association of blood pressure lowering on cognitive outcomes. The control groups consisted of either placebo, alternative antihypertensive agents, or higher blood pressure targets. Data Extraction and Synthesis Data were screened and extracted independently by 2 authors. Random-effects meta-analysis models were used to report pooled treatment effects and CIs. Main Outcomes and Measures The primary outcome was dementia or cognitive impairment. The secondary outcomes were cognitive decline and changes in cognitive test scores. Results Fourteen randomized clinical trials were eligible for inclusion (96 158 participants), of which 12 reported the incidence of dementia (or composite of dementia and cognitive impairment [3 trials]) on follow-up and were included in the primary meta-analysis, 8 reported cognitive decline, and 8 reported changes in cognitive test scores. The mean (SD) age of trial participants was 69 (5.4) years and 40 617 (42.2%) were women. The mean systolic baseline blood pressure was 154 (14.9) mm Hg and the mean diastolic blood pressure was 83.3 (9.9) mm Hg. The mean duration of follow-up was 49.2 months. Blood pressure lowering with antihypertensive agents compared with control was significantly associated with a reduced risk of dementia or cognitive impairment (12 trials; 92 135 participants) (7.0% vs 7.5% of patients over a mean trial follow-up of 4.1 years; odds ratio [OR], 0.93 [95% CI, 0.88-0.98]; absolute risk reduction, 0.39% [95% CI, 0.09%-0.68%];I2 = 0.0%) and cognitive decline (8 trials) (20.2% vs 21.1% of participants over a mean trial follow-up of 4.1 years; OR, 0.93 [95% CI, 0.88-0.99]; absolute risk reduction, 0.71% [95% CI, 0.19%-1.2%];I2 = 36.1%). Blood pressure lowering was not significantly associated with a change in cognitive test scores. Conclusions and Relevance In this meta-analysis of randomized clinical trials, blood pressure lowering with antihypertensive agents compared with control was significantly associated with a lower risk of incident dementia or cognitive impairment.

The contribution of frailty, cognition, activity of daily life and comorbidities on outcome in acutely admitted patients over 80 years in European ICUs: the VIP2 study

Abstract: Premorbid conditions affect prognosis of acutely-ill aged patients. Several lines of evidence suggest geriatric syndromes need to be assessed but little is known on their relative effect on the 30-day survival after ICU admission. The primary aim of this study was to describe the prevalence of frailty, cognition decline and activity of daily life in addition to the presence of comorbidity and polypharmacy and to assess their influence on 30-day survival. Prospective cohort study with 242 ICUs from 22 countries. Patients 80 years or above acutely admitted over a six months period to an ICU between May 2018 and May 2019 were included. In addition to common patients’ characteristics and disease severity, we collected information on specific geriatric syndromes as potential predictive factors for 30-day survival, frailty (Clinical Frailty scale) with a CFS > 4 defining frail patients, cognitive impairment (informant questionnaire on cognitive decline in the elderly (IQCODE) with IQCODE ≥ 3.5 defining cognitive decline, and disability (measured the activity of daily life with the Katz index) with ADL ≤ 4 defining disability. A Principal Component Analysis to identify co-linearity between geriatric syndromes was performed and from this a multivariable model was built with all geriatric information or only one: CFS, IQCODE or ADL. Akaike’s information criterion across imputations was used to evaluate the goodness of fit of our models. We included 3920 patients with a median age of 84 years (IQR: 81–87), 53.3% males). 80% received at least one organ support. The median ICU length of stay was 3.88 days (IQR: 1.83–8). The ICU and 30-day survival were 72.5% and 61.2% respectively. The geriatric conditions were median (IQR): CFS: 4 (3–6); IQCODE: 3.19 (3–3.69); ADL: 6 (4–6); Comorbidity and Polypharmacy score (CPS): 10 (7–14). CFS, ADL and IQCODE were closely correlated. The multivariable analysis identified predictors of 1-month mortality (HR; 95% CI): Age (per 1 year increase): 1.02 (1.–1.03, p = 0.01), ICU admission diagnosis, sequential organ failure assessment score (SOFA) (per point): 1.15 (1.14–1.17, p < 0.0001) and CFS (per point): 1.1 (1.05–1.15, p < 0.001). CFS remained an independent factor after inclusion of life-sustaining treatment limitation in the model. We confirm that frailty assessment using the CFS is able to predict short-term mortality in elderly patients admitted to ICU. Other geriatric syndromes do not add improvement to the prediction model. Since CFS is easy to measure, it should be routinely collected for all elderly ICU patients in particular in connection to advance care plans, and should be used in decision making.

Sarcopenia during COVID-19 lockdown restrictions: long-term health effects of short-term muscle loss.

Abstract: The COVID-19 pandemic is an extraordinary global emergency that has led to the implementation of unprecedented measures in order to stem the spread of the infection. Internationally, governments are enforcing measures such as travel bans, quarantine, isolation, and social distancing leading to an extended period of time at home. This has resulted in reductions in physical activity and changes in dietary intakes that have the potential to accelerate sarcopenia, a deterioration of muscle mass and function (more likely in older populations), as well as increases in body fat. These changes in body composition are associated with a number of chronic, lifestyle diseases including cardiovascular disease (CVD), diabetes, osteoporosis, frailty, cognitive decline, and depression. Furthermore, CVD, diabetes, and elevated body fat are associated with greater risk of COVID-19 infection and more severe symptomology, underscoring the importance of avoiding the development of such morbidities. Here we review mechanisms of sarcopenia and their relation to the current data on the effects of COVID-19 confinement on physical activity, dietary habits, sleep, and stress as well as extended bed rest due to COVID-19 hospitalization. The potential of these factors to lead to an increased likelihood of muscle loss and chronic disease will be discussed. By offering a number of home-based strategies including resistance exercise, higher protein intakes and supplementation, we can potentially guide public health authorities to avoid a lifestyle disease and rehabilitation crisis post-COVID-19. Such strategies may also serve as useful preventative measures for reducing the likelihood of sarcopenia in general and in the event of future periods of isolation.

Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies.

Abstract: The clinical diagnosis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliable specific markers for synucleinopathies would consequently be of great aid to the diagnosis and management of these disorders. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique that has been previously used to detect self-templating amyloidogenic proteins in the cerebrospinal fluid (CSF) and other biospecimens in prion disease and synucleinopathies. Using a wild-type recombinant α-synuclein as a substrate, we applied RT-QuIC to a large cohort of 439 CSF samples from clinically well-characterized, or post-mortem verified patients with parkinsonism or dementia. Of significance, we also studied patients with isolated REM sleep behavior disorder (iRBD) (n = 18) and pure autonomic failure (PAF) (n = 28), representing clinical syndromes that are often caused by a synucleinopathy, and may precede the appearance of parkinsonism or cognitive decline. The results show that our RT-QuIC assay can accurately detect α-synuclein seeding activity across the spectrum of Lewy Body (LB)-related disorders (LBD), including DLB, PD, iRBD, and PAF, with an overall sensitivity of 95.3%. In contrast, all but two patients with MSA showed no α-synuclein seeding activity in the applied experimental setting. The analysis of the fluorescence response reflecting the amount of α-synuclein seeds revealed no significant differences between the clinical syndromes associated with LB pathology. Finally, the assay demonstrated 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology. In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pathology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein.

Association of Delirium With Long-term Cognitive Decline: A Meta-analysis

Abstract: Importance Delirium is associated with increased hospital costs, health care complications, and increased mortality. Long-term consequences of delirium on cognition have not been synthesized and quantified via meta-analysis. Objective To determine if an episode of delirium was an independent risk factor for long-term cognitive decline, and if it was, whether it was causative or an epiphenomenon in already compromised individuals. Data Sources A systematic search in PubMed, Cochrane, and Embase was conducted from January 1, 1965, to December 31, 2018. A systematic review guided by Preferred Reporting Items for Systematic Reviews and Meta-analyses was conducted. Search terms included delirium AND postoperative cognitive dysfunction; delirium and cognitive decline; delirium AND dementia; and delirium AND memory. Study Selection Inclusion criteria for studies included contrast between groups with delirium and without delirium; an objective continuous or binary measure of cognitive outcome; a final time point of 3 or more months after the delirium episode. The electronic search was conducted according to established methodologies and was executed on October 17, 2018. Data Extraction and Synthesis Three authors extracted data on individual characteristics, study design, and outcome, followed by a second independent check on outcome measures. Effect sizes were calculated as Hedgesg. If necessary, binary outcomes were also converted tog. Only a single effect size was calculated for each study. Main Outcomes and Measures The planned main outcome was magnitude of cognitive decline in Hedgesgeffect size in delirium groups when contrasted with groups that did not experience delirium. Results Of 1583 articles, data subjected from the 24 studies (including 3562 patients who experienced delirium and 6987 controls who did not) were included in a random-effects meta-analysis for pooled effect estimates and random-effects meta-regressions to identify sources of study variance. One study was excluded as an outlier. There was a significant association between delirium and long-term cognitive decline, as the estimated effect size (Hedgesg) for 23 studies was 0.45 (95% CI, 0.34-0.57;P Conclusions and Relevance In this meta-analysis, delirium was significantly associated with long-term cognitive decline in both surgical and nonsurgical patients.

Plasma p-tau181 accurately predicts Alzheimer's disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline.

Abstract: The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer's disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2 years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8 years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC = 97.4%, 95% CI = 94.1-100%) even 8 years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4 years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials.

Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology.

Abstract: Cortical iron has been shown to be elevated in Alzheimer's disease (AD), but the impact of the directly measured iron on the clinical syndrome has not been assessed. We investigated the association between post-mortem iron levels with the clinical and pathological diagnosis of AD, its severity, and the rate of cognitive decline in the 12 years prior to death in subjects from the Memory and Aging Project (n = 209). Iron was elevated (β [SE] = 9.7 [2.6]; P = 3.0 × 10-4) in the inferior temporal cortex only in subjects who were diagnosed with clinical AD during life and had a diagnosis of AD confirmed post-mortem by standardized criteria. Although iron was weakly associated with the extent of proteinopathy in tissue with AD neuropathology, it was strongly associated with the rate of cognitive decline (e.g., global cognition: β [SE] = -0.040 [0.005], P = 1.6 × 10-14). Thus, cortical iron might act to propel cognitive deterioration upon the underlying proteinopathy of AD, possibly by inducing oxidative stress or ferroptotic cell death, or may be related to an inflammatory response.

Myelin degeneration and diminished myelin renewal contribute to age-related deficits in memory.

Abstract: Cognitive decline remains an unaddressed problem for the elderly. We show that myelination is highly active in young mice and greatly inhibited in aged mice, coinciding with spatial memory deficits. Inhibiting myelination by deletion of Olig2 in oligodendrocyte precursor cells impairs spatial memory in young mice, while enhancing myelination by deleting the muscarinic acetylcholine receptor 1 in oligodendrocyte precursor cells, or promoting oligodendroglial differentiation and myelination via clemastine treatment, rescues spatial memory decline during aging.

Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals.

Abstract: Importance The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid. Objective To investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self- and study partner reports of cognitive function. Design, Setting, and Participants This cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal [Clinical Dementia Rating = 0] and cognitively unimpaired [Mini-Mental State Examination score, ≥25; logical memory IIa 6-18]). Main Outcomes and Measures Screening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self- and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ−). Results Amyloid PET results were acquired for 4486 participants (mean [SD] age, 71.29 [4.67] years; 2647 women [59%]), with 1323 (29.5%) classified as Aβ+. Aβ+ participants were slightly older than Aβ−, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ [74%] vs 3050 Aβ− [68%]) and at least 1 APOE e4 allele (2602 Aβ+ [58%] vs 1122 Aβ− [25%]). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index. Conclusions and Relevance Among a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE e4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.

COVID-19 and Mental Health

Abstract: The infection caused by the novel coronavirus (COVID-19) started from China and reached the whole world and was declared as pandemic by WHO. The COVID 19 poses challenges in all aspects of life including mental health for the entire human race. In the disturbed and crisis situation, the mental health care of people at different levels carries great importance: promotion, prevention and clinical care. First of all, we should not refer “COVID-19 case,” “victim,” “COVID-19 family,” but “person who have COVID-19,” “people who are being treated for COVID-19”, etc. Social distancing is a public health strategy to limit the spread of COVID-19. There may be a feeling of ostracism, abandonment and being neglected in people, particularly the elderly when they are isolated. Older adults, especially in isolation and those with cognitive decline or dementia, may become more anxious, angry, stressed, agitated, and withdrawn during the outbreak or while in quarantine. These people need emotional support through informal networks (families) and health professionals. Maintaining social networks in situations of isolations is essential for mental health. The treating physician should ensure basic emotional and practical support to affected people. Children need special attention to express their fear and sadness. Media has highlighted COVID-19 as a unique threat, rather than one of many, which has added to panic, stress, and the potential for hysteria. Information should be sought from WHO website and government health authorities’ platforms, in order to distinguish facts from rumours. Individuals with mental illness may be particularly vulnerable to the effects of widespread panic and threat. Instead of harassment, people with COVID 19 should be offer compassion, support via phone and texts, and assistance as appropriate, but never hostility or judgment. How to cite this article:Jiloha RC. COVID-19 and Mental Health. Epidem Int 2020; 5(1): 7-9. DOI: https://doi.org/10.24321/2455.7048.202002

A 3D human brain-like tissue model of herpes-induced Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive decline, memory loss, and inability to perform everyday functions. Hallmark features of AD-including generation of amyloid plaques, neurofibrillary tangles, gliosis, and inflammation in the brain-are well defined; however, the cause of the disease remains elusive. Growing evidence implicates pathogens in AD development, with herpes simplex virus type I (HSV-1) gaining increasing attention as a potential causative agent. Here, we describe a multidisciplinary approach to produce physiologically relevant human tissues to study AD using human-induced neural stem cells (hiNSCs) and HSV-1 infection in a 3D bioengineered brain model. We report a herpes-induced tissue model of AD that mimics human disease with multicellular amyloid plaque-like formations, gliosis, neuroinflammation, and decreased functionality, completely in the absence of any exogenous mediators of AD. This model will allow for future studies to identify potential downstream drug targets for treating this devastating disease.

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

Abstract: In Alzheimer's diseases (AD), tau pathology is strongly associated with cognitive decline. Preclinical evidence suggests that tau spreads across connected neurons in an activity-dependent manner. Supporting this, cross-sectional AD studies show that tau deposition patterns resemble functional brain networks. However, whether higher functional connectivity is associated with higher rates of tau accumulation is unclear. Here, we combine resting-state fMRI with longitudinal tau-PET in two independent samples including 53 (ADNI) and 41 (BioFINDER) amyloid-biomarker defined AD subjects and 28 (ADNI) vs. 16 (BioFINDER) amyloid-negative healthy controls. In both samples, AD subjects show faster tau accumulation than controls. Second, in AD, higher fMRI-assessed connectivity between 400 regions of interest (ROIs) is associated with correlated tau-PET accumulation in corresponding ROIs. Third, we show that a model including baseline connectivity and tau-PET is associated with future tau-PET accumulation. Together, connectivity is associated with tau spread in AD, supporting the view of transneuronal tau propagation.

Cellular Senescence in Neurodegenerative Diseases.

Abstract: Cellular senescence is a homeostatic biological process characterized by a permanent state of cell cycle arrest that can contribute to the decline of the regenerative potential and function of tissues. The increased presence of senescent cells in different neurodegenerative diseases suggests the contribution of senescence in the pathophysiology of these disorders. Although several factors can induce senescence, DNA damage, oxidative stress, neuroinflammation, and altered proteostasis have been shown to play a role in its onset. Oxidative stress contributes to accelerated aging and cognitive dysfunction stages affecting neurogenesis, neuronal differentiation, connectivity, and survival. During later life stages, it is implicated in the progression of cognitive decline, synapse loss, and neuronal degeneration. Also, neuroinflammation exacerbates oxidative stress, synaptic dysfunction, and neuronal death through the harmful effects of pro-inflammatory cytokines on cell proliferation and maturation. Both oxidative stress and neuroinflammation can induce DNA damage and alterations in DNA repair that, in turn, can exacerbate them. Another important feature associated with senescence is altered proteostasis. Because of the disruption in the function and balance of the proteome, senescence can modify the proper synthesis, folding, quality control, and degradation rate of proteins producing, in some diseases, misfolded proteins or aggregation of abnormal proteins. There is an extensive body of literature that associates cellular senescence with several neurodegenerative disorders including Alzheimer's disease (AD), Down syndrome (DS), and Parkinson's disease (PD). This review summarizes the evidence of the shared neuropathological events in these neurodegenerative diseases and the implication of cellular senescence in their onset or aggravation. Understanding the role that cellular senescence plays in them could help to develop new therapeutic strategies.

Mechanisms of cognitive dysfunction in CKD.

Abstract: Cognitive impairment is an increasingly recognized major cause of chronic disability and is commonly found in patients with chronic kidney disease (CKD). Knowledge of the relationship between kidney dysfunction and impaired cognition may improve our understanding of other forms of cognitive dysfunction. Patients with CKD are at an increased risk (compared with the general population) of both dementia and its prodrome, mild cognitive impairment (MCI), which are characterized by deficits in executive functions, memory and attention. Brain imaging in patients with CKD has revealed damage to white matter in the prefrontal cortex and, in animal models, in the subcortical monoaminergic and cholinergic systems, accompanied by widespread macrovascular and microvascular damage. Unfortunately, current interventions that target cardiovascular risk factors (such as anti-hypertensive drugs, anti-platelet agents and statins) seem to have little or no effect on CKD-associated MCI, suggesting that the accumulation of uraemic neurotoxins may be more important than disturbed haemodynamic factors or lipid metabolism in MCI pathogenesis. Experimental models show that the brain monoaminergic system is susceptible to uraemic neurotoxins and that this system is responsible for the altered sleep pattern commonly observed in patients with CKD. Neural progenitor cells and the glymphatic system, which are important in Alzheimer disease pathogenesis, may also be involved in CKD-associated MCI. More detailed study of CKD-associated MCI is needed to fully understand its clinical relevance, underlying pathophysiology, possible means of early diagnosis and prevention, and whether there may be novel approaches and potential therapies with wider application to this and other forms of cognitive decline.