No association between peripheral serotonin-gene-related DNA methylation and brain serotonin neurotransmission in the healthy and depressed state.

BACKGROUND: Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. RESULTS: We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. CONCLUSIONS: We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.

Hot and cold cognitive disturbances in antidepressant-free patients with major depressive disorder: a NeuroPharm study.

BACKGROUND: Cognitive disturbances are common and disabling features of major depressive disorder (MDD). Previous studies provide limited insight into the co-occurrence of hot (emotion-dependent) and cold (emotion-independent) cognitive disturbances in MDD. Therefore, we here map both hot and cold cognition in depressed patients compared to healthy individuals. METHODS: We collected neuropsychological data from 92 antidepressant-free MDD patients and 103 healthy controls. All participants completed a comprehensive neuropsychological test battery assessing hot cognition including emotion processing, affective verbal memory and social cognition as well as cold cognition including verbal and working memory and reaction time. RESULTS: The depressed patients showed small to moderate negative affective biases on emotion processing outcomes, moderate increases in ratings of guilt and shame and moderate deficits in verbal and working memory as well as moderately slowed reaction time compared to healthy controls. We observed no correlations between individual cognitive tasks and depression severity in the depressed patients. Lastly, an exploratory cluster analysis suggested the presence of three cognitive profiles in MDD: one characterised predominantly by disturbed hot cognitive functions, one characterised predominantly by disturbed cold cognitive functions and one characterised by global impairment across all cognitive domains. Notably, the three cognitive profiles differed in depression severity. CONCLUSION: We identified a pattern of small to moderate disturbances in both hot and cold cognition in MDD. While none of the individual cognitive outcomes mapped onto depression severity, cognitive profile clusters did. Overall cognition-based stratification tools may be useful in precision medicine approaches to MDD.

Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women.

OBJECTIVE: Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register-based studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin 4 receptor (5-HT4R) brain imaging. METHODS: [11C]SB207145-PET imaging data on 53 healthy women, of whom 16 used OCs, were available from the Cimbi database. We evaluated global effects of OC use on 5-HT4R binding in a latent variable model based on 5-HT4R binding across cortical and subcortical regions. RESULTS: We demonstrate that OC users have 9-12% lower global brain 5-HT4R binding potential compared to non-users. Univariate region-based analyses (pallidostriatum, caudate, hippocampus, amygdala, anterior cingulate cortex, and neocortex) supported the global effect of OC use with the largest difference present in the hippocampus (-12.8% (95% CI [-21.0; -3.9], Pcorrected = 0.03). CONCLUSION: We show that women who use OCs have markedly lower brain 5-HT4R binding relative to non-users, which constitutes a plausible molecular link between OC use and increased risk of depressive episodes. We propose that this reflects a reduced 5-HT4R gene expression, possibly related to a blunted ovarian hormone state among OC users.

Associations between Frailty, Complex Care Needs and Quality of Life in Multi-Morbid Older People.

BACKGROUND: Little is known regarding the complex care needs, level of frailty or quality of life of multi-morbid older patients. OBJECTIVES: The objective of this study was to determine the relationship between frailty, complexity of care and quality of life in multi-morbid older people. DESIGN: Cross-sectional study. SETTING: Thirteen primary care practices in the Netherlands. PARTICIPANTS: 1,150 multi-morbid older people living in the community. MEASUREMENTS: The level of frailty was assessed with the Groningen Frailty Indicator. Complexity of care needs was measured with the Intermed for the Elderly Self-Assessment. Quality of life (QoL) was measured with two items of the RAND-36. RESULTS: In total, 758 out of 1,150 (65.9%) patients were frail, 8.3% had complex care needs, and the mean QoL score was 7.1 (standard deviation 1.2). Correlations between frailty and complexity, frailty and QoL, and complexity of care and QoL were 0.67, -0.51 and -0.52 (all p<0.001) respectively. All patients with complex care needs were frail, but, only 12.5% of the frail patients had complex care needs. Problems at climbing up stairs was associated with higher levels of frailty and complexity of care but with a lower QoL. CONCLUSIONS: Higher levels of frailty and complexity of care are associated with a lower QoL in multi-morbid older people. The results of this study contribute to a better understanding these concepts and are valuable for the development of tailored interventions for older persons in the future.

[Proactive and structured care for the elderly in primary care]. / Proactieve en gestructureerde zorg voor kwetsbare oudere patiënten in de eerstelijn: Achtergrond, opzet en uitvoering van een screenings- en zorgprogramma.

BACKGROUND: Currently, primary care for the older, vulnerable patient is reactive, fragmented and does not meet patients needs. Given the expected increase of home-dwelling frail elderly people a transition is needed to proactive and integrated care. METHODS: In the described study, we explore two innovative interventions in primary care. First we describe a newly developed screening and monitoring program for frail elderly patients based on routine care information in general practice. Second, we describe a multidisciplinary intervention program by trained nurses for frail elderly patients in general practice. The effectiveness of the interventions is examined in a three-armed, cluster randomized trial, taking place in 58 primary care practices in Utrecht, the Bilt and Maarsenbroek. RESULTS: Three thousand eight patients are included. Primary outcome measure is the impact of the interventions on the daily activities, measured with the Katz questionnaire. Secondary outcomes measures are the quality of life, mortality, recording in a care or nursing home, visit to an emergency room or outpatient unit, recording in the hospital and volunteer caregivers tax.

Measuring longitudinal white matter changes: comparison of a visual rating scale with a volumetric measurement.

BACKGROUND AND PURPOSE: Detection of longitudinal changes in white matter hyperintensities (WMH) by using visual rating scales is problematic. We compared a widely used visual rating scale with a volumetric method to study longitudinal white matter changes. METHODS: WMH were assessed with the visual Scheltens scale and a volumetric method in 100 elderly subjects aged 70-81 years for whom repetitive MR images were available with an interval of 33 (SD, 1.4) months. Reliability was determined by intraclass correlation coefficients. To examine the sensitivity of both the visual and volumetric method, we calculated Spearman rank correlations of WMH ratings and volume measurements with age. RESULTS: Reliability of the visual rating scale was good, whereas reliability of the volumetric measurement was excellent. For baseline measurements of WMH, we found weaker associations between WMH and age when assessed with the visual scale (r = 0.20, P = .045) than with the volumetric method (r = 0.31, P = .002). Longitudinal evaluation of WMH assessments showed regression in 26% of the subjects when analyzed with the visual rating scale against 12% of the subjects when using volumetric measurements. Compared with the visual rating, the correlation between progression in WMH and age was twice as high when using the volumetric measurement (r = 0.19, P = .062 and r = 0.39, P < .001, respectively). CONCLUSION: Volumetric measurements of WMH offer a more reliable, sensitive, and objective alternative to visual rating scales in studying longitudinal white matter changes.

Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population.

OBJECTIVE: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. METHODS: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. RESULTS: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. CONCLUSION: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.

Effect of pravastatin on cerebral infarcts and white matter lesions.

The authors examined the effect of pravastatin 40 mg daily on the progression of ischemic brain lesions using repeated brain MRI. After a mean treatment period of 33 months, there was an increase in total ischemic lesion load of 1.1 cm3 (p < 0.001) in the 270 placebo-treated subjects and 1.1 cm3 (p < 0.001) in the 265 pravastatin-treated subjects. There was no difference between the two treatment groups (p = 0.73).

Different progression rates for deep white matter hyperintensities in elderly men and women.

The authors investigated the progression of white matter hyperintensities (WMHs) in a large population of elderly men and women. After 3 years of follow-up, women had accumulated approximately twice as much deep WMH (DWMH) as men. The progression of periventricular WMH was the same for men and women. Gender differences may affect the pathogenesis of DWMH, which in turn may result in different clinical consequences in women.

[Role of statins in prevention of stroke and dementia]. / De rol van statinen bij de preventie van beroerte en dementie.

There is accumulating evidence that statins reduce stroke risk, even though total cholesterol is not a risk factor for stroke. The explanation for this discrepancy is subject to discussion. It should be realised that the beneficial effects of statins on stroke risk have only been demonstrated in a select population, i.e. middle-aged men with ischaemic heart disease. Several clinical trials are underway to examine the effects of statins on stroke risk in more characteristic groups of patients who are at increased risk of developing stroke. The results of these studies should be awaited before statins are recommended for the prevention of stroke. Recently it has been reported that statins lower the risk of developing dementia. These conclusions were drawn from two cross-sectional studies. Because of the nature of the studies, only an association between the use of statins and a lower risk of developing dementia was shown, and not a causal relationship. Experimentally-controlled studies have to be designed to investigate the effect of statins on dementia.