A High-Methionine Diet for One-Week Induces a High Accumulation of Methionine in the Cerebrospinal Fluid and Confers Bipolar Disorder-like Behavior in Mice

Methionine (Met) is considered the most toxic amino acid in mammals. Here, we investigated biochemical and behavioral impacts of ad libitum one-week feeding of high-Met diets on mice. Adult male mice were fed the standard rodent diet that contained 0.44% Met (1×) or a diet containing 16 graded Met doses (1.2×–13×). High-Met diets for one-week induced a dose-dependent decrease in body weight and an increase in serum Met levels with a 2.55 mM peak (versus basal 53 µM) on the 12×Met diet. Total homocysteine (Hcy) levels were also upregulated while concentrations of other amino acids were almost maintained in serum. Similarly, levels of Met and Hcy (but not the other amino acids) were highly elevated in the cerebrospinal fluids of mice on the 10×Met diet; the Met levels were much higher than Hcy and the others. In a series of behavioral tests, mice on the 10×Met diet displayed increased anxiety and decreased traveled distances in an open-field test, increased activity to escape from water soaking and tail hanging, and normal learning/memory activity in a Y-maze test, which were reflections of negative/positive symptoms and normal cognitive function, respectively. These results indicate that high-Met ad libitum feeding even for a week can induce bipolar disorder-like disease models in mice.

Is The Association Between Cognitive Decline And Mortality Modified By High Blood Pressure Among The Oldest Old?

Few studies have systematically explored the association between cognitive decline and mortality among the aged (above 80 years old) and also have limited evidence of the potential effect modifiers between them. Therefore, this study included 14,891 aged (mean age: 90.3±7.5 years) and 10,904 aged deaths with 34,486 person-years were observed. Cognitive decline was continuous and stratified into ten categories. Potential effect modifiers were identified as age, sex, blood pressure (BP) and high BP related diseases, including hypertension and cardiovascular disease (CVD) mortality. Cox proportional hazards model was used to evaluate the relationship between them after adjusting for demographic characteristics, socioeconomic status, lifestyle factors, leisure activities and health conditions. Compared to those with maintained high normal cognitive function, participants who have declined to severe cognitive impairment from a high normal cognitive function, low normal cognitive function and mild cognitive impairment have 55%, 56% and 63% mortality risks respectively. The multivariable-adjusted model indicated that the aged with decreasing one more point in MMSE score per year, had around 4% higher risk of mortality. There was a significant association of interaction of cognitive decline-mortality and sex (P=0.013) as well as hypertension (P=0.004) but with no significant association among age (P=0.277), high BP (P=0.082), and CVD mortality (P=0.058). Our findings suggest that periodic screen cognitive decline and strengthen BP control may be necessary for public health.

Apathy as a Risky Neuropsychiatric Syndrome of Progression From Normal Aging to Mild Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis

Background: Apathy has been suggested as a potential predictor of mild cognitive impairment (MCI) progression to dementia. Whether it might predict the transition from normal cognitive function to cognitive impairment has been less studied. The current study aimed to provide a comprehensive summary of the evidence on the association between apathy and the transition from normal cognitive function to cognitive impairment.Methods: We searched the PubMed, Embase, and Web of Science databases for longitudinal prospective cohort studies that evaluated apathy at baseline in the cognitively normal population and had cognitive impairment as the outcome. Random effects models were used, and heterogeneity was explored with stratification. The stability of the synthesized result was indicated using sensitivity analysis by excluding one study each time and recalculating the overall effect.Results: Ten studies comprising 26,195 participants were included. Apathy status was available for 22,101 participants. Apathy was present in 1,803 of 22,101 participants (8.16%). Follow-up ranged from 1 to 13 years. The combined odds ratio (OR) of cognitive impairment for patients with apathy was 2.07 (95% CI: 1.43–2.99; I2 = 86%), and the combined hazard ratio was 2.70 (95% CI: 1.38–5.27; I2 = 94%). The OR meta-analyses for different conversion outcomes were MCI (OR = 3.38, 95% CI: 1.57–7.28; I2 =71%), cognitive decline (OR = 1.27, 95% CI: 0.81–2.00; I2 = 64%) and dementia (OR = 2.12, 95% CI: 1.32–3.41; I2 = 86%). Subgroup analysis suggested that the association between apathy and cognitive impairment changed with age, depression adjustments, apathy measurement, and follow-up time.Conclusions: Apathy was associated with a greater than 2-fold increased risk of progression to cognitive impairment in the cognitively normal population. Future interventions targeting apathy management in the general population may reduce the risk of cognitive impairment.

Urinary Incontinence and Alzheimer’s Disease: Insights From Patients and Preclinical Models

Alzheimer’s disease effects a large percentage of elderly dementia patients and is diagnosed on the basis of amyloid plaques and neurofibrillary tangles (NFTs) present in the brain. Urinary incontinence (UI) is often found in the elderly populations and multiple studies have shown that it is more common in Alzheimer’s disease patients than those with normal cognitive function. However, the link between increased UI and Alzheimer’s disease is still unclear. Amyloid plaques and NFTs present in micturition centers of the brain could cause a loss of signal to the bladder, resulting in the inability to properly void. Additionally, as Alzheimer’s disease progresses, patients become less likely to recognize the need or understand the appropriate time and place to void. There are several treatments for UI targeting the muscarinic and β3 adrenergic receptors, which are present in the bladder and the brain. While these treatments may aid in UI, they often have effects on the brain with cognitive impairment side-effects. Acetylcholine esterase inhibitors are often used in treatment of Alzheimer’s disease and directly oppose effects of anti-muscarinics used for UI, making UI management in Alzheimer’s disease patients difficult. There are currently over 200 pre-clinical models of Alzheimer’s disease, however, little research has been done on voiding disfunction in these models. There is preliminary data suggesting these models have similar voiding behavior to Alzheimer’s disease patients but much more research is needed to understand the link between UI and Alzheimer’s disease and discover better treatment options for managing both simultaneously.

The maintained attention assessment in patients affected by Myalgic encephalomyelitis/chronic fatigue syndrome: a reliable biomarker?

The maintained attention is the cause of great functional limitations in CFS/ME, a disease that mainly affects women in the central period of life. Cognitive function is explored using the Montreal Cognitive Assessment, the maintained attention using the Toulouse-Piéron test with which the Global Index of Attention and Perception (GIAP) is obtained, the fatigue using the visual analog scale and the perception of effort using the modified Borg scale. The final sample were 84 patients (66 women/18 men) who met diagnostic criteria (Fukuda-1994, Carruthers-2011) and 22 healthy controls (14 women/8 men). Most of patients maintain normal cognitive function, showing low or very low attention score in the 70% of patients with a marked cognitive fatigue compared to the control group (p < 0.05). There were no significant differences between genders in GIAP or fatigue for CFS/ME; however, sick women perceive cognitive effort higher than men. Deficits in sustained attention and the perception of fatigue, so effort after performing the proposed test are a sensitive and reliable indicator that allows us to substantiate a clinical suspicion and refer patients for further studies in order to confirm or rule out CFS/ME.

Cognitive Decline Risk Stratification in People with Late-Onset Epilepsy of Unknown Etiology: An Electroencephalographic Connectivity and Graph Theory Pilot Study

Background: Although people with late onset epilepsy of unknown etiology (LOEU) are at higher risk of cognitive decline compared to the general population, we still lack affordable tools to predict and stratify their risk of dementia. Objective: This pilot-study investigates the potential application of electroencephalography (EEG) network small-world (SW) properties in predicting cognitive decline among patients with LOEU. Methods: People diagnosed with LOEU and normal cognitive examination at the time of epilepsy diagnosis were included. Cerebrospinal fluid biomarkers, brain imaging, and neuropsychological assessment were performed at the time of epilepsy diagnosis. Baseline EEG was analyzed for SW properties. Patients were followed-up over time with neuropsychological testing to define the trajectory of cognitive decline. Results: Over 5.1 years of follow-up, among 24 patients diagnosed with LOEU, 62.5% were female, mean age was 65.3 years, thirteen developed mild cognitive impairment (MCI), and four developed dementia. Patients with LOEU developing MCI had lower values of SW coefficients in the delta (p = 0.03) band and higher SW values in the alpha frequency bands (p = 0.02) compared to patients having normal cognition at last follow-up. The two separate ANOVAs, for low and alpha bands, confirmed an interaction between SW and cognitive decline at follow-up. A similar gradient was confirmed for patients developing dementia compared to those with normal cognitive function as well as to those developing MCI. Conclusion: Baseline EEG analysis through SW is worth investigating as an affordable, widely available tool to stratify LOEU patients for their risk of cognitive decline.

Correlation of CD4+CD57+, CD8+CD57+, CD4+KLRG1+, CD8+KLRG1+ T Cells Percentage and Serum MMP-9 Level with Cognitive Dysfunction among Systemic Lupus Erythematosus Patients

Background: ‘Lupus brain fog’ is a phenomenon of cognitive function decline in SLE patients. Premature immunosenescence in SLE was presumed to play a significant role in the mechanism of cognitive dysfunction. Aim: To prove the correlation between the terminally-differentiated CD4+CD57+, CD8+CD57+, CD4+KLRG1+, and CD8+KLRG1+ T cells & serum levels of MMP-9 with cognitive dysfunction in SLE patients. Methods: 53 women SLE were conducted to perform MMSE and MoCA-Ina tests to evaluate cognitive function. Immunosenescence was observed by measuring the terminallydifferentiated CD4+CD57+, CD8+CD57+, CD4+KLRG1+, and CD8+KLRG1+ T cells, which were measured by flowcytometry. In addition, MMP-9, an enzyme produced by terminallydifferentiated T cells, was measured using ELISA. Results: SLE patients with cognitive dysfunction based on MMSE and MoCA-Ina test had higher percentage of CD4+CD57+, CD8+CD57+, CD4+KLRG1+, CD8+KLRG1+ T cells and serum levels of MMP-9 compared to patients with normal cognitive function. CD4+CD57+, CD8+CD57+, CD4+KLRG1+, CD8+KLRG1+ T cells percentage and serum MMP-9 level showed negative correlation with both MMSE scores (r = -0.286; r = -0.447; r = -0.279; r = -0.537; r = 0,411) and MoCA-Ina scores (r = -0.454; r = -0.539; r = -0.435; r = -0.535; r = -0.648). Meanwhile, percentage of CD4+CD57+, CD8+CD57+, CD4+KLRG1+ and CD8+KLRG1+ T cells showed positive correlation with serum MMP-9 level (r = 0.292; r = 0.414; r = 0.449; r = 0.374). Conclusion: Expansion of CD4+CD57+, CD8+C57+, CD4+KLRG1+, CD8+KLRG1+ terminally differentiated T cells & increase of serum MMP-9 level are correlated with cognitive dysfunction in SLE patients

Prevalence of cognitive impairment in Chinese older inpatients and its relationship with 1-year adverse health outcomes: a multi-center cohort study

Background Previous studies on the relationship between cognitive impairment and adverse outcomes among geriatric inpatients are not representative of older inpatients in China because of insufficient sample sizes or single-center study designs. The purpose of our study was to examine the prevalence of cognitive impairment and the relationship between cognitive impairment and 1-year adverse health outcomes in older inpatients. Methods This study was a large-scale multi-center cohort study conducted from October 2018 to February 2020. Six tertiary hospitals across China were selected using a two-stage cluster sampling method, and eligible older inpatients were selected for the baseline survey and follow-up. The Mini Cognitive Scale and the FRAIL scale were used to screen for cognitive impairment and frailty, respectively. The EuroQol-5 Dimension-5 Level questionnaire was used to assess health-related quality of life (HRQoL). We used a generalized estimating model to evaluate the relationship between cognitive impairment and adverse outcomes. Results The study included 5008 men (58.02%) and 3623 women (41.98%), and 70.64% were aged 65–75 years, and 26.27% were aged 75–85 years. Cognitive impairment was observed in 1756 patients (20.35%). There were significant differences between participants with cognitive impairment and those with normal cognitive function for age, gender, surgery status, frailty, depression, handgrip strength and so on. After adjusting for multiple covariates, compared with patients with normal cognitive function, the odds ratio for 1-year mortality was 1.216 (95% confidence interval [CI]: 1.076–1.375) and for 1-year incidence of frailty was 1.195 (95% CI: 1.037–1.376) in patients with cognitive impairment. Similarly, the regression coefficient of 1-year HRQoL was − 0.013 (95% CI: − 0.024−− 0.002). In the stratified analysis, risk of adverse outcome within 1 year was higher in older patients with cognitive impairment aged over 75 years than those aged 65–74 years. Conclusions We revealed that cognitive impairment was highly correlated with occurrence of 1-year adverse health outcomes (death, frailty, and decreased HRQoL) in older inpatients, which provides a basis for formulating effective intervention measures. Trial registration Chinese Clinical Trial Registry, ChiCTR1800017682, registered 09 August 2018.

Occupational Risk Exposures and Adverse Health Findings Among Farmers in Southern Philippines

Introduction. Pesticides are widely used in the agricultural sector to increase production by cutting costs and improving product quality. However, these chemicals come with serious health effects when individuals are exposed to large quantities at once or low amounts over time. Objective. This study aimed to identify the health symptoms and physical assessment findings affecting farmers from their repeated occupational exposure to pesticides in a rural region in the Philippines. Methods. This research study used a cross-sectional design, and samples were drawn based on a multistage sampling of 387 agricultural workers. The target site was in the southern Philippines, and the sample was selected randomly from the identified municipalities. Survey questionnaires were given to the respondents, and a physical assessment was made by medical doctors and trained registered nurses. The data were encoded using SPSS™ 13.0. The statistics used were both descriptive and inferential. Results. The farmers used pesticides in their farms with an average of 2.3 days per week (SD: 2.13). The mean total spraying time was 3.07 hours (SD: ± 14.76) per day. The average amount of pesticide used in an application was 1.33 L per application (SD: ± 6.53). Sixty-three percent (63%) had spills while spraying, and 47% reported having spilled pesticides while mixing. Farmers were assessed and found to have experienced symptoms and exhibited physical assessment findings surrounding the following body systems: general, EENT, neurologic, gastrointestinal, respiratory, cardiovascular, and integumentary systems. Abnormalities in laboratory parameters were also observed among the respondents. The mini-mental state examination was done to test if the respondents showed signs of cognitive impairment. The results showed that most respondents (93.95%) had normal cognitive function, while 6.05% of respondents had some level of cognitive impairment. Associations were also tested using Phi Coefficient, and certain pesticide exposure variables were associated with farmers' physical findings and symptoms experienced by farmers. Conclusion. This study translates pesticide’s health impact by identifying the common symptoms experienced by farmers and concerning physical assessment findings. The study found that farmers suffered from various symptoms concerning the general health, eye, ears, nose, and throat region, neurological system, gastrointestinal system, respiratory system, cardiovascular system, and the integumentary system. In addition, the laboratory parameters of the participants also exhibited abnormalities indicative of exposure and possible adverse effects from pesticides.

Is the Association Between Cognitive Decline and Mortality Modified by High Blood Pressure Among the Oldest Old?

BackgroundFew studies have systematically explored the association between cognitive decline and mortality among the oldest old (above 80 years old) and also have limited evidence of the potential effect modifiers between them. The purpose of this study is to evaluate the association between cognitive decline, stratified by detailed levels, and mortality as well as the potential effect modifiers between them.MethodsThis study included 14,891 oldest old (mean age: 90.3±7.5 years) and 10,904 oldest old deaths with 34,486 person-years were observed. Cognitive decline was continuous and stratified into ten categories. Potential effect modifiers were identified as age, sex, blood pressure (BP) and high BP related diseases, including hypertension and cardiovascular disease (CVD) mortality. Cox proportional hazards model was used to evaluate the relationship between them after adjusting for demographic characteristics, socioeconomic status, lifestyle factors, leisure activities and health conditions.ResultsIn the ten categories, compared to those with maintained high normal cognitive function, participants who have declined to severe cognitive impairment from a high normal cognitive function, low normal cognitive function and mild cognitive impairment have 55%, 56% and 63% mortality risks respectively. Cognitive function declined to mild cognitive impairment from a high normal cognitive function and low normal cognitive function with mortality risks 25% and 17% respectively. The multivariable-adjusted model indicated that the oldest old with decreasing one more point in MMSE score per year, had around 4% higher risk of mortality. There was a significant association of interaction of cognitive decline-mortality and sex (P=0.013) as well as hypertension (P=0.004) but with no significant association among age (P=0.277), high BP (P=0.082), and CVD mortality (P=0.058).ConclusionsOur findings suggest that cognitive decline is associated with an elevated risk of all-cause mortality among the oldest old, even at a low level of cognitive decline. Low BP, non-hypertension and non-CVD mortality may be potentially beneficial in the cognitive decline-mortality association.