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Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in T2DM, obesity and cognitive impairment. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in T2DM and explore potential differences between obese and nonobese individuals. The study included 51 obese and 57 nonobese participants (mean age 63.0 ± 9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, second Edition. Four LA-derived oxylipins were analyzed by ultra-high-pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. Models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and education. The sEH-derived 12,13-DiHOME was associated with poorer executive function scores (F1,98 = 7.513, P = 0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F1,98 = 7.222, P = 0.008 and F1,98 = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F1,97 = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F1,97 = 4.126, P = 0.045), predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway as a potential therapeutic target for cognitive decline in T2DM. For some markers, relationships may be obesity dependent.

Abstract Background Alzheimer's disease (AD) is common among older adults and leads to significant disability. Volatile anesthetic gases administered during general anesthesia (GA) have been hypothesized to be a risk factor for the development of AD. The objective of this study is to systematically review the association between exposure to GA and risk of AD. Methods We searched electronic databases including MEDLINE, Embase, and Google scholar for observational studies examining the association between exposure to GA and risk of AD. We examined study quality using a modified version of the Newcastle-Ottawa risk of bias assessment for observational studies. We used standard meta-analytic techniques to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). Subgroup and sensitivity analyses were undertaken to evaluate the robustness of the findings. Results A total of 15 case-control studies were included in the review. No cohort studies were identified that met inclusion criteria. There was variation in the methodological quality of included studies. There was no significant association between any exposure to GA and risk of AD (pooled OR: 1.05; 95% CI: 0.93 - 1.19, Z = 0.80, p = 0.43). There was also no significant association between GA and risk of AD in several subgroup and sensitivity analyses. Conclusions A history of exposure to GA is not associated with an increased risk of AD although there are few high-quality studies in this area. Prospective cohort studies with long-term follow-up or randomized controlled trials are required to further understand the association between GA and AD.

Abstract Background Activation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality. While lower tryptophan or a higher ratio of kynurenine/tryptophan (K/T) in peripheral blood have been associated with dementia and the severity of cognitive symptoms in Alzheimer's disease, the association between K/T ratios and post-stroke cognitive impairment (PSCI) has not been investigated. Methods Patients were recruited from the acute stroke unit of a general hospital within 1 month post-stroke. Assessments included the Standardized Mini-Mental State Examination (sMMSE) for cognition, the National Institutes of Health Stroke Scale (NIHSS) for stroke severity, and the Center for Epidemiological Studies-Depression Scale (CES-D) for depressive symptoms. Tryptophan and kynurenine concentrations were determined by high-performance liquid chromatography. Results A total of 41 patients with ischemic stroke ([mean ± SD] age 72.3 ± 12.2 years, 53.7% male, sMMSE 25.6 ± 4.1, NIHSS 7.27 ± 5.55) were recruited. Higher K/T ratios were associated with lower post-stroke global cognition (i.e. sMMSE scores; β = -.327, P = .037). A backward stepwise elimination linear regression (F1,40=6.15, P=.005, adjusted R2=.205) showed that the highest K/T ratio tertile (β = -.412, P = .006) predicted lower sMMSE scores, controlling for age (β = -.253, p = .081), with NIHSS (β = -.027, P = 0.859), and lesion volume (β = -.066, P = 0.659) removed from the model. In receiver operating characteristic analysis, a K/T ratio of 78.3 μmol/mmol (top tertile) predicted significant cognitive impairment (sMMSE score ≤ 24) with 67% sensitivity and 86% specificity (area under the curve = 0.730, p = .022). Conclusions These data suggest an inflammatory response characterized by IDO activation may be relevant to the development of PSCI. Since the neuroactivity of kynurenine metabolites may be amenable to pharmacotherapeutic intervention, the K/T ratio may be a clinically important biomarker.

White matter hyperintensities (WMH) are presumed to indicate subcortical ischemic vascular disease but their underlying pathobiology remains incompletely understood. The soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory and vasoactive cytochrome p450-derived polyunsaturated fatty acid epoxides into their less active corresponding diol species. Under the hypothesis that the activity of sEH might be associated with subcortical ischemic vascular disease and vascular cognitive impairment, this study aimed to compare the relative abundance of sEH substrates and products in peripheral blood between patients with extensive WMH (discovered due to transient ischemic attack; n = 29) and healthy elderly with minimal WMH (n = 25). The concentration of 12,13-DiHOME (a sEH-derived linoleic acid metabolite), and the ratio of 12,13-DiHOME to its sEH substrate, 12,13-EpOME, were elevated in the extensive WMH group (F1,53 = 5.9, p = 0.019), as was the 9,10-DiHOME/9,10-EpOME ratio (F1,53 = 5.4, p = 0.024). The 12,13-DiHOME/12,13-EpOME ratio was associated with poorer performance on a composite score derived from tests of psychomotor processing speed, attention, and executive function (β = - 0.473, p = 0.001, adjusted r2 = 0.213), but not with a composite verbal memory score. In a mediation model, periventricular WMH (but not deep WMH), explained 37% of the effect of the 12,13-DiHOME/12,13-EpOME ratio on the speed/attention/executive function composite score (indirect effect = - 0.50, 95% bootstrap confidence interval [- 0.99, - 0.17] Z-score units). Serum oxylipin changes consistent with higher sEH activity were markers of vascular cognitive impairment, and this association was partly explained by injury to the periventricular subcortical white matter.

The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these conditions. To date, no pharmacological interventions have been proven effective in significantly modifying the course of these disorders. This study critically reviews the construct and methodology of previously published randomised controlled trials (RCTs) in FTD spectrum disorders in order to identify limitations and potential reasons for negative results. Moreover, recommendations based on the identified gaps are elaborated in order to guide future clinical trial design. A systematic literature review was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A total of 23 RCTs in cohorts with diagnoses of behavioural and language variants of FTD, corticobasal syndrome and progressive supranuclear palsy syndrome were identified out of the 943 citations retrieved and were included in the qualitative review. Most studies identified were early-phase clinical trials that were small in size, short in duration and frequently underpowered. Diagnoses of populations enrolled in clinical trials were based on clinical presentation and rarely included precision-medicine tools, such as genetic and molecular testing. Uniformity and standardisation of research outcomes in the FTD spectrum are essential. Several elements should be carefully considered and planned in future clinical trials. We anticipate that precision-medicine approaches will be crucial to adequately address heterogeneity in the FTD spectrum research.

This randomized clinical trial assesses the efficacy of cognitive remediation plus transcranial direct current stimulation targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to dementia in older adults with remitted major depressive disorder, mild cognitive impairment, or both. Key Points: Question: Does cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) slow cognitive decline in older adults with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI)? Findings: In this randomized clinical trial including 375 participants with rMDD or MCI, those randomized to receive active CR plus active tDCS experienced a slower cognitive decline over a median follow-up of 4 years than those randomized to receive sham-plus-sham treatments. The effects were more prominent in the rMDD (with or without MCI) than in the MCI without rMDD group. Meaning: The treatment of CR plus tDCS is effective in slowing cognitive decline in older adults with rMDD. Importance: Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. Objective: To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. Design, Setting, and Participants: This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. Interventions: CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. Main Outcomes and Measures: The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Results: Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active − sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P =.006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active − sham] at month 2, 0.06, 95% CI, −0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P =.10). Preplanned analyses showed treatment effects for executive function (LRT P =.04) and verbal memory (LRT P =.02) and interactions with diagnosis (P =.01) and APOE ε4 (P <.001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. Conclusions and Relevance: The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease. Trial Registration: ClinicalTrials.gov Identifier: NCT02386670 [ABSTRACT FROM AUTHOR]

Background: Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. Objective: To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. Method: Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. Results: Higher plasma NfL was correlated with worse MoCA scores at baseline (β = −.352, P =.029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition (b [SE] = −4.81[2.06], P =.023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups (F (1, 76) = 1.37, P =.245). Conclusion: Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI. [ABSTRACT FROM AUTHOR]

Objectives: Among participants with Alzheimer's disease (AD) we estimated the minimal clinically important difference (MCID) in apathy symptom severity on three scales. Design: Retrospective anchor- and distribution-based analyses of change in apathy symptom scores. Setting: Apathy in Dementia Methylphenidate Trial (ADMET) and ADMET 2 randomized controlled trials conducted at three and ten clinics specialized in dementia care in United States and Canada, respectively. Participants: Two hundred and sixty participants (60 ADMET, 200 ADMET 2) with clinically significant apathy in Alzheimer's disease. Measurements: The Clinical Global Impression of Change in Apathy scale was used as the anchor measure and the MCID on the Neuropsychiatric Inventory – Apathy (NPI-A), Dementia Apathy Interview and Rating (DAIR), and Apathy Evaluation Scale-Informant (AES-I) were estimated with linear mixed models across all study visits. The estimated thresholds were evaluated with performance metrics. Results: Among the MCID was a decrease of four points (95% CI: −4.0 to −4.8) on the NPI-A, 0.56 points (95% CI: −0.47 to −0.65) on the DAIR, and three points on the AES-I (95% CI: −0.9 to −5.4). Distribution-based analyses were largely consistent with the anchor-based analyses. The MCID across the three measures showed ∼60% accuracy. Sensitivity analyses found that MMSE scores and apathy severity at baseline influenced the estimated MCID. Conclusions: MCIDs for apathy on three scales will help evaluate treatment efficacy at the individual level. However, the modest correspondence between MCID and clinical impression of change suggests the need to consider other scales. [ABSTRACT FROM AUTHOR]

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