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Background and aims: Cell-free DNA (cfDNA) is elevated in several disease states. Metabolic syndrome is a constellation of factors associated with poor cardiometabolic outcomes. This study examined associations of cfDNA from the nucleus (cf-nDNA) and mitochondria (cf-mtDNA), C-reactive protein (CRP), and metabolic syndrome risk, in low-active smokers with depressive symptoms. Methods: Participants (N = 109; mean age 47) self-reported medical history. Physical activity was determined by accelerometry and anthropometrics were measured. Blood was collected and analyzed for cf-nDNA, cf-mtDNA, CRP, triglycerides, high-density lipoprotein, hemoglobin A1c. A continuous metabolic syndrome composite risk score was calculated. Relationships of cf-nDNA, cf-mtDNA, CRP, and cardiometabolic risk were examined with correlations and linear regression. Results: CRP and cf-nDNA were significantly associated with metabolic syndrome risk (r = .39 and r = .31, respectively), cf-mtDNA was not (r = .01). In a linear regression, CRP and cf-nDNA significantly predicted the metabolic syndrome risk score, findings that remained significant controlling for age, gender, nicotine dependence, and physical activity. Conclusions: Associations of cf-nDNA with both CRP and metabolic risk suggest a role for cf-nDNA in inflammatory processes associated with metabolic syndrome. The negative findings for cf-mtDNA suggest distinct roles for cf-nDNA and cf-mtDNA in these processes.

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Background: While efforts have been made to validate intrinsic capacity (IC) as a multidimensional indicator of healthy aging in high-income countries, we still need evidence from lower-income countries. We examined associations of IC with wide ranges of activities of daily living in a nationally representative sample of Brazilians aged≥50 years. Methods: This cross-sectional analysis included 7175 participants from the Brazilian Longitudinal Study of Aging. IC domains (cognitive, psychological, sensory, locomotor, and vitality) were determined using self-reported and physical performance measures. IC was operationalized through factorial analysis. We investigated associations of IC and its domains with functional ability in basic, instrumental, and advanced activities of daily living (ADL, IADL, and AADL) using logistic regressions adjusted for sociodemographic, clinical, and modifiable risk factors. Findings: The IC bi-factorial model revealed satisfactory goodness-of-fit. Preserved ability in ADL and IADL, respectively, ranged from 69% and 29% to 89% and 74% across IC quartiles. In adjusted analyses, every standard deviation increment in IC composite score was associated with almost twice the odds of preserved ADL (OR=1·72; 95%CI=1·54-1·93), preserved IADL (OR=1·95; 95%CI=1·77-2·16), and high performance in AADL (OR=1·79; 95%CI=1·59-2·00). Similar results were reported using the IC domains as predictors. Although age, race/ethnicity, and education did not modify associations of IC with functional ability, we found sex differences with stronger relationships of IC with preserved ADL or IADL in females. Interpretation: Our results support IC validity and reliability to measure healthy aging in diverse socioeconomic and cultural settings. Incorporating IC in routine practices can promote holistic and person-centered care approaches in aging societies. Funding: The Brazilian Ministry of Health and Ministry of Science, Technology, Innovation, and Communication.

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OBJECTIVE: To develop and implement a customized toolkit within the electronic medical record (EMR) to standardize care of patients with brain tumors. PATIENTS AND METHODS: We built a customized structured clinical documentation support toolkit to capture standardized data at office visits. We detail the process by which this toolkit was conceptualized and developed. Toolkit development was a physician-led process to determine a work flow and necessary elements to support best practices as defined by the neuro-oncology clinical team. RESULTS: We have developed in our EMR system a customized work flow for clinical encounters with neuro-oncology patients. In addition to providing a road map for clinical care by our neuro-oncology team, the toolkit is designed to maximize discrete data capture. Several hundred fields of discrete data are captured through the toolkit in the context of our routine office visits. We describe the characteristics of patients seen at our clinic, the adoption of the toolkit, current initiatives supported by the toolkit, and future applications. CONCLUSION: The EMR can be effectively structured to standardize office visits and improve discrete data capture. This toolkit can be leveraged to support quality improvement and practice-based research initiatives at the point of care in a neuro-oncology practice.

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Background: Cerebral small vessel diseases (SVDs) are a major cause of stroke and dementia. Yet, specific treatment strategies are lacking in part because of a limited understanding of the underlying disease processes. There is therefore an urgent need to study SVDs at their core, the small vessels themselves. Objective: This paper presents the rationale and design of the ZOOM@SVDs study, which aims to establish measures of cerebral small vessel dysfunction on 7T MRI as novel disease markers of SVDs. Methods: ZOOM@SVDs is a prospective observational cohort study with two years follow-up. ZOOM@SVDs recruits participants with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL, N = 20), sporadic SVDs (N = 60), and healthy controls (N = 40). Participants undergo 7T brain MRI to assess different aspects of small vessel function including small vessel reactivity, cerebral perforating artery flow, and pulsatility. Extensive work-up at baseline and follow-up further includes clinical and neuropsychological assessment as well as 3T brain MRI to assess conventional SVD imaging markers. Measures of small vessel dysfunction are compared between patients and controls, and related to the severity of clinical and conventional MRI manifestations of SVDs. Discussion: ZOOM@SVDs will deliver novel markers of cerebral small vessel function in patients with monogenic and sporadic forms of SVDs, and establish their relation with disease burden and progression. These small vessel markers can support etiological studies in SVDs and may serve as surrogate outcome measures in future clinical trials to show target engagement of drugs directed at the small vessels.

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BACKGROUND: Maternal depression and anxiety during pregnancy may enhance fetal exposure to glucocorticoids (GCs) and harm neurodevelopment. We tested whether a novel cross-tissue polyepigenetic biomarker indicative of in utero exposure to GC is associated with mental and behavioral disorders and their severity in children, possibly mediating the associations between maternal prenatal depressive and anxiety symptoms and these child outcomes. METHODS: Children (n = 814) from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study were followed-up from birth to age 7.1-10.7 years. A weighted polyepigenetic GC exposure score was calculated based on the methylation profile of 24 CpGs from umbilical cord blood. Child diagnosis of mental and behavioral disorder (n = 99) and its severity, defined as the number of days the child had received treatment (all 99 had received outpatient treatment and 8 had been additionally in inpatient treatment) for mental or behavioral disorder as the primary diagnosis, came from the Care Register for Health Care. Mothers (n = 408) reported on child total behavior problems at child's age of 2.3-5.8 years and their own depressive and anxiety symptoms during pregnancy (n = 583). RESULTS: The fetal polyepigenetic GC exposure score at birth was not associated with child hazard of mental and behavioral disorder (HR = 0.82, 95% CI 0.54; 1.24, p = 0.35) or total behavior problems (unstandardized beta = -0.10, 95% CI -0.31; 0.10, p = 0.33). However, for one standard deviation decrease in the polyepigenetic score, the child had spent 2.94 (95%CI 1.59; 5.45, p < 0.001) more days in inpatient or outpatient treatment with any mental and behavioral disorder as the primary diagnosis. Criteria for mediation tests were not met. CONCLUSIONS: These findings suggest that fetal polyepigenetic GC exposure score at birth was not associated with any mental or behavioral disorder diagnosis or mother-rated total behavior problems, but it may contribute to identifying children at birth who are at risk for more severe mental or behavioral disorders.

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OBJECTIVE: To examine the effectiveness of an interdisciplinary pain rehabilitation program (IPRP) that incorporates medication tapering on improving pain-related and performance-based outcomes for older adults with chronic noncancer pain and determine the proportion who demonstrated reliable improvement in outcome. PATIENTS AND METHODS: This 2-year retrospective clinical cohort study examined treatment outcomes of 134 older adult patients 65 years or older with chronic noncancer pain who completed a 3-week IPRP with physician-supervised medication tapering between January 1, 2015, and December 31, 2017. Pain, pain catastrophizing, depressive symptoms, and quality of life were assessed at pretreatment, posttreatment, and follow-up. Physical performance and medication use were assessed pre- and posttreatment. Outcomes were examined using a series of repeated-measures analyses of variance, examining effect size and reliable change. RESULTS: Significant treatment effects (P<.001) with large effect sizes were observed for all self-report and physical performance outcome measures at posttreatment and 6-month follow-up (42.5% response rate). There were no significant differences in outcome based on opioid use status at admission. Reliable change analyses revealed that 76.9% (n=103 of 134) evidenced improvement in at least 1 pain-related outcome measure at posttreatment, and 87.7% (n=50 of 57), at follow-up. Patients also had significant reductions (P<.01) in medications at posttreatment (opioids, benzodiazepines, sedative-hypnotics, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and anticonvulsants). CONCLUSION: Older adults with chronic noncancer pain demonstrated improved pain-related outcomes, physical performance, and decreased medication use following IPRP treatment. Results support the effectiveness of IPRPs in enhancing the physical and emotional functioning of older adults with chronic pain while also facilitating the reduction of medications that place them at risk for adverse events.

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BACKGROUND: Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. METHODS: We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. RESULTS: Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. CONCLUSIONS: ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.

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This study investigated bidirectional associations between intake of food groups and depressive symptoms in 1058 Italian participants (aged 20-102 years) of the Invecchiare in Chianti study. Dietary intake, assessed with a validated FFQ, and depressive symptoms, measured with the Center for Epidemiologic Studies Depression scale (CES-D), were assessed at baseline and after 3, 6 and 9 years. Associations of repeated measurements of intakes of thirteen food groups with 3-year changes in depressive symptoms, and vice versa, were analysed using linear mixed models and logistic generalised estimating equations. Fish intake was inversely (quartile (Q)4 v. Q1, B=-0·97, 95 % CI -1·74, -0·21) and sweet food intake positively (Q4 v. Q1, B=1·03, 95 % CI 0·25, 1·81) associated with subsequent CES-D score. In the other direction, higher CES-D scores were associated with decreases in intakes of vegetables (ratio: 0·995, 95 % CI 0·990, 0·999) and red and processed meat (B=-0·006, 95 % CI -0·010, -0·001), an increase in dairy product intake (ratio: 1·008, 95 % CI 1·004, 1·013), and increasing odds of eating savoury snacks (OR: 1·012, 95 % CI 1·000, 1·024). Fruit, nuts and legumes, potatoes, wholegrain bread, olive oil, sugar-sweetened beverages, and coffee and tea were not significantly associated in either direction. Our study confirmed bidirectional associations between food group intakes and depressive symptoms. Fish and sweet food intakes were associated with 3-year improvement and deterioration in depressive symptoms, respectively. Depressive symptoms were associated with 3-year changes in vegetable, meat, dairy product and savoury snack intakes. Trials are necessary to examine the causal associations between food groups and depression.

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Epidemiological evidence has linked low vitamin D status to a range of mood disorders. However, studies examining whether vitamin D supplementation can improve mood-related outcomes in healthy populations are limited. We investigated whether vitamin D supplementation over winter is beneficial for improving mood-related outcomes in healthy women. A total of 152 healthy women (18-40 years) in Dunedin, New Zealand were randomly assigned to receive 50 000 IU (1·25 mg) of oral vitamin D3 or placebo once per month for 6 months. They completed the Center for Epidemiologic Studies Depression Scale, the anxiety subscale of the Hospital Anxiety and Depression Scale and the Flourishing Scale every month. Additionally, they reported their positive and negative mood each day for three consecutive days every 2 months. Participants provided a blood sample at the beginning and at the end of the study for 25-hydroxyvitamin D3 analysis. ANCOVA was used to compare the outcome measures between the groups, controlling for baseline. We found no evidence of lower depression (P = 0·339), lower anxiety (P = 0·862), higher flourishing (P = 0·453), higher positive moods (P = 0·518) or lower negative moods (P = 0·538) in the treatment group compared with the control group at follow-up. Mood outcomes over the study period were similar for the two groups. We found no evidence of any beneficial effect of monthly vitamin D3 supplementation on mood-related outcomes in healthy premenopausal women over the winter period, so recommendations for supplementations are not warranted in this population for mood-related outcomes.

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A posteriori healthier dietary patterns and several nutrients have been associated with lower risks of depression in various studies; however, evidence is lacking with regard to the prospective association between adherence to nutritional recommendations (food-based and nutrient-based recommendations) and incident depression or depressive symptoms. In this study, we investigate such associations in the NutriNet Santé cohort. The study sample included 26 225 participants (aged 18-86 years) who were initially free of depressive symptoms. Adherence to nutritional recommendations was measured by four scores namely modified French Programme National Nutrition Santé-Guideline Score (mPNNS-GS), Alternative Healthy Eating Index-2010 (AHEI-2010), Probability of Adequate Nutrient Intake Dietary Score (PANDiet) and Diet Quality Index-International (DQI-I), using non-consecutive dietary record data during the first 2 years of follow-up (mean number of recording days=8, sd 2). Depressive symptoms were defined by a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥17 for men and ≥23 for women. We used Cox proportional hazards models to estimate hazard ratios and 95 % CI, modelling the dietary scores as standardised continuous variables and as tertiles. Over a mean follow-up of 6 years, we identified 2166 incident cases of depressive symptoms. All dietary scores with the exception of the AHEI-2010 were significantly inversely associated with incident depressive symptoms. In the fully adjusted model, an increase of 1 sd in the mPNNS-GS, PANDiet and DQI-I was, respectively, associated with an 8 % (95 % CI 4, 13), 5 % (95 % CI 1, 9) and 9 % (95 % CI 5, 13) reduction in the risk of depressive symptoms. Overall, these findings suggest that diet in accordance with national or international guidelines could have beneficial effects with regard to mental health.

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Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [18F]fallypride, a high affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BPND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D2/3 receptors, where reduced BPND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.

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The effect of n-3 long-chain PUFA (n-3 LCPUFA) on depression in healthy subjects is unclear, and most of the previous studies have focused on populations eating Western diets with lower fish intake. The present study investigated the association between blood levels of n-3 LCPUFA and depressive symptoms in Japanese community dwellers with higher n-3 LCPUFA blood levels. A cross-sectional study was conducted from 2006 to 2008, including 1050 men and 1073 women aged 40 years or older from the National Institute for Longevity Sciences--the Longitudinal Study of Aging. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms. Multiple logistic regression analysis was performed to estimate the OR and 95% CI for a CES-D score ≥ 16. Serum concentrations of n-3 PUFA, but not n-6 PUFA, were inversely associated with depressive symptoms. Compared with the lowest quintile, the adjusted OR for serum EPA at the fourth and fifth quintiles were 0·55 (95% CI 0·35, 0·85) and 0·64 (95% CI 0·42, 0·98), respectively, and at the fifth quintile for DHA it was 0·58 (95% CI 0·37, 0·92), for the presence of depressive symptoms (P for trend=0·013 and 0·011, respectively). Serum levels of EPA and DHA were inversely associated with depressive symptoms in Japanese community dwellers with higher blood levels of n-3 LCPUFA, suggesting that n-3 LCPUFA intakes corresponding to higher levels in a Japanese population may have implications for a lower prevalence of depression.

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Depressive symptoms, even at a subclinical level, have been associated with structural brain abnormalities. However, previous studies have used regions of interest or small sample sizes, limiting the ability to generalize the results. In this study, we examined neuroanatomical structures of both gray matter and white matter associated with depressive symptoms across the whole brain in a large sample. A total of 810 community-dwelling adult participants underwent measurement of depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D). The participants were not demented and had no neurological or psychiatric history. To examine the gray and white matter volume, we used structural MRI scans and voxel-based morphometry (VBM); to examine the white matter integrity, we used diffusion tensor imaging with tract-based spatial statistics (TBSS). In female participants, VBM revealed a negative correlation between bilateral anterior cingulate gray matter volume and the CES-D score. TBSS showed a CES-D-related decrease in fractional anisotropy and increase in radial and mean diffusivity in several white matter regions, including the right anterior cingulum. In male participants, there was no significant correlation between gray or white matter volume or white matter integrity and the CES-D score. Our results indicate that the reduction in gray matter volume and differences in white matter integrity in specific brain regions, including the anterior cingulate, are associated with depressive symptoms in women.

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