Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: a randomized controlled trial (PAM study).

BACKGROUND: Up to 60% of breast cancer patients treated with chemotherapy is confronted with cognitive problems, which can have a significant impact on daily activities and quality of life (QoL). We investigated whether exercise training improves cognition in chemotherapy-exposed breast cancer patients 2-4 years after diagnosis. METHODS: Chemotherapy-exposed breast cancer patients, with both self-reported cognitive problems and lower than expected performance on neuropsychological tests, were randomized to an exercise or control group. The 6-month exercise intervention consisted of supervised aerobic and strength training (2 h/week), and Nordic/power walking (2 h/week). Our primary outcome was memory functioning (Hopkins Verbal Learning Test-Revised; HVLT-R). Secondary outcomes included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognition (MD Anderson Symptom Inventory for multiple myeloma; MDASI-MM), physical fitness (relative maximum oxygen uptake; VO2peak), fatigue (Multidimensional Fatigue Inventory), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ C-30), depression (Patient Health Questionnaire-9, Hospital Anxiety and Depression Scale; HADS), and anxiety (HADS). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement (≥ 5 words). Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors. RESULTS: We randomized 181 patients to the exercise (n = 91) or control group (n = 90). Two-third of the patients attended ≥ 80% of the exercise sessions, and physical fitness significantly improved compared to control patients (B VO2peak 1.4 ml/min/kg, 95%CI:0.6;2.2). No difference in favor of the intervention group was seen on the primary outcome. Significant beneficial intervention effects were found for self-reported cognitive functioning [MDASI-MM severity (B-0.7, 95% CI - 1.2; - 0.1)], fatigue, QoL, and depression. A hypothesis-driven analysis in highly fatigued patients showed positive exercise effects on tested cognitive functioning [ACS Reaction Time (B-26.8, 95% CI - 52.9; - 0.6) and ACS Wordlist Learning (B4.4, 95% CI 0.5; 8.3)]. CONCLUSIONS: A 6-month exercise intervention improved self-reported cognitive functioning, physical fitness, fatigue, QoL, and depression in chemotherapy-exposed breast cancer patients with cognitive problems. Tested cognitive functioning was not affected. However, subgroup analysis indicated a positive effect of exercise on tested cognitive functioning in highly fatigued patients. Trial Registration Netherlands Trial Registry: Trial NL5924 (NTR6104). Registered 24 October 2016, https://www.trialregister.nl/trial/5924 .

Depression in Stroke Survivors: Ten-Year Follow-Up. Determinants of the Natural Course of Depressive Symptoms in Stroke Survivors in the Netherlands: The SMART-Medea Study.

OBJECTIVES: Stroke is the second most common cause of death and a major cause of disability. Besides the physical consequences, depressive symptoms are frequent in the aftermath after stroke. Every year, approximately 15 million stroke survivors worldwide are at risk of developing post-stroke depression. In this study we describe the natural course of depressive symptoms in stroke patients over a long-period of time post stroke and identify associated determinants. MATERIALS AND METHODS: From the Second Manifestations of ARTerial disease-Memory, depression and aging (SMART-Medea) study, an observational prospective cohort study, we selected patients with cerebrovascular disease, and used the biannually collected data of the Patient Health Questionnaire-9 for depressive symptoms. A score of ≥10 indicated the presence of depressive symptoms. A multinomial logistic regression analysis was used to identify prognostic determinants for courses of depressive symptoms after stroke. RESULTS: During a mean follow-up time of 7.9 years, 62% of the 172 participants was never depressed, 19% had a single episode and 19% had recurrent depressive symptoms. Physical function was associated with increased risk for single episode and recurrent depressive symptoms (OR=1.06 [1.01-1.11]). OR's for social, mental and (vascular) comorbidities variables were not significant. Participants' physical function was only measured at baseline. Several relevant variables were not present in this dataset, including information about clinical events during follow-up. CONCLUSION: Nearly 40% of the participants are confronted with depressive symptoms on the long-term. Physical function plays a substantial part for stroke survivors in the development of these symptoms.

Hippocampal volume and the course of depressive symptoms over eight years of follow-up.

OBJECTIVE: To estimate the association between hippocampal and total brain volume and the course of depressive symptoms over eight years of follow-up in patients with a history of vascular disease. METHOD: Within the SMART-Medea study, 636 participants (62 ± 10 years) had a 1.5-tesla brain MRI obtaining hippocampal and total brain volumes. Depressive symptoms were assessed with the Patient Health Questionnaire-9 biannually during eight-year follow-up. Generalized estimating equation models with robust standard errors were used to assess the associations of hippocampal and total brain volumes with depressive symptoms during follow-up adjusting for age, sex, education, and intracranial volume. An interaction term between volume and time (6-month intervals) was included to examine whether the course of depressive symptoms differed according to hippocampal and total brain volume. RESULTS: The mean PHQ-9 score was 2.8 ± 3.5. Smaller hippocampal volumes were associated with an increasing course of depressive symptom levels, while larger volumes were associated with decreasing levels (P-value interaction = 0.07). Smaller total brain volume was associated with consistently higher levels of depressive symptoms, but not with change in course of depressive symptoms (P-value interaction = 0.45). CONCLUSION: Smaller hippocampal volume but not total brain volume is associated with poorer course of depressive symptoms over eight years of follow-up.

Cognitive performance and the course of depressive symptoms over 7 years of follow-up: the SMART-MR study.

BACKGROUND: Depressive symptoms and cognitive impairment often co-occur, but their interactive relationship is complex and the direction of causation is still a topic of research. We examined the influence of cognitive performance on the course of depressive symptoms during 7 years of follow-up in patients with vascular disease. METHOD: Within the SMART-MR study, 736 patients (mean age 62 ± 10 years) had neuropsychological assessment on four cognitive domains at baseline [memory (MEM), working memory (WMEM), executive functioning (EXEC), and information processing speed (SPEED)]. Depressive symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9) at baseline and every 6 months during 7 years of follow-up. Generalized Estimating Equation (GEE) models were used to assess the association between cognitive performance with depressive symptoms at multiple time points during follow-up. Interaction terms between the respective cognitive domains and time was included to examine if the course of depressive symptoms differed according to baseline cognitive performance. RESULTS: The GEE analyses showed no significant interactions between the respective cognitive domains and time indicating no different course of depressive symptoms according to baseline cognitive performance. Lower MEM, EXEC or SPEED, but not WMEM performance, was significantly associated with more depressive symptoms during follow-up per z score decrease: MEM [B = 0.70, 95% confidence interval (CI) 0.35-1.05]; EXEC (B = 0.88, 95% CI 0.41-1.36), and SPEED (B = 0.57, 95% CI 0.21-0.92). CONCLUSIONS: Poorer cognitive performance on the domains MEM, EXEC and SPEED, but not WMEM, was associated with higher levels of depressive symptoms over 7 years of follow-up, but not with a different course of depressive symptoms over time.

[Development of an algorithm to predict the incidence of major depression among primary care consultants]. / Desarrollo y validación de un algoritmo para predecir riesgo de depresión en consultantes de atención primaria en Chile.

BACKGROUND: The reduction of major depression incidence is a public health challenge. AIM: To develop an algorithm to estimate the risk of occurrence of major depression in patients attending primary health centers (PHC). MATERIAL AND METHODS: Prospective cohort study of a random sample of 2832 patients attending PHC centers in Concepción, Chile, with evaluations at baseline, six and twelve months. Thirty nine known risk factors for depression were measured to build a model, using a logistic regression. The algorithm was developed in 2,133 patients not depressed at baseline and compared with risk algorithms developed in a sample of 5,216 European primary care attenders. The main outcome was the incidence of major depression in the follow-up period. RESULTS: The cumulative incidence of depression during the 12 months follow up in Chile was 12%. Eight variables were identified. Four corresponded to the patient (gender, age, depression background and educational level) and four to patients' current situation (physical and mental health, satisfaction with their situation at home and satisfaction with the relationship with their partner). The C-Index, used to assess the discriminating power of the final model, was 0.746 (95% confidence intervals (CI = 0,707-0,785), slightly lower than the equation obtained in European (0.790 95% CI = 0.767-0.813) and Spanish attenders (0.82; 95% CI = 0.79-0.84). CONCLUSIONS: Four of the factors identified in the risk algorithm are not modifiable. The other two factors are directly associated with the primary support network (family and partner). This risk algorithm for the incidence of major depression provides a tool that can guide efforts towards design, implementation and evaluation of effectiveness of interventions to prevent major depression.

Low blood pressure and antihypertensive treatment are independently associated with physical and mental health status in patients with arterial disease: the SMART study.

OBJECTIVE: To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease. DESIGN AND SETTING: Cross-sectional analyses were conducted within the single-centre Secondary Manifestations of ARTerial disease (SMART) study, in a hospital care setting. SUBJECTS: A total of 5877 patients (mean age 57 years) with symptomatic and asymptomatic arterial disease underwent standardized vascular screening. MAIN OUTCOME MEASURE: The primary outcome was self-rated physical and mental health assessed using the 36-item short-form health survey. RESULTS: In the total population, antihypertensive drug use and increased intensity of antihypertensive treatment were associated with poorer health status independent of important confounders including BP levels; adjusted mean differences [95% confidence interval (CI)] in physical and mental health between n = 0 and n ≥ 3 antihypertensives were -1.2 (-2.1; -0.3) and -3.5 (-4.4; -2.6), respectively. Furthermore, both lower systolic and lower diastolic BP levels were related to poorer physical and mental health status independent of antihypertensive treatment. Mean differences (95% CI) in physical and mental health status per SD decrease in systolic BP were -0.56 (-0.84; -0.27) and -0.32 (-0.61; -0.03) and per SD decrease in diastolic BP were -0.50 (-0.78; -0.23) and -0.08 (-0.36; 0.20), respectively. The association between low BP and poor health status was particularly present in patients with coronary artery disease. CONCLUSIONS: In a population of patients with asymptomatic and symptomatic arterial disease, antihypertensive treatment and lower BP levels are independently associated with poorer self-rated physical and mental health. These findings suggest that different underlying mechanisms may explain these independent associations.

Spiritual and religious beliefs as risk factors for the onset of major depression: an international cohort study.

BACKGROUND: Several studies have reported weak associations between religious or spiritual belief and psychological health. However, most have been cross-sectional surveys in the U.S.A., limiting inference about generalizability. An international longitudinal study of incidence of major depression gave us the opportunity to investigate this relationship further. METHOD: Data were collected in a prospective cohort study of adult general practice attendees across seven countries. Participants were followed at 6 and 12 months. Spiritual and religious beliefs were assessed using a standardized questionnaire, and DSM-IV diagnosis of major depression was made using the Composite International Diagnostic Interview (CIDI). Logistic regression was used to estimate incidence rates and odds ratios (ORs), after multiple imputation of missing data. RESULTS: The analyses included 8318 attendees. Of participants reporting a spiritual understanding of life at baseline, 10.5% had an episode of depression in the following year compared to 10.3% of religious participants and 7.0% of the secular group (p<0.001). However, the findings varied significantly across countries, with the difference being significant only in the U.K., where spiritual participants were nearly three times more likely to experience an episode of depression than the secular group [OR 2.73, 95% confidence interval (CI) 1.59­4.68]. The strength of belief also had an effect, with participants with strong belief having twice the risk of participants with weak belief. There was no evidence of religion acting as a buffer to prevent depression after a serious life event. CONCLUSIONS: These results do not support the notion that religious and spiritual life views enhance psychological well-being.

Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study.

BACKGROUND: To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia. METHOD: Within the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, 4354 persons (mean age 76 ± 5 years, 58% women) without dementia had a 1.5-T brain magnetic resonance imaging (MRI) scan. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy [B = -1.25%, 95% confidence interval (CI) -2.05 to -0.44], including more gray- and white-matter atrophy in most lobes, and also more atrophy of the hippocampus and thalamus. Participants with current, first-onset MDD also had more brain atrophy (B = -1.62%, 95% CI -3.30 to 0.05) whereas those remitted did not (B = 0.06%, 95% CI -0.54 to 0.66). CONCLUSIONS: In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD was associated with widespread gray- and white-matter brain atrophy. Prospective studies should examine whether MDD is a consequence of, or contributes to, brain volume loss and development of dementia.

Effect of physical exercise on the hippocampus and global grey matter volume in breast cancer patients: A randomized controlled trial (PAM study).

BACKGROUND: Physical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory. METHODS: Chemotherapy-exposed breast cancer patients (stage I-III, 2-4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale 'fatigue' of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients. RESULTS: Multiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm3, 95 % CI = 3.0 - 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = -52.3 mm3, 95 % CI = -100.3 - -4.4)), which was related to improved memory functioning (HVLT-R total recall: B = -0.022, 95 % CI = -0.039 - -0.005; ACS Wordlist Learning: B = -0.039, 95 % CI = -0.062 - -0.015). CONCLUSIONS: No exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding.

Subfields of the hippocampal formation at 7 T MRI: in vivo volumetric assessment.

Animal and human autopsy studies suggest that subfields of the hippocampal formation are differentially affected by neuropsychiatric diseases. Therefore, subfield volumes may be more sensitive to effects of disease processes. The few human studies that segmented subfields of the hippocampal formation in vivo either assessed the subfields only in the body of the hippocampus, assessed only three subfields, or did not take the differential angulation of the head of the hippocampus into account. We developed a protocol using 7 Tesla MRI with isotropic voxels to reliably delineate the entorhinal cortex (ERC), subiculum (SUB), CA1, CA2, CA3, dentate gyrus (DG)&CA4 along the full-length of the hippocampus. Fourteen subjects (aged 54-74 years, 2 men and 12 women) were scanned with a 3D turbo spin echo (TSE) sequence with isotropic voxels of 0.7 × 0.7 × 0.7 mm(3) on a 7 T MRI whole body scanner. Based on previous protocols and extensive anatomic atlases, a new protocol for segmentation of subfields of the hippocampal formation was formulated. ERC, SUB, CA1, CA2, CA3 and DG&CA4 were manually segmented twice by one rater from coronal MR images. Good-to-excellent consistency was found for all subfields (Intraclass Correlation Coefficient's (ICC) varying from 0.74 to 0.98). Accuracy as measured with the Dice Similarity Index (DSI) was above 0.82 for all subfields, with the exception of the smaller subfield CA3 (0.68-0.70). In conclusion, this study shows that it is possible to delineate the main subfields of the hippocampal formation along its full-length in vivo at 7 T MRI. Our data give evidence that this can be done in a reliable manner. Segmentation of subfields in the full-length of the hippocampus may bolster the study of the etiology neuropsychiatric diseases.

Self-rated health status as a risk factor for future vascular events and mortality in patients with symptomatic and asymptomatic atherosclerotic disease: the SMART study.

OBJECTIVES: Lower self-rated health status has been associated with worse prognosis in patients with coronary artery disease (CAD). We investigated the influence of self-rated physical and mental health status on the risk of future vascular events and mortality for various locations of symptomatic atherosclerotic disease and asymptomatic disease. DESIGN: Patients with CAD (n = 2547), cerebrovascular disease (n = 1061), peripheral arterial disease (PAD; n = 648), abdominal aortic aneurysm (AAA; n = 272) and asymptomatic atherosclerotic disease (n = 1933) were followed for a median of 4 years for the occurrence of a new vascular event or death. Self-rated health status was assessed with the Short Form-36 physical and mental component summary scales. Cox regression models were used to estimate associations between health status and vascular events and death, adjusted for age, sex, vascular risk factors and intima-media thickness. RESULTS: In the total population, lower self-rated physical health status (per 10-point decrease) increased the risk of vascular events [hazard ratio (HR) = 1.37, 95% confidence interval (CI) 1.24-1.52], and all-cause (HR = 1.45, 95% CI 1.29-1.63) and vascular mortality (HR = 1.40, 95% CI 1.20-1.64). A 10-point decrease in mental health status was associated with a modest increase in the risk of vascular events (HR = 1.19, 95% CI 1.08-1.32), and all-cause (HR = 1.19, 95% CI 1.05-1.34) and vascular mortality (HR = 1.28, 95% CI 1.09-1.49). Risk estimates of physical and mental health status were highest in patients with asymptomatic atherosclerotic disease and lowest in those with PAD. CONCLUSIONS: Poorer self-rated physical and mental health status increases the risk of vascular events and mortality in a broad population of patients with symptomatic and asymptomatic atherosclerotic disease.

Location and progression of cerebral small-vessel disease and atrophy, and depressive symptom profiles: the Second Manifestations of ARTerial disease (SMART)-Medea study.

BACKGROUND: The 'vascular depression' hypothesis states that brain changes located in frontal-subcortical pathways increase vulnerability for specific depressive symptom profiles, but studies examining locations of small-vessel and degenerative changes with individual symptoms are scarce. We examined whether location and progression of white-matter lesions (WMLs), lacunar infarcts and atrophy were associated with motivational and mood symptoms in patients with symptomatic atherosclerotic disease. METHOD: In 578 patients [63 (s.d.=8) years] of the Second Manifestations of ARTerial disease (SMART)-Medea study, volumes of WMLs and atrophy and visually rated infarcts were obtained with 1.5 T magnetic resonance imaging at baseline and after 3.9 (s.d.=0.4) years' follow-up. Depressive symptoms were assessed with Patient Health Questionnaire-9 at follow-up and categorized into motivational and mood symptoms. RESULTS: Regression analyses adjusted for age, gender, education, Mini-Mental State Examination, physical functioning, antidepressant use and vascular risk factors showed that location in mainly deep white-matter tracts and progression of WMLs were associated with symptoms of anhedonia, concentration problems, psychomotor retardation and appetite disturbance. Lacunar infarcts in deep white matter were associated with greater motivational [Incidence rate ratio (IRR) 1.7, 95% confidence interval (CI) 1.2-2.4] and mood (IRR 1.7, 95% CI 1.1-2.6) sumscores, and with symptoms of psychomotor retardation, energy loss and depressed mood; lacunar infarcts in the thalamus were associated with psychomotor retardation only. Cortical atrophy was associated with symptoms of anhedonia and appetite disturbance. Excluding patients with major depression did not materially change the results. CONCLUSIONS: Our findings suggest that disruption of frontal-subcortical pathways by small-vessel lesions leads to a symptom profile that is mainly characteristic of motivational problems, also in the absence of major depression.

Microinfarcts in the Deep Gray Matter on 7T MRI: Risk Factors, MRI Correlates, and Relation to Cognitive Functioning-The SMART-MR Study.

BACKGROUND AND PURPOSE: The clinical relevance of cortical microinfarcts has recently been established; however, studies on microinfarcts in the deep gray matter are lacking. We examined the risk factors and MR imaging correlates of microinfarcts in the deep gray matter on 7T MR imaging and their relation to cognitive functioning. MATERIALS AND METHODS: Within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, 213 patients (mean age, 68 [SD, 8] years) had a risk-factor assessment, 7T and 1.5T brain MR imaging, and a cognitive examination. Microinfarcts on 7T MR imaging were defined as lesions of <5 mm. Regression models were used to examine the age-adjusted associations among risk factors, MR imaging markers, and microinfarcts. Cognitive function was summarized as composite and domain-specific z scores. RESULTS: A total of 47 microinfarcts were found in 28 patients (13%), most commonly in the thalamus. Older age, history of stroke, hypertension, and intima-media thickness were associated with microinfarcts. On 1.5T MR imaging, cerebellar infarcts (relative risk = 2.75; 95% CI, 1.4-5.33) and lacunes in the white (relative risk = 3.28; 95% CI, 3.28-6.04) and deep gray matter (relative risk = 3.06; 95% CI, 1.75-5.35) were associated with microinfarcts, and on 7T MR imaging cortical microinfarcts (relative risk = 2.33; 95% CI, 1.32-4.13). Microinfarcts were also associated with poorer global cognitive functioning (mean difference in the global z score between patients with multiple microinfarcts versus none = -0.97; 95% CI, -1.66 to -0.28, P = .006) and across all cognitive domains. CONCLUSIONS: Microinfarcts in the deep gray matter on 7T MR imaging were associated with worse cognitive functioning and risk factors and MR imaging markers of small-vessel and large-vessel disease. Our findings suggest that microinfarcts in the deep gray matter may represent a novel imaging marker of vascular brain injury.

Automatic quantification of perivascular spaces in T2-weighted images at 7 T MRI.

Perivascular spaces (PVS) are believed to be involved in brain waste disposal. PVS are associated with cerebral small vessel disease. At higher field strengths more PVS can be observed, challenging manual assessment. We developed a method to automatically detect and quantify PVS. A machine learning approach identified PVS in an automatically positioned ROI in the centrum semiovale (CSO), based on -resolution T2-weighted TSE scans. Next, 3D PVS tracking was performed in 50 subjects (mean age 62.9 years (range 27-78), 19 male), and quantitative measures were extracted. Maps of PVS density, length, and tortuosity were created. Manual PVS annotations were available to train and validate the automatic method. Good correlation was found between the automatic and manual PVS count: ICC (absolute/consistency) is 0.64/0.75, and Dice similarity coefficient (DSC) is 0.61. The automatic method counts fewer PVS than the manual count, because it ignores the smallest PVS (length <2 mm). For 20 subjects manual PVS annotations of a second observer were available. Compared with the correlation between the automatic and manual PVS, higher inter-observer ICC was observed (0.85/0.88), but DSC was lower (0.49 in 4 persons). Longer PVS are observed posterior in the CSO compared with anterior in the CSO. Higher PVS tortuosity are observed in the center of the CSO compared with the periphery of the CSO. Our fully automatic method can detect PVS in a 2D slab in the CSO, and extract quantitative PVS parameters by performing 3D tracking. This method enables automated quantitative analysis of PVS.

Residual cardiovascular risk reduction guided by lifetime benefit estimation in patients with symptomatic atherosclerotic disease: effectiveness and cost-effectiveness.

AIMS: To determine the (cost)-effectiveness of blood pressure lowering, lipid-lowering, and antithrombotic therapy guided by predicted lifetime benefit compared to risk factor levels in patients with symptomatic atherosclerotic disease. METHODS AND RESULTS: For all patients with symptomatic atherosclerotic disease in the UCC-SMART cohort (1996-2018; n = 7697) two treatment strategies were compared. The lifetime benefit-guided strategy was based on individual estimation of gain in cardiovascular disease (CVD)-free life with the SMART-REACH model. In the risk factor-based strategy, all patients were treated the following: low-density lipoprotein cholesterol (LDL-c) < 1.8 mmol/L, systolic blood pressure <140 mmHg, and antithrombotic medication. Outcomes were evaluated for the total cohort using a microsimulation model. Effectiveness was evaluated as total gain in CVD-free life and events avoided, cost-effectiveness as incremental cost-effectivity ratio (ICER). In comparison to baseline treatment, treatment according to lifetime benefit would lead to an increase of 24 243 CVD-free life years [95% confidence interval (CI) 19 980-29 909] and would avoid 940 (95% CI 742-1140) events in the next 10 years. For risk-factor based treatment, this would be an increase of 18 564 CVD-free life years (95% CI 14 225-20 456) and decrease of 857 (95% CI 661-1057) events. The ICER of lifetime benefit-based treatment with a treatment threshold of ≥1 year additional CVD-free life per therapy was €15 092/QALY gained and of risk factor-based treatment €9933/QALY gained. In a direct comparison, lifetime benefit-based treatment compared to risk factor-based treatment results in 1871 additional QALYs for the price of €36 538/QALY gained. CONCLUSION: Residual risk reduction guided by lifetime benefit estimation results in more CVD-free life years and more CVD events avoided compared to the conventional risk factor-based strategy. Lifetime benefit-based treatment is an effective and potentially cost-effective strategy for reducing residual CVD risk in patients with clinical manifest vascular disease.

An international risk prediction algorithm for the onset of generalized anxiety and panic syndromes in general practice attendees: predictA.

BACKGROUND: There are no risk models for the prediction of anxiety that may help in prevention. We aimed to develop a risk algorithm for the onset of generalized anxiety and panic syndromes. METHOD: Family practice attendees were recruited between April 2003 and February 2005 and followed over 24 months in the UK, Spain, Portugal and Slovenia (Europe4 countries) and over 6 months in The Netherlands, Estonia and Chile. Our main outcome was generalized anxiety and panic syndromes as measured by the Patient Health Questionnaire. We entered 38 variables into a risk model using stepwise logistic regression in Europe4 data, corrected for over-fitting and tested it in The Netherlands, Estonia and Chile. RESULTS: There were 4905 attendees in Europe4, 1094 in Estonia, 1221 in The Netherlands and 2825 in Chile. In the algorithm four variables were fixed characteristics (sex, age, lifetime depression screen, family history of psychological difficulties); three current status (Short Form 12 physical health subscale and mental health subscale scores, and unsupported difficulties in paid and/or unpaid work); one concerned country; and one time of follow-up. The overall C-index in Europe4 was 0.752 [95% confidence interval (CI) 0.724-0.780]. The effect size for difference in predicted log odds between developing and not developing anxiety was 0.972 (95% CI 0.837-1.107). The validation of predictA resulted in C-indices of 0.731 (95% CI 0.654-0.809) in Estonia, 0.811 (95% CI 0.736-0.886) in The Netherlands and 0.707 (95% CI 0.671-0.742) in Chile. CONCLUSIONS: PredictA accurately predicts the risk of anxiety syndromes. The algorithm is strikingly similar to the predictD algorithm for major depression, suggesting considerable overlap in the concepts of anxiety and depression.

Predicting the onset of major depression in primary care: international validation of a risk prediction algorithm from Spain.

BACKGROUND: The different incidence rates of, and risk factors for, depression in different countries argue for the need to have a specific risk algorithm for each country or a supranational risk algorithm. We aimed to develop and validate a predictD-Spain risk algorithm (PSRA) for the onset of major depression and to compare the performance of the PSRA with the predictD-Europe risk algorithm (PERA) in Spanish primary care. METHOD: A prospective cohort study with evaluations at baseline, 6 and 12 months. We measured 39 known risk factors and used multi-level logistic regression and inverse probability weighting to build the PSRA. In Spain (4574), Chile (2133) and another five European countries (5184), 11 891 non-depressed adult primary care attendees formed our at-risk population. The main outcome was DSM-IV major depression (CIDI). RESULTS: Six variables were patient characteristics or past events (sex, age, sex×age interaction, education, physical child abuse, and lifetime depression) and six were current status [Short Form 12 (SF-12) physical score, SF-12 mental score, dissatisfaction with unpaid work, number of serious problems in very close persons, dissatisfaction with living together at home, and taking medication for stress, anxiety or depression]. The C-index of the PSRA was 0.82 [95% confidence interval (CI) 0.79-0.84]. The Integrated Discrimination Improvement (IDI) was 0.0558 [standard error (s.e.)=0.0071, Zexp=7.88, p<0.0001] mainly due to the increase in sensitivity. Both the IDI and calibration plots showed that the PSRA functioned better than the PERA in Spain. CONCLUSIONS: The PSRA included new variables and afforded an improved performance over the PERA for predicting the onset of major depression in Spain. However, the PERA is still the best option in other European countries.

Early and late life events and salivary cortisol in older persons.

BACKGROUND: It has been hypothesized that stressful life events are associated with changes in hypothalamic-pituitary-adrenal (HPA) axis regulation, which increases susceptibility to psychiatric disorders. We investigated the association of early and late life events with HPA axis regulation in older persons. METHOD: Within the Longitudinal Aging Study Amsterdam (LASA) 1055 participants (47% male), aged 63-93 years, collected saliva within 30 min after waking and late in the evening. Early and late life events were assessed during a home interview. The associations between life events and cortisol levels were examined using linear regression and analysis of covariance with adjustments for demographics, cardiovascular risk factors and depressive symptoms. RESULTS: Within our sample, the median morning and evening cortisol levels were 15.0 nmol/l [interdecile range (10-90%): 7.4-27.0 nmol/l] and 2.8 nmol/l (10-90%: 1.5-6.3 nmol/l), respectively. Persons who reported early life events showed lower levels of natural log-transformed morning cortisol [B=-0.10, 95% confidence interval (CI) -0.17 to -0.04] and flattened diurnal variability of cortisol (B=-1.06, 95% CI -2.05 to -0.08). Those reporting two or more late life events showed higher levels of natural log-transformed morning cortisol (B=0.10, 95% CI 0.02-0.18) and higher diurnal variability (B=1.19, 95% CI 0.05-2.33). No associations were found with evening cortisol. CONCLUSIONS: The results of this large population-based study of older persons suggest a differential association of early and late life events with HPA axis regulation; early life events were associated with a relative hypo-secretion of morning cortisol and flattened diurnal variability, while late life events were associated with elevated secretion of morning cortisol and high diurnal variability of cortisol.