The inverse association between the apolipoprotein E ε4 allele and C-reactive protein levels is stronger in persons with obesity and diabetes.

BACKGROUND: C-reactive protein (CRP) is lower in patients who carry the apolipoprotein E epsilon 4 allele variant (APOEε4) of the APOE gene. This could however be explained by other factors observed in APOEε4 carriers, such as lower body mass index (BMI), possibly less diabetes and more use of statins, all associated with CRP concentrations. OBJECTIVES: To assess the association between CRP and APOEε4 stratified by BMI, statin use and diabetes. METHODS: We included 2700 community-dwelling older adults from the Hordaland health study with genotyping of the APOE gene by a one-step polymerase chain reaction and CRP measured using immuno-MALDI-TOF MS. Differences in CRP concentrations by APOE (ε4 vs no ε4) were assessed using the Mann-Whitney U tests, also stratified by statin use, diabetes and BMI categories. Finally, we performed linear regression with log (CRP) as the outcome and APOEε4 together with statin use, diabetes, BMI and their respective interactions. RESULTS: CRP was higher in APOEε4 carriers irrespective of BMI, diabetes and statin use. In APOEε4 non-carriers, CRP was elevated with diabetes and obesity as expected. However, this was attenuated or even reversed in APOEε4 carriers. Such differences were not observed for statin use. CONCLUSIONS: Statin use, obesity or diabetes did not confound the known association between the APOEε4 allele and lower CRP. Our data suggest that CRP is less responsive to inflammatory cues involved in diabetes and obesity in APOEε4 carriers. Epidemiological studies should take note of these relationships, as CRP, APOEε4, diabetes and obesity are both linked to neurodegenerative and cardiovascular disease.

Corrigendum: Effects of Anthocyanin Supplementation on Serum Lipids, Glucose, Markers of Inflammation and Cognition in Adults With Increased Risk of Dementia - A Pilot Study.

[This corrects the article DOI: 10.3389/fgene.2019.00536.].

Pulmonary embolism in a patient with Klinefelter's syndrome. / Lungeembolisme hos en pasient med Klinefelters syndrom.

BACKGROUND: Dyspnoea and syncope are common causes of admission to hospitals. Pulmonary embolism is often a differential diagnosis, and by examining the clinical history the clinician searches for known predisposing factors. This case report highlights the importance of Klinefelter's syndrome as a predisposing factor for venous thromboembolism. The syndrome is caused by an extra X chromosome in men, among whom the prevalence is estimated to be 1:500-1:1000. Probably only 25 % of men with the syndrome are diagnosed. CASE PRESENTATION: A man in his forties was admitted to hospital due to dyspnoea and syncope. CT showed submassive pulmonary embolism. The course illustrates the challenges of pulmonary embolism and its association with Klinefelter's syndrome. INTERPRETATION: Several studies have shown an increased incidence of venous thromboembolism in patients with Klinefelter's syndrome. Klinefelter's patients have a higher pre-test likelihood of venous thromboembolism than other patients, similar to patients with hereditary thrombophilia. Klinefelter's syndrome is a persistent risk factor for recurrent thromboembolism. Thus, Klinefelter's syndrome impacts both the diagnosis and treatment of thromboembolic disease.

Association of Malnutrition with Functional and Cognitive Trajectories in People Living with Dementia: A Five-Year Follow-Up Study.

BACKGROUND: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline. OBJECTIVE: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia. METHODS: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer's disease (AD) (n = 103), Lewy body dementia (LBD) (n = 74), and other dementias (OD) (n = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models. RESULTS: At baseline, the prevalence of general malnutrition was 28.7%; 17.3% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline. CONCLUSION: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis.

The Truth behind the Zeros: A New Approach to Principal Component Analysis of the Neuropsychiatric Inventory.

Psychiatric syndromes in dementia are often derived from the Neuropsychiatric Inventory (NPI) using principal component analysis (PCA). The validity of this statistical approach can be questioned, since the excessive proportion of zeros and skewness of NPI items may distort the estimated relations between the items. We propose a novel version of PCA, ZIBP-PCA, where a zero-inflated bivariate Poisson (ZIBP) distribution models the pairwise covariance between the NPI items. We compared the performance of the method to classical PCA under zero-inflation using simulations, and in two dementia-cohorts (N = 830, N = 1349). Simulations showed that component loadings from PCA were biased due to zero-inflation, while the loadings of ZIBP-PCA remained unaffected. ZIBP-PCA obtained a simpler component structure of "psychosis," "mood" and "agitation" in both dementia-cohorts, compared to PCA. The principal components from ZIBP-PCA had component loadings as follows: First, the component interpreted as "psychosis" was loaded by the items delusions and hallucinations. Second, the "mood" component was loaded by depression and anxiety. Finally, the "agitation" component was loaded by irritability and aggression. In conclusion, PCA is not equipped to handle zero-inflation. Using the NPI, PCA fails to identify components with a valid interpretation, while ZIBP-PCA estimates simple and interpretable components to characterize the psychopathology of dementia.

Correction: Plasma kynurenines and prognosis in patients with heart failure.

[This corrects the article DOI: 10.1371/journal.pone.0227365.].

The Effect of Drug-Eluting Stents on Target Lesion Revascularization in Native Coronary Arteries: Results from the NORSTENT Randomized Study.

BACKGROUND: The NORSTENT trial randomized 9,013 patients to percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) or bare-metal stent (BMS) with 5-year follow-up. No difference was found in the composite primary outcome of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up. Secondary outcomes included repeat revascularizations, which were reduced by DES. We report the occurrence of target lesion revascularization (TLR) in time and across demographic and clinical subgroups in patients with lesions in native coronary arteries (n = 8,782). RESULTS: Clinically driven TLR was performed on 488 (5.6%) of the 8,782 patients during 5 years of follow-up. Male gender, older age, visible thrombus in the lesion, and larger stent diameter were associated with less TLR; multivessel disease and longer stents were associated with a higher risk of TLR. There was a substantial and highly significant reduction of the risk of any TLR after 5 years in the DES group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.36-0.52], p < 0.001). The effect of DES on TLR was limited in time to the first 2 years in the study with no evidence of a later rebound effect. The reduction in TLR after DES insertion was consistent across subgroups defined by gender, age, diabetes status, renal function, and lesion and stent characteristics. The number needed to treat with DES (vs. BMS) to prevent 1 TLR ranged from 4 to 110 across clinically relevant subgroups. CONCLUSION: DES have a time-limited effect on the rate of TLR, but with a substantial and highly significant reduction in the first 2 years after the procedure. This effect was found to be consistent across all important clinical subgroups.

Severe delirium after GHB abuse. / Alvorlig delir etter GHB-misbruk.

BACKGROUND: The management of benzodiazepine-resistant GHB withdrawal requires careful consideration of GHB pharmacodynamics. CASE PRESENTATION: A young woman was admitted with tachycardia, confusion, agitation and delusions the day after attempting to quit a daily, high-dose GHB habit. A total of 225 mg of diazepam had no effect. She was sedated with propofol and intubated. An extubation attempt after 24 hours was followed by recurrence of delirium. After reintubation she required high doses of propofol, alfentanil and dexmedetomidine to maintain sedation for two days. Baclofen and diazepam were introduced on the third day, allowing dose reductions in anaesthetic agents the fourth day and extubation on the fifth day with resolution of the delirium. INTERPRETATION: GHB targets the GABAB receptor and downregulates it with abuse. Most anaesthetic agents affect the GABAA receptor. Our report suggests that baclofen, a GABAB receptor agonist, may reduce the need for anaesthetic agents and facilitate recovery.

Greater Variability in Cognitive Decline in Lewy Body Dementia Compared to Alzheimer's Disease.

Studies indicate more rapid cognitive decline in patients with Lewy body dementia (LBD) compared to Alzheimer's disease (AD). However, there has been less focus on any difference in the variability of cognitive decline. We assessed Mini-Mental State Examination (MMSE) test performance at baseline and annually for 5 years in 222 patients with mild dementia in the DemVest study who had either AD (137) or LBD (85). We used linear mixed models (LMMs) with random intercepts (variability in MMSE at baseline) and slopes (variability in MMSE decline), with years in study, age, gender, and diagnosis as independent variables. A non-linear (quadratic) trajectory was selected, interacting with age and diagnosis. To study differences in variance, we compared a regular LMM (i.e., a homoscedastic model), which assumes equal variance across groups, to a heteroscedastic model, assuming unequal intercept and slope variance based on diagnosis. The heteroscedastic model gave a better fit (Likelihood ratio test: χ2 = 30.3, p < 0.001), showing overall more variability in LBD. Further, the differences in intercept and slope variances were tested using a modified Wald test. The MMSE intercept variance (AD: 2.78, LBD: 7.75, difference: 4.97, p = 0.021) and slope variance (AD: 2.62, LBD 7.81, difference: 5.19, p = 0.004) were both higher in LBD. In conclusion, patients with LBD in the DemVest study have a higher variability in MMSE scores at study inclusion, and in MMSE decline compared to AD. Accordingly, clinical trials on LBD may need a larger sample size compared to AD.

Plasma kynurenines and prognosis in patients with heart failure.

BACKGROUND: Metabolites of the kynurenine pathway (mKP) relate to important aspects of heart failure pathophysiology, such as inflammation, energy-homeostasis, apoptosis, and oxidative stress. We aimed to investigate whether mKP predict mortality in patients with heart failure. METHODS: The study included 202 patients with heart failure (73.8% with coronary artery disease (CAD)), propensity score matched to 384 controls without heart disease, and 807 controls with CAD (71%). All underwent coronary angiography and ventriculography at baseline. Plasma mKP, pyridoxal 5'phosphate (PLP) and CRP were measured at baseline. Case-control differences were assessed by logistic regression and survival by Cox regression, adjusted for age, gender, smoking, diabetes, ejection fraction, PLP, eGFR and CRP. Effect measures are reported per standard deviation increments. RESULTS: Higher plasma levels of kynurenine, 3- hydroxykynurenine (HK), quinolinic acid (QA), the kynurenine-tryptophan-ratio (KTR) and the ratio of HK to xanthurenic acid (HK/XA) were detected in heart failure compared to both control groups. The mortality rate per 1000 person-years was 55.5 in patients with heart failure, 14.6 in controls without heart disease and 22.2 in CAD controls. QA [HR 1.80, p = 0.013], HK [HR 1.77, p = 0.005], HK/XA [HR 1.67, p < 0.001] and KTR [HR 1.55, p = 0.009] were associated with increased mortality in patients with heart failure, while XA [HR 0.68-0.80, p = 0.013-0.037] were associated with lower mortality in all groups. HK and HK/XA had weak associations with increased mortality in CAD-controls. CONCLUSION: Elevated plasma levels of mKP and metabolite ratios are associated with increased mortality, independent of CAD, in patients with heart failure.

The individual course of neuropsychiatric symptoms in people with Alzheimer's and Lewy body dementia: 12-year longitudinal cohort study.

INTRODUCTION: Understanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals. METHOD: Primary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia). RESULTS: We found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms. CONCLUSIONS: We observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.

Components of the choline oxidation pathway modify the association between the apolipoprotein ε4 gene variant and cognitive decline in patients with dementia.

BACKGROUND: Metabolites involved in one-carbon metabolism (OCM) may predict cognitive prognosis in dementia. The link between OCM, apolipoprotein E (APOE), and DNA methylation creates a biologically plausible mechanism of interaction. AIM: To assess OCM metabolites as predictors of 5-year cognitive prognosis in patients with mild dementia, and in subgroups defined by the APOEε4 allele variant. METHODS: We followed one-hundred and fifty-two patients with mild dementia (86 with Alzheimer's disease, 66 with Lewy body dementia, including 90 with at least one APOEε4 allele) for 5 years with annual Mini-Mental State Examinations (MMSE). Total homocysteine, methionine, choline, betaine, dimethylglycine, sarcosine, folate, cobalamin and pyridoxal 5'-phoshate were measured in serum at baseline. We used linear mixed models to assess metabolite-MMSE associations, including 3-way interactions between metabolites, time, and APOEε4. False-discovery rate adjusted p-values (Q-values) are reported. RESULTS: Metabolite concentrations were not different in patients with dementia according to the presence of APOEε4. Overall, serum concentration of total homocysteine was inversely associated with MMSE performance, while betaine was positively associated with MMSE (Q < 0.05), but neither was associated with MMSE decline. Serum concentrations of betaine, dimethylglycine and sarcosine, however, were associated with slower MMSE decline in patients with APOEε4, but with faster MMSE decline in patients without the allele (all 3-way interactions: Q < 0.05). CONCLUSION: Components of the choline oxidation pathway are associated with a better cognitive prognosis in APOEε4 carriers and a worse cognitive prognosis in non-carriers. Further research investigating targeted metabolic interventions according to APOE allele status is warranted.

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia.

BACKGROUND: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain. AIM: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis. METHODS: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis. RESULTS: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele (P-value of the interactions < .05). CONCLUSIONS: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.

Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia.

INTRODUCTION: Circulating tryptophan (Trp) and its downstream metabolites, the kynurenines, are potentially neuroactive. Consequently, they could be associated with neuropsychiatric symptoms and cognitive prognosis in patients with dementia. OBJECTIVE: The objective of this study was to assess associations between circulating kynurenines, cognitive prognosis, and neuropsychiatric symptoms. METHODS: We measured baseline serum Trp, neopterin, pyridoxal 5'-phosphate (PLP), and 9 kynurenines in 155 patients with mild dementia (90 with Alzheimer's disease, 65 with Lewy body dementia). The ratios between kynurenine and Trp and kynurenic acid (KA) to kynurenine (KKR) were calculated. The Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were administered at baseline and annually over 5 years. Associations between baseline metabolite concentrations with MMSE and the NPI total score were assessed using a generalized structural equation model (mixed-effects multiprocess model), adjusted for age, sex, current smoking, glomerular filtration rate, and PLP. Post hoc associations between KKRs and individual NPI items were assessed using logistic mixed-effects models. False discovery rate (0.05)-adjusted P values (Q values) are reported. RESULTS: Kynurenine had a nonlinear quadratic relationship with the intercept of the MMSE scores over 5 years (Q < 0.05), but not with the slope of MMSE decline. Kynurenine was associated with a higher NPI total score over time (Q < 0.001). Post hoc, both KKR and KA were associated with more hallucinations (Q < 0.05). CONCLUSIONS: Kynurenine has a complex relationship with cognition, where both low and high levels were associated with poor cognitive performance. A higher KKR indicated risk for neuropsychiatric symptoms, especially hallucinations.

Effects of Anthocyanin Supplementation on Serum Lipids, Glucose, Markers of Inflammation and Cognition in Adults With Increased Risk of Dementia - A Pilot Study.

BACKGROUND: Anthocyanins may protect against cardiovascular related cognitive decline and dementia. OBJECTIVE: Open-label study to measure changes in serum lipids, glucose, glycosylated hemoglobin (HbA1c), and markers of inflammation after anthocyanin supplementation in people with increased risk of dementia. As a secondary endpoint we examined potential changes in a battery of cognitive test in the anthocyanin group (AG). A total of 27 individuals with mild cognitive impairment (MCI) (n = 8) or stable non-obstructive coronary artery disease (CAD) (n = 19) consumed two Medox® capsules, each containing 80 mg of natural purified anthocyanins, twice daily for 16 weeks. They provided blood samples and performed a short battery of cognitive tests. Twenty healthy normal controls (NC) (n = 20) provided blood samples, but did not receive any intervention and did not perform cognitive tests. RESULTS: There was a significant difference between groups for CCL-5/RANTES [regulated on activation, normal T-cell expressed and secreted (RANTES)]. In addition, total cholesterol and triglycerides were significantly increased in the AG. Improvements in memory and executive test scores were observed. No adverse effects were reported. CONCLUSION: The results of this pilot study were largely inconclusive with regard to the potential protective effects of anthocyanin supplementation. However, anthocyanins were well tolerated, and compliance was high. Larger, placebo-controlled studies to explore the potential effects of anthocyanins on dementia risk are encouraged. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02409446.

Does pain, psychological distress and deteriorated family economy follow traumatic amputation among war casualties? A retrospective, cross-sectional study from Gaza.

OBJECTIVES: The aim of this study was to explore determinants of psychosocial distress and pain in patients who have survived severe extremity amputation in Gaza. SETTING: This study was conducted in a secondary care rehabilitation centre in Gaza, Palestine. The clinic is Gaza's sole provider of artificial limbs. PARTICIPANTS: We included 254 civilian Palestinians who had survived but lost one or more limb(s) during military incursions from 2006 to 2016. We included patients with surgically treated amputation injuries who attended physical rehabilitation at a specialist prosthesis centre in Gaza. Amputees with injuries prior to 2006 or non-military related injuries were excluded.We assessed their pain and psychological stress using the General Health Questionnaire (GHQ-12). We used income, amputation severity scored by proximity to torso, current employment status, loss of family members and loss of home as independent variables. RESULTS: The amputees median age was 23 years at the time of trauma, while a median of 4.3 years had passed from trauma to study inclusion. Nine of 10 were male, while 43 were children when they were amputated (17%≤18 years). One hundred and ninety-one (75%) were unemployed and 112 (44%) reported unemployment caused by being amputated. Pain was the most frequent problem, and 80 amputees (32%) reported to suffer from daily pain. Family income was significantly correlated with the physical pain (OR=0.54, CI 0.36 to 0.80, p=0.002). Psychological distress was higher among unemployed amputees (OR=1.36, CI 1.07 to 1.72, p=0.011). We found no association between psychological distress (GHQ-scores) and the extent of the initial amputation. CONCLUSION: Pain and psychological distress following war-related extremity amputation of one or more limbs correlated stronger with deteriorated family economy and being unemployed than with the anatomical and medical severity of extremity amputations.

Plasma Amino Acids and Incident Type 2 Diabetes in Patients With Coronary Artery Disease.

OBJECTIVE: Altered plasma amino acid levels have been implicated as markers of risk for incident type 2 diabetes; however, amino acids are also related to established diabetes risk factors. Therefore, potential for confounding and the impact from competing risks require evaluation. RESEARCH DESIGN AND METHODS: We prospectively followed 2,519 individuals with coronary artery disease but without diabetes. Mixed Gaussian modeling identified potential for confounding. Confounding, defined as a change in effect estimate (≥10%), was investigated by comparing amino acid-incident diabetes risk in a Cox model containing age and sex with that in models adjusted for potential confounders (BMI, estimated glomerular filtration rate, HDL cholesterol, triacylglycerol, C-reactive protein), which were further adjusted for plasma glucose, competing risks, and multiple comparisons (false discovery rate = 0.05, Benjamini-Hochberg method). Finally, component-wise likelihood-based boosting analysis including amino acids and confounders was performed and adjusted for competing risks in order to identify an optimal submodel for predicting incident diabetes. RESULTS: The mean age of the source population was 61.9 years; 72% were men. During a median follow-up of 10.3 years, 267 incident cases of diabetes were identified. In age- and sex-adjusted models, several amino acids, including the branched-chain amino acids, significantly predicted incident diabetes. Adjustment for confounders, however, attenuated associations. Further adjustment for glucose and multiple comparisons rendered only arginine significant (hazard ratio/1 SD 1.21 [95% CI 1.07-1.37]). The optimal submodel included arginine and asparagine. CONCLUSIONS: Adjustment for relevant clinical factors attenuated the amino acid-incident diabetes risk. Although these findings do not preclude the potential pathogenic role of other amino acids, they suggest that plasma arginine is independently associated with incident diabetes. Both arginine and asparagine were identified in an optimal model for predicting new-onset type 2 diabetes.

Serum Potassium Is Associated with Cognitive Decline in Patients with Lewy Body Dementia.

BACKGROUND: Epidemiological studies link serum potassium (K+) to cognitive performance, but whether cognitive prognosis in dementia is related to K+ levels is unknown. OBJECTIVE: To determine if K+ levels predict cognitive prognosis in dementia and if this varies according to diagnosis or neuropathological findings. METHODS: This longitudinal cohort study recruited 183 patients with mild Alzheimer's disease or Lewy body dementia (LBD). Serum K+ and eGFR were measured at baseline and medications which could affect K+ registered. The Mini-Mental State Examination (MMSE) was measured annually over 5 years, and mortality registered. Association between K+ and √(30 -MMSE) was estimated overall, and according to diagnosis (joint model). Associations between MMSE-decline and K+ were assessed in two subgroups with neuropathological examination (linear regression) or repeated measurements of K+ over 3 years (mixed model). RESULTS: Serum K+ at baseline was associated with more errors on MMSE over time (Estimate 0.18, p = 0.003), more so in LBD (p = 0.048). The overall association and LBD interaction were only significant in the 122 patients not using K+ relevant medication. Repeated K+ measures indicated that the association with MMSE errors over time was due to a between-person effect (p < 0.05, n = 57). The association between the annual MMSE decline was stronger in patients with autopsy confirmed LBD and more α-synuclein pathology (all: p < 0.05, n = 41). CONCLUSION: Higher serum K+ predicts poorer cognitive prognosis in demented patients not using medications which affect K+, likely a between-person effect seen mainly in LBD.

The kynurenine pathway and cognitive performance in community-dwelling older adults. The Hordaland Health Study.

INTRODUCTION: Tryptophan, its downstream metabolites in the kynurenine pathway and neopterin have been associated with inflammation and dementia. We aimed to study the associations between plasma levels of these metabolites and cognitive function in community-dwelling, older adults. METHODS: This cross-sectional study included 2174 participants aged 70-72 years of the community-based Hordaland Health Study. Tryptophan, kynurenine, neopterin and eight downstream kynurenines were measured in plasma. Kendrick Object Learning Test (KOLT), Digit Symbol Test (DST) and the Controlled Oral Word Association Test (COWAT) were all outcomes in standardized Zellner's regression. The Wald test of a composite linear hypothesis of an association with each metabolite was adjusted by the Bonferroni method. Age, body mass index, C-reactive protein, depressive symptoms, diabetes, education, glomerular filtration rate, hypertension, previous myocardial infarction, prior stroke, pyridoxal 5'phosphate, sex and smoking were considered as potential confounders. RESULTS: Higher levels of the kynurenine-to-tryptophan ratio (KTR) and neopterin were significantly associated with poorer, overall cognitive performance (p < 0.002). Specifically, KTR was negatively associated with KOLT (ß -0.08, p = 0.001) and COWAT (ß -0.08, p = 0.001), but not with DST (ß -0.03, p = 0.160). This pattern was also seen for neopterin (KOLT: ß -0.07; p = 0.001; COWAT: ß -0.06, p = 0.010; DST: ß -0.01, p = 0.800). The associations were not confounded by the examined variables. No significant associations were found between the eight downstream kynurenines and cognition. CONCLUSION: Higher KTR and neopterin levels, biomarkers of cellular immune activation, were associated with reduced cognitive performance, implying an association between the innate immune system, memory, and language.