Syenna Schievink

Temporal Evolution of Cognitive Changes in Incident Hypertension Prospective Cohort Study Across the Adult Age Span

Midlife hypertension is a risk factor for dementia, but little is known about the cognitive trajectories of individuals with incident hypertension. This study follows the cognitive functioning in prevalent and incident hypertension for 12 years and in relation to age and treatment status. Cognitively intact adults aged 25 to 84 years (n=1805) were serially assessed at baseline, 6 years, and 12 years. Hypertension was defined by sphygmomanometry or antihypertensive medication use, and its association with cognitive decline was tested in random-effects models. At baseline, 638 (35.3%) participants had hypertension. They showed faster decline in memory (&khgr;2 test for homogeneity=35.75; df=2; P<0.001), executive functions (&khgr;2=21.68; df=2; P<0.001), and information processing speed (&khgr;2=81.96; df= 2; P<0.001) than baseline normotensive participants. At follow-up, 352 individuals (30.2%) developed incident hypertension. They showed faster decline in memory (&khgr;2=7.88; df=2; P=0.019) and information processing speed (&khgr;2= 18.06; df=2; P<0.001), especially from 6- to 12-year follow-up. Effects were most pronounced and widespread in midlife for both prevalent and incident hypertension and in those with untreated and uncontrolled hypertension. This study shows that incident hypertension predicts cognitive decline in middle-aged individuals, and those with poorly controlled blood pressure are most at risk. In newly diagnosed individuals, decline evolves gradually, possibly opening a window for early intervention.Midlife hypertension is a risk factor for dementia, but little is known about the cognitive trajectories of individuals with incident hypertension. This study follows the cognitive functioning in prevalent and incident hypertension for 12 years and in relation to age and treatment status. Cognitively intact adults aged 25 to 84 years (n=1805) were serially assessed at baseline, 6 years, and 12 years. Hypertension was defined by sphygmomanometry or antihypertensive medication use, and its association with cognitive decline was tested in random-effects models. At baseline, 638 (35.3%) participants had hypertension. They showed faster decline in memory (χ2 test for homogeneity=35.75; df =2; P <0.001), executive functions (χ2=21.68; df =2; P <0.001), and information processing speed (χ2=81.96; df = 2; P <0.001) than baseline normotensive participants. At follow-up, 352 individuals (30.2%) developed incident hypertension. They showed faster decline in memory (χ2=7.88; df =2; P =0.019) and information processing speed (χ2= 18.06; df =2; P <0.001), especially from 6- to 12-year follow-up. Effects were most pronounced and widespread in midlife for both prevalent and incident hypertension and in those with untreated and uncontrolled hypertension. This study shows that incident hypertension predicts cognitive decline in middle-aged individuals, and those with poorly controlled blood pressure are most at risk. In newly diagnosed individuals, decline evolves gradually, possibly opening a window for early intervention. # Novelty and Significance {#article-title-38}

Cognitive changes in prevalent and incident cardiovascular disease: a 12-year follow-up in the Maastricht Aging Study (MAAS)

Aims Cardiovascular disease (CVD) has been suggested to accelerate cognitive decline and to be a risk factor for dementia, but still little is known about the cognitive course after a first cardiovascular event. Therefore, the present study aims to investigate the cognitive trajectories in both prevalent and incident CVD over a 12-year time period in the general population. Methods and results Cognitively healthy participants (age 24-82 years, n = 1823) of a prospective cohort study were serially assessed at baseline, 6 and 12 years. Verbal memory, executive function, and information processing speed were analysed in adults with prevalent, incident, and no CVD. Random effects models were used to test the association between CVD and change in cognitive function over time. At baseline, participants with prevalent CVD showed more decline in memory and information processing speed than healthy controls. Participants with incident CVD also showed more decline in these cognitive domains, but this was only significant in the follow-up period from 6 to 12 years. Associations were more pronounced in participants aged younger than 65 years at baseline, and in sub-analyses with angina pectoris or myocardial infarction as the most prevalent CVD conditions. Conclusion Prevalent and incident CVD predict cognitive decline in middle-aged individuals. Findings for incident CVD suggest that the onset of decline is linked in time with the vascular event itself. Timely CVD management may delay the onset of decline.

Coronary heart disease and risk for cognitive impairment or dementia: Systematic review and meta-analysis

Aims/Hypothesis Accumulating evidence suggests an association between coronary heart disease and risk for cognitive impairment or dementia, but no study has systematically reviewed this association. Therefore, we summarized the available evidence on the association between coronary heart disease and risk for cognitive impairment or dementia. Methods Medline, Embase, PsycINFO, and CINAHL were searched for all publications until 8th January 2016. Articles were included if they fulfilled the inclusion criteria: (1) myocardial infarction, angina pectoris or coronary heart disease (combination of both) as predictor variable; (2) cognition, cognitive impairment or dementia as outcome; (3) population-based study; (4) prospective (≥1 year follow-up), cross-sectional or case-control study design; (5) ≥100 participants; and (6) aged ≥45 years. Reference lists of publications and secondary literature were hand-searched for possible missing articles. Two reviewers independently screened all abstracts and extracted information from potential relevant full-text articles using a standardized data collection form. Study quality was assessed with the Newcastle-Ottawa Scale. We pooled estimates from the most fully adjusted model using random-effects meta-analysis. Results We identified 6,132 abstracts, of which 24 studies were included. A meta-analysis of 10 prospective cohort studies showed that coronary heart disease was associated with increased risk of cognitive impairment or dementia (OR = 1.45, 95%CI = 1.21–1.74, p<0.001). Between-study heterogeneity was low (I2 = 25.7%, 95%CI = 0–64, p = 0.207). Similar significant associations were found in separate meta-analyses of prospective cohort studies for the individual predictors (myocardial infarction, angina pectoris). In contrast, meta-analyses of cross-sectional and case-control studies were inconclusive. Conclusion/Interpretation This meta-analysis suggests that coronary heart disease is prospectively associated with increased odds of developing cognitive impairment or dementia. Given the projected worldwide increase in the number of people affected by coronary heart disease and dementia, insight into causal mechanisms or common pathways underlying the heart-brain connection is needed.

High-frequency stimulation of the substantia nigra induces serotonin-dependent depression-like behavior in animal models.

To the Editor: H igh-frequency stimulation (HFS; deep brain stimulation) of the subthalamic nucleus (STN) is a popular neurosurgical therapy to treat motor disability in advanced Parkinson’s disease (PD) (1). In some patients, psychiatric effects, including depression and increased risk of suicide, are a recognized postoperative problem (2,3). Some authors, including ourselves, have linked these effects to interactions between the STN and limbic circuitry, and specifically the midbrain serotonin (5-HT; 5-hydroxytryptamine) system, which, when acutely lowered, can trigger low mood in individuals at risk of depression (4 –7). Others, however, have suggested that current spread or even direct stimulation of the ventrally located substantia nigra pars reticulata (SNR) through misplaced electrodes contributes to the psychiatric effects of STN stimulation. In this respect, three case reports described acute depression caused by accidental electrode placement and stimulation in the SNR, by a still unknown mechanism (8-10). Here we report the induction of acute depression-like behavior by HFS of the SNR by a 5-HT– dependent mechanism in animal models. Naïve male Sprague-Dawley rats (270 g; Harlan, Bicester, United Kingdom; Charles River, Rotterdam, The Netherlands) underwent bilateral stereotaxic implantation of stimulation electrodes into the SNR (bregma: anteroposterior (AP) –5.3 mm, mediolateral (ML) 2.5 mm, dorsoventral (DV) – 8.2 mm [11,12]). After 1 week of recovery, each electrode was connected to a current isolator (DS100 or A360, WPI Europe, Berlin, Germany) driven by a pulse generator (DS8000, WPI Europe or Master 8, AMPI Israel, Jerusalem, Israel). For stimulation a clinically relevant paradigm (100 A, 60 sec, and 130 Hz) was applied (12). Nonstimulated controls were connected to the stimulator without stimulation being performed. Motor and nonmotor behavior were evaluated in SNR HFS treated rats and nonstimulated controls (n 8 –10 per group). Spontaneus locomotor activity was measured in the open field during a 0-minute trial (5). Anxiety behavior was analyzed by the time spent n the open and closed arms of the elevated zero maze during 5 inutes (13). Motivation and hedonia-like behavior were evaluated ith food consumption and sucrose intake tests, respectively 13,14). In the food consumption test, rats were food deprived for 4 hours followed by presentation of 60 g food pellets for 2 hours. In he sucrose intake test, rats were food and water deprived for 14 ours after which sucrose intake was measured over a 1-hour peiod. The food consumption and sucrose intake tests were repeated fter 7 days treatment with the 5-HT reuptake inhibitor escitaloram (5 mg/kg subcutaneously). The effect of HFS of the SNR on xtracellular 5-HT in medial prefrontal cortex (mPFC) was investiated by in vivo microdialysis (n 4 per group). Bilateral SNR HFS lectrodes and a single mPFC microdialysis probe were surgically mplanted (bregma: AP 3.2 mm, ML – 0.6 mm, DV –5.4 mm [11]) nder general anesthesia as described (4), and 1 week later microialysis was performed in awake freely moving rats. Perfusates were ollected every 5 minutes and analyzed using high-pressure liquid hromatography with electrochemical detection for 5-HT (4). Postortem verification of electrode (Figure 1A) and microdialysis robe placements was performed. Analysis of the behavioral data showed that HFS of the SNR did ot alter spontaneous locomotor activity in the open field (Figure B). Moreover, anxiety behavior in the elevated zero maze was omparable between animals with stimulation and nonstimulated a

Co-occurrence of depressive symptoms and executive dysfunction after stroke: associations with brain pathology and prognosis

Objective To examine, first, whether the co-occurrence of executive dysfunction (ED) and poststroke depression (PSD) shows different associations with neuroimaging markers and the course of depression and executive function, and second, whether it is associated with a different course on other cognitive domains and quality of life. Methods The present study included 245 stroke patients (35.9% female, mean age 67.5 years (SD=11.9). All patients completed neuropsychological and neuropsychiatric assessment 3 months poststroke, which were repeated at 6-month and 12-month follow-up. A subset (n=186) received 3-Tesla brain MRI at baseline to evaluate lesion-related imaging markers, white matter hyperintensity volume, global brain atrophy and total cerebral small vessel disease burden. Results Patients with ‘depression–executive dysfunction syndrome’ (DES) showed higher white matter hyperintensity volumes compared with all other groups and more frequently showed left-sided lesions compared with ED only and PSD only. They also had more frequently old infarcts and higher total cerebral small vessel disease burden compared with PSD only and patients with neither ED nor PSD, and more global brain atrophy compared with PSD only. Longitudinal analyses showed that patients with DES had a more chronic course of depressive symptoms relative to PSD only, and a stable pattern of worse cognitive performance similar to patients with ED only. Conclusions The co-occurrence of ED and PSD is associated with a worse prognosis of depression, persistent cognitive impairment and a higher amount of vascular and degenerative brain pathology. Future studies are needed to examine whether these patients represent a more severe subtype within the PSD spectrum. Clinical trial registration NCT02585349;Results.

Baseline Vascular Cognitive Impairment Predicts the Course of Apathetic Symptoms After Stroke: The CASPER Study

OBJECTIVE To examine the influence of vascular cognitive impairment (VCI) on the course of poststroke depression (PSD) and poststroke apathy (PSA). METHODS Included were 250 stroke patients who underwent neuropsychological and neuropsychiatric assessment 3 months after stroke (baseline) and at a 6- and 12-month follow-up after baseline. Linear mixed models tested the influence of VCI in at least one cognitive domain (any VCI) or multidomain VCI (VCI in multiple cognitive domains) at baseline and domain-specific VCI at baseline on levels of depression and apathy over time, with random effects for intercept and slope. RESULTS Almost half of the patients showed any VCI at baseline, and any VCI was associated with increasing apathy levels from baseline to the 12-month follow-up. Patients with multidomain VCI had higher apathy scores at the 6- and 12-month follow-up compared with patients with VCI in a single cognitive domain. Domain-specific analyses showed that impaired executive function and slowed information processing speed went together with increasing apathy levels from baseline to 6- and 12-month follow-up. None of the cognitive variables predicted the course of depressive symptoms. CONCLUSION Baseline VCI is associated with increasing apathy levels from baseline to the chronic stroke phase, whereas no association was found between baseline VCI and the course of depressive symptoms. Health professionals should be aware that apathy might be absent early after stroke but may evolve over time in patients with VCI.

Personality traits and course of symptoms of depression and apathy after stroke: Results of the CASPER study

OBJECTIVE Post-stroke depression (PSD) and post-stroke apathy (PSA) are both associated with adverse outcome after stroke. This study aimed to examine whether personality traits predict the course of PSD and PSA. METHODS In this prospective cohort study, 240 stroke patients completed the NEO Five Factor Inventory, Montgomery-Åsberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months post-stroke. Neuropsychiatric assessment was repeated at 6- and 12-month follow-up after initial testing. RESULTS Linear mixed models showed that high neuroticism scores were associated with higher depression levels at baseline, and this association remained stable at follow-up. High extraversion scores and high conscientiousness scores were associated with lower apathy levels at baseline. For neuroticism, a significant interaction with time was found, with higher neuroticism scores at baseline being associated with an increase in apathy scores from 6-month to 12-month follow-up. Prospective analyses showed that high extraversion predicted low apathy levels at 6-month and 12-month follow-up independent of its relations with baseline depression and apathy. High neuroticism predicted high apathy levels at 12-month follow-up, whereas high agreeableness and high openness predicted high apathy levels and low apathy levels, respectively, at 6-month follow-up. None of the personality traits predicted depression scores at follow-up. CONCLUSION Personality traits are associated with the development and sustainability of PSD and PSA. The traits associated with PSD and PSA were different, providing support for the independence of these constructs. The findings highlight the importance to take personality traits into account as a potential vulnerability factor for PSD and PSA.

Temporal Evolution of Cognitive Changes in Incident Hypertension

Midlife hypertension is a risk factor for dementia, but little is known about the cognitive trajectories of individuals with incident hypertension. This study follows the cognitive functioning in prevalent and incident hypertension for 12 years and in relation to age and treatment status. Cognitively intact adults aged 25 to 84 years (n=1805) were serially assessed at baseline, 6 years, and 12 years. Hypertension was defined by sphygmomanometry or antihypertensive medication use, and its association with cognitive decline was tested in random-effects models. At baseline, 638 (35.3%) participants had hypertension. They showed faster decline in memory (&khgr;2 test for homogeneity=35.75; df=2; P<0.001), executive functions (&khgr;2=21.68; df=2; P<0.001), and information processing speed (&khgr;2=81.96; df= 2; P<0.001) than baseline normotensive participants. At follow-up, 352 individuals (30.2%) developed incident hypertension. They showed faster decline in memory (&khgr;2=7.88; df=2; P=0.019) and information processing speed (&khgr;2= 18.06; df=2; P<0.001), especially from 6- to 12-year follow-up. Effects were most pronounced and widespread in midlife for both prevalent and incident hypertension and in those with untreated and uncontrolled hypertension. This study shows that incident hypertension predicts cognitive decline in middle-aged individuals, and those with poorly controlled blood pressure are most at risk. In newly diagnosed individuals, decline evolves gradually, possibly opening a window for early intervention.Midlife hypertension is a risk factor for dementia, but little is known about the cognitive trajectories of individuals with incident hypertension. This study follows the cognitive functioning in prevalent and incident hypertension for 12 years and in relation to age and treatment status. Cognitively intact adults aged 25 to 84 years (n=1805) were serially assessed at baseline, 6 years, and 12 years. Hypertension was defined by sphygmomanometry or antihypertensive medication use, and its association with cognitive decline was tested in random-effects models. At baseline, 638 (35.3%) participants had hypertension. They showed faster decline in memory (χ2 test for homogeneity=35.75; df =2; P <0.001), executive functions (χ2=21.68; df =2; P <0.001), and information processing speed (χ2=81.96; df = 2; P <0.001) than baseline normotensive participants. At follow-up, 352 individuals (30.2%) developed incident hypertension. They showed faster decline in memory (χ2=7.88; df =2; P =0.019) and information processing speed (χ2= 18.06; df =2; P <0.001), especially from 6- to 12-year follow-up. Effects were most pronounced and widespread in midlife for both prevalent and incident hypertension and in those with untreated and uncontrolled hypertension. This study shows that incident hypertension predicts cognitive decline in middle-aged individuals, and those with poorly controlled blood pressure are most at risk. In newly diagnosed individuals, decline evolves gradually, possibly opening a window for early intervention. # Novelty and Significance {#article-title-38}

IMAGING MARKERS ASSOCIATED WITH THE DEVELOPMENT OF POST-STROKE DEPRESSION AND APATHY: RESULTS OF THE CASPER STUDY

P3-310 IMAGING MARKERS ASSOCIATEDWITH THE DEVELOPMENT OF POST-STROKE DEPRESSION AND APATHY: RESULTS OF THE CASPER STUDY Elles Douven, Julie Staals, Syenna H. J. Schievink, Whitney M. Freeze, Danique Hellebrekers, Robin Wolz, Jacobus F. A. Jansen, Robert J. van Oostenbrugge, Frans R. J. Verhey, Sebastiaan Koehler, Pauline Aalten, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands; Maastricht University Medical Center, School for Mental Health and Neuroscience, Maastricht, Netherlands; Imperial College London, London, United Kingdom. Contact e-mail: p.aalten@ maastrichtuniversity.nl

Temporal Associations between Fatigue, Depression, and Apathy after Stroke: Results of the Cognition and Affect after Stroke, a Prospective Evaluation of Risks Study

Background: Poststroke fatigue (PSF) is a form of pathological fatigue that can develop after stroke and has a negative impact on functional outcome. PSF is associated with poststroke depression (PSD), which in turn shows similarities with poststroke apathy (PSA). This study aimed at disentangling the temporal associations between PSF and PSD and between PSF and PSA. Methods: A total of 250 stroke patients were included, of which 243 completed the Fatigue Severity Scale, Montgomery-Åsberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months poststroke, with follow-up measurements at 6 and 12 months after initial testing. Linear mixed models and linear regressions were performed to evaluate the temporal associations between PSF and PSD, and between PSF and PSA. Results: PSF was present in 119 patients (49%), of whom 62 patients also had PSD (26%), and 21 patients (9%) also had PSA. At baseline, PSF patients showed higher depression levels, which remained stable at follow-up. PSD patients had higher fatigue levels compared with no-PSD patients at baseline, which remained stable at follow-up. No association between apathy and fatigue was found at baseline and no interaction with time was found. Change in fatigue from baseline to 12-month follow-up was associated with change in depression and with change in apathy. Conclusions: Bidirectional associations were found between PSF and PSD. In treatment and rehabilitation programs, early focus on the presence of PSD and PSF is important, since these conditions tend to persist. As there are currently more treatment options for PSD, attention for PSD is important and might also have a beneficial effect on PSF.