Alzheimer's Disease and Cognitive Decline in Patients with Cardiovascular Diseases Along the Heart-Brain Axis.

Background: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-ß42/40 (Aß42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aß42/40 was not associated with cognitive performance at baseline. However, lower Aß42/40 was associated with steeper decline in global cognition (ß±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

Lower cerebral blood flow predicts cognitive decline in patients with vascular cognitive impairment.

INTRODUCTION: Chronic cerebral hypoperfusion is one of the assumed pathophysiological mechanisms underlying vascular cognitive impairment (VCI). We investigated the association between baseline cerebral blood flow (CBF) and cognitive decline after 2 years in patients with VCI and reference participants. METHODS: One hundred eighty-one participants (mean age 66.3 ± 7.4 years, 43.6% women) underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) and neuropsychological assessment at baseline and at 2-year follow-up. We determined the association between baseline global and lobar CBF and cognitive decline with multivariable regression analysis. RESULTS: Lower global CBF at baseline was associated with more global cognitive decline in VCI and reference participants. This association was most profound in the domain of attention/psychomotor speed. Lower temporal and frontal CBF at baseline were associated with more cognitive decline in memory. DISCUSSION: Our study supports the role of hypoperfusion in the pathophysiological and clinical progression of VCI. HIGHLIGHTS: Impaired cerebral blood flow (CBF) at baseline is associated with faster cognitive decline in VCI and normal aging. Our results suggest that low CBF precedes and contributes to the development of vascular cognitive impairment. CBF determined by ASL might be used as a biomarker to monitor disease progression or treatment responses in VCI.

Effects of a 1 year aerobic and strength training on cognitive functioning after transient ischemic attack or minor stroke: A randomized controlled trial.

OBJECTIVES: Patients who have recently suffered a transient ischemic attack (TIA) or minor ischemic stroke are at increased risk of cognitive impairment. In the present study, we aimed to investigate the effect of a 1-year exercise intervention on cognitive functioning up to 2 years post intervention. MATERIAL AND METHODS: We conducted a single-blind randomized controlled trial to investigate the effect of an exercise intervention on cognitive functioning, compared with usual care, for up to 2 years. Patients with a TIA or minor stroke were randomly allocated to an intervention group receiving the 1-year exercise intervention (n = 60) or to usual care (n = 59). Outcome measures were assessed at baseline and after 1 and 2 years. We measured cognition with neuropsychological tests on three domains: (1) executive functioning, (2) attention-psychomotor speed, and (3) memory. Linear mixed models were used for longitudinal data to determine the effect of the exercise intervention on cognitive functioning. Statistical analyses were performed using IBM SPSS software 24.0. RESULTS: We found that over the two years study period -and corrected for age, sex, and educational level- the intervention group on average improved significantly more in executive functioning than the control group (ß = 0.13; 95 % CI [0.02 to 0.25]; p = 0.03). No significant intervention effects were found on either memory or attention-psychomotor speed. CONCLUSIONS: Our data show that a 1-year exercise intervention significantly improved executive functioning over time, compared to usual care. We recommend that health care professionals consider broadening standard secondary stroke prevention treatment in patients with TIA/minor stroke by adding exercise and physical activity.

The link between cardiac status and depression and anxiety in implantable cardioverter defibrillator patients: Design and first results of the PSYCHE-ICD study.

OBJECTIVE: Depression and anxiety in patients with an implantable cardioverter-defibrillator (ICD) are associated with adverse outcomes. This study describes the design of the PSYCHE-ICD study and evaluates the correlation between cardiac status and depression and anxiety in ICD patients. METHODS: We included 178 patients. Prior to implantation, patients completed validated psychological questionnaires for depression, anxiety and personality traits. Cardiac status was evaluated by means of left ventricular ejection fraction assessment (LVEF), New York Heart Association (NYHA) functional class, 6-minute walk test (6MWT), and 24-h Holter monitoring for heart rate variability (HRV). A cross-sectional analysis was performed. Follow-up with annual study visits, including repeated full cardiac evaluation, will continue 36 months after ICD implantation. RESULTS: Depressive symptoms were present in 62 (35%) and anxiety in 56 (32%) patients. Values of depression and anxiety significantly increased with higher NYHA class (P < 0.001). Depression symptoms were correlated with a reduced 6MWT (411 ± 128 vs. 488 ± 89, P < 0.001), higher heart rate (74 ± 13 vs. 70 ± 13, P = 0.02), higher thyroid stimulation hormone levels (1.8 [1.3-2.8] vs 1.5 [1.0-2.2], P = 0.03) and multiple HRV parameters. Anxiety symptoms were correlated with higher NYHA class and a reduced 6MWT (433 ± 112 vs 477 ± 102, P = 0.02). CONCLUSION: A substantial part of patients receiving an ICD have symptoms of depression and anxiety at time of ICD implantation. Depression and anxiety were correlated with multiple cardiac parameters, suggesting a possible biological links between psychological distress and cardiac disease in ICD patients.

Sex and Cardiovascular Function in Relation to Vascular Brain Injury in Patients with Cognitive Complaints.

BACKGROUND: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function. OBJECTIVE: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function. METHODS: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker). RESULTS: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05). CONCLUSION: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns.

Hypertensive Exposure Markers by MRI in Relation to Cerebral Small Vessel Disease and Cognitive Impairment.

OBJECTIVES: This study sought to investigate the extent of hypertensive exposure as assessed by cardiovascular magnetic resonance imaging (MRI) in relation to cerebral small vessel disease (CSVD) and cognitive impairment, with the aim of understanding the role of hypertension in the early stages of deteriorating brain health. BACKGROUND: Preserving brain health into advanced age is one of the great challenges of modern medicine. Hypertension is thought to induce vascular brain injury through exposure of the cerebral microcirculation to increased pressure/pulsatility. Cardiovascular MRI provides markers of (subclinical) hypertensive exposure, such as aortic stiffness by pulse wave velocity (PWV), left ventricular (LV) mass index (LVMi), and concentricity by mass-to-volume ratio. METHODS: A total of 559 participants from the Heart-Brain Connection Study (431 patients with manifest cardiovascular disease and 128 control participants), age 67.8 ± 8.8 years, underwent 3.0-T heart-brain MRI and extensive neuropsychological testing. Aortic PWV, LVMi, and LV mass-to-volume ratio were evaluated in relation to presence of CSVD and cognitive impairment. Effect modification by patient group was investigated by interaction terms; results are reported pooled or stratified accordingly. RESULTS: Aortic PWV (odds ratio [OR]: 1.17; 95% confidence interval [CI]: 1.05 to 1.30 in patient groups only), LVMi (in carotid occlusive disease, OR: 5.69; 95% CI: 1.63 to 19.87; in other groups, OR: 1.30; 95% CI: 1.05 to 1.62]) and LV mass-to-volume ratio (OR: 1.81; 95% CI: 1.46 to 2.24) were associated with CSVD. Aortic PWV (OR: 1.07; 95% CI: 1.02 to 1.13) and LV mass-to-volume ratio (OR: 1.27; 95% CI: 1.07 to 1.51) were also associated with cognitive impairment. Relations were independent of sociodemographic and cardiac index and mostly persisted after correction for systolic blood pressure or medical history of hypertension. Causal mediation analysis showed significant mediation by presence of CSVD in the relation between hypertensive exposure markers and cognitive impairment. CONCLUSIONS: The extent of hypertensive exposure is associated with CSVD and cognitive impairment beyond clinical blood pressure or medical history. The mediating role of CSVD suggests that hypertension may lead to cognitive impairment through the occurrence of CSVD.

Cerebral blood flow and cognitive functioning in patients with disorders along the heart-brain axis: Cerebral blood flow and the heart-brain axis.

INTRODUCTION: We examined the role of hemodynamic dysfunction in cognition by relating cerebral blood flow (CBF), measured with arterial spin labeling (ASL), to cognitive functioning, in patients with heart failure (HF), carotid occlusive disease (COD), and patients with cognitive complaints and vascular brain injury on magnetic resonance imaging (MRI; ie, possible vascular cognitive impairment [VCI]). METHODS: We included 439 participants (124 HF; 75 COD; 127 possible VCI; 113 reference participants) from the Dutch multi-center Heart-Brain Study. We used pseudo-continuous ASL to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and four cognitive domains. RESULTS: CBF values were lowest in COD, followed by VCI and HF, compared to reference participants. This did not explain cognitive impairment, as we did not find an association between CBF and cognitive functioning. DISCUSSION: We found that reduced CBF is not the major explanatory factor underlying cognitive impairment in patients with hemodynamic dysfunction along the heart-brain axis.

Frequent Cognitive Impairment in Patients With Disorders Along the Heart-Brain Axis.

Background and Purpose- Patients with cardiovascular disease are at increased risk for cognitive decline. We studied the occurrence and profile of cognitive impairment in 3 patient groups as exemplar conditions of hemodynamic disturbances at different levels of the heart-brain axis, including patients with heart failure (HF), carotid occlusive disease (COD), and patients with cognitive complaints and vascular brain injury on magnetic resonance imaging (possible vascular cognitive impairment [VCI]). Methods- In 555 participants (160 HF, 107 COD, 160 possible VCI, 128 reference participants; 68±9 years; 36% F; Mini-Mental State Examination 28±2), we assessed cognitive functioning with a comprehensive test battery. Test scores were transformed into z-scores. Compound z-scores were constructed for: memory, language, attention/psychomotor speed, executive functioning, and global cognitive functioning. We rated cognitive domains as impaired when z-score≤-1.5. Based on the number of impaired domains, patients were classified as cognitively normal, minor, or major cognitive impairment. We used general linear models and χ2 tests to compare cognitive functioning between patient groups and the reference group. Results- Age, sex, and education adjusted global cognitive functioning z-score was lower in patients with COD (ß [SE]=-0.46 [0.10], P<0.001) and possible VCI (ß [SE]=-0.80 [0.09], P<0.001) compared with reference participants. On all domains, z-scores were lower in patients with COD and possible VCI compared with reference participants. Patients with HF had lower z-scores on attention/speed and language compared with reference participants. Cognitive impairment was observed in 18% of HF, 36% of COD, and 45% possible VCI. There was no difference in profile of impaired cognitive domains between patient groups. Memory and attention-psychomotor speed were most commonly affected, followed by executive functioning and language. Conclusions- A substantial part of patients with HF and COD had cognitive impairment, which warrants vigilance for the occurrence of cognitive impairment. These results underline the importance of an integrative approach in medicine in patients presenting with disorders in the heart-brain axis.

Nonfocal transient neurological attacks are related to cognitive impairment in patients with heart failure.

INTRODUCTION: Nonfocal transient neurological attacks (TNAs) are associated with an increased risk of future dementia, but it is unclear whether TNAs are also associated with concurrent cognitive impairment. We hypothesized that recent TNAs are related to worse cognitive functioning. We tested our hypothesis in patients with heart failure, as these patients are at risk of cerebral hypoperfusion, which might play a role in the etiology of TNAs. METHODS: We performed neuropsychological testing in all patients with heart failure enrolled in the Heart Brain Connection study. We assessed global cognition, attention-psychomotor speed, executive functioning, memory and language. All patients were interviewed with a standardized questionnaire on the occurrence of TNAs in the preceding 6 months. We studied associations between TNAs and cognitive functioning with linear and logistic regression analyses, adjusted for age, sex and education. We performed additional analyses in patients without previous stroke or TIA and in patients without brain infarction on MRI. RESULTS: Thirty-seven (23%) of 158 patients (mean age 70 years, 67% men) experienced one or more TNAs. Patients with a recent TNA were more likely to be impaired on ≥ 1 cognitive domains than patients without TNAs [41% vs. 18%, adjusted odds ratio 4.6, 95% confidence interval (CI) 1.8-11.8]. Patients with TNAs performed worse than patients without TNAs on global cognition (mean difference in z scores - 0.36, 95% CI - 0.54 to - 0.18), and on the cognitive domains attention-psychomotor speed (mean difference - 0.40, 95% CI - 0.66 to - 0.14), memory (mean difference - 0.57, 95% CI - 0.98 to - 0.15) and language (mean difference - 0.47, 95% CI - 0.79 to - 0.16). These associations were independent of cardiac output and volume of white matter hyperintensities. Subgroup analyses in patients without previous stroke or TIA or brain infarction on MRI (n = 78) yielded comparable results, with the exception of the cognitive domain language, which was no longer different between patients with and without TNAs. CONCLUSION: Among patients with heart failure, TNAs are associated with cognitive impairment, which warrants the need for more clinical awareness of this problem.

Web-Based Multidomain Lifestyle Programs for Brain Health: Comprehensive Overview and Meta-Analysis.

BACKGROUND: The number of people living with dementia is increasing worldwide, mainly because of aging of the population. To date, there is no pharmaceutical intervention to delay or treat cognitive decline or dementia. As an estimated one-third of dementia cases might be attributable to modifiable lifestyle factors (such as cognitive and physical activity), multidomain lifestyle interventions are a promising way to maintain or improve brain health. Offering programs online would enable large-scale implementation. An overview of multidomain Web-based lifestyle programs for brain health would facilitate comparison and improvement of such programs to develop effective and sustainable interventions. OBJECTIVE: This study aimed to (1) provide a comprehensive overview of Web-based multidomain lifestyle programs aimed at optimizing brain health in healthy adult populations and (2) describe the programs and targeted lifestyle factors, availability, and evaluation of adherence and user experience. In addition, a meta-analysis was performed to evaluate the effectiveness of these programs. METHODS: Electronic databases (PubMed, EMBASE, and PsycINFO) were searched for Web-based lifestyle programs that were included when the program (1) aimed to optimize brain health, (2) focused on multiple lifestyle factors, (3) was completely Web-based (website, Web application or mobile app), (4) consisted of multiple sessions, and (5) focused on a healthy adult population. Program characteristics (target population, duration, frequency, tailoring, platform, and availability) and results of program evaluations (effectiveness, user evaluations, and adherence) were extracted and compared. Studies using a controlled design were included in a random-effects meta-analysis on the effectiveness on brain health outcomes. Study quality was assessed using the physiotherapy evidence database (PEDro) scale. RESULTS: The electronic searches yielded 44 documents describing 14 Web-based lifestyle programs; physical and cognitive activities were targeted in all programs. Four programs (4/14, 29%) were publicly available and free of charge, whereas others were restricted to research settings (5/14, 36%), available after payment (1/14, 7%), or not available at all (2/14, 14%). User evaluations were reported for 8 (57%) of the 14 programs. Reported dropout of the intervention groups ranged from 2% to 52%. Overall, 3 studies evaluated the effectiveness of a program using a controlled design and were included in the meta-analysis (moderate-to-high quality). Pooled results showed a significant small-to-medium effect of the Web-based multidomain lifestyle interventions on outcome measures for brain health (global cognition score, subjective cognitive score, and lifestyle risk score; standard mean difference=0.45; 95% CI 0.12-0.78), with a high degree heterogeneity across studies (I2=75%; P=.02). CONCLUSIONS: In total, 14 Web-based multidomain lifestyle programs aimed at optimizing brain health were found. The programs showed heterogeneity in both characteristics and effectiveness evaluation. Despite this heterogeneity, this meta-analysis suggests that Web-based lifestyle programs can positively influence brain health outcomes and have the potential to contribute to the prevention of dementia.

Impact of white matter hyperintensity location on depressive symptoms in memory-clinic patients: a lesion­symptom mapping study

Background: We investigated the association between white matter hyperintensity location and depressive symptoms in a memoryclinic population using lesion­symptom mapping. Methods: We included 680 patients with vascular brain injury from the TRACE-VCI cohort (mean age ± standard deviation: 67 ± 8 years; 52% female): 168 patients with subjective cognitive decline, 164 with mild cognitive impairment and 348 with dementia. We assessed depressive symptoms using the Geriatric Depression Scale. We applied assumptionfree voxel-based lesion­symptom mapping, adjusted for age, sex, total white matter hyperintensity volume and multiple testing. Next, we applied exploratory region-of-interest linear regression analyses of major white matter tracts, with additional adjustment for diagnosis. Results: Voxel-based lesion­symptom mapping identified voxel clusters related to the Geriatric Depression Scale in the left corticospinal tract. Region-of-interest analyses showed no relation between white matter hyperintensity volume and the Geriatric Depression Scale, but revealed an interaction with diagnosis in the forceps minor, where larger regional white matter hyperintensity volume was associated with more depressive symptoms in subjective cognitive decline (ß = 0.26, p < 0.05), but not in mild cognitive impairment or dementia. Limitations: We observed a lack of convergence of findings between voxel-based lesion­symptom mapping and region-of-interest analyses, which may have been due to small effect sizes and limited lesion coverage despite the large sample size. This warrants replication of our findings and further investigation in other cohorts. Conclusion: This lesion­symptom mapping study in depressive symptoms indicates the corticospinal tract and forceps minor as strategic tracts in which white matter hyperintensity is associated with depressive symptoms in memory-clinic patients with vascular brain injury. The impact of white matter hyperintensity on depressive symptoms is modest, but it appears to depend on the location of white matter hyperintensity and disease severity.

Wishes and preferences for an online lifestyle program for brain health-A mixed methods study.

INTRODUCTION: Individuals with subjective cognitive decline (SCD) are at increased risk of Alzheimer's disease and could benefit from a prevention strategy targeting lifestyle factors. Making a program available through the Internet gives a widespread reach at low cost, but suboptimal adherence is a major threat to effectiveness. As a first step in developing an online lifestyle program (OLP), we aimed to identify factors that are barriers and/or facilitators for the use of an OLP in individuals with SCD in three European countries. METHODS: As part of the Euro-SCD project, SCD subjects were recruited at memory clinics in the Netherlands, Germany, and Spain. We combined quantitative and qualitative methods, using a mixed methods approach. We conducted an online 18-item survey on the preferences of SCD patients for an OLP (N = 238). In addition, we held semi-structured interviews (N = 22) to gain in-depth understanding of factors acting as a facilitator and/or barrier for intended use of an OLP. Audio recordings were transcribed verbatim. Content analysis was performed. RESULTS: One hundred seventy-six individuals completed the survey (response rate 74%). Almost all participants regularly use the Internet (97%). Participants reported trustworthiness (93%), user-friendliness (91%), and up-to-date information (88%) as main facilitators, whereas having contact with other users (26%), needing an account (21%), and assignments (16%) were reported as barriers. Barriers differed slightly between countries, but facilitators were largely similar. In-depth interviews revealed that both program characteristics (e.g., trustworthiness, user-friendliness, and personalization) and personal factors (e.g., expectancy to receive negative feedback) are likely to influence the intended use of an OLP. DISCUSSION: Involving users provided in-depth understanding of factors associated with the intended use of an OLP for brain health. Both program characteristics and personal factors are likely to influence the use of an OLP. Based on this input from the end-users, we will develop an OLP for individuals with SCD.

Microbleeds are associated with depressive symptoms in Alzheimer's disease.

INTRODUCTION: Co-occurrence of cerebrovascular disease and depression led to the "vascular depression hypothesis". White matter hyperintensities (WMHs) have been associated with depressive symptoms in population-based studies. We studied the association between small vessel disease and depressive symptoms in a memory clinic population. METHODS: We included >2000 patients with subjective cognitive decline (SCD), mild cognitive impairment, and Alzheimer's disease (AD). Magnetic resonance imaging was rated for WMHs, lacunes, and microbleeds. Depressive symptoms were assessed using the Geriatric Depression Scale. We performed logistic regression analysis. RESULTS: Depressive symptoms were present in AD: 17%; mild cognitive impairment: 25%; and SCD: 23%. SCD patients with WMHs showed higher propensity of depressive symptoms than AD patients with WMHs. AD patients with microbleeds were more likely to have depressive symptoms compared with AD patients without microbleeds (odds ratio = 1.70; 95% confidence interval: 1.08-2.68). DISCUSSION: Microbleeds are associated with depressive symptoms in AD, supporting a potential role of cerebral amyloid angiopathy in the occurrence of depressive symptoms in AD.

Design of the ExCersion-VCI study: The effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment.

There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise increases cerebral blood flow (CBF) in patients with vascular cognitive impairment (VCI). This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in CBF. We expect this study to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status.

The Missing Link in the Pathophysiology of Vascular Cognitive Impairment: Design of the Heart-Brain Study.

BACKGROUND: Hemodynamic balance in the heart-brain axis is increasingly recognized as a crucial factor in maintaining functional and structural integrity of the brain and thereby cognitive functioning. Patients with heart failure (HF), carotid occlusive disease (COD), and vascular cognitive impairment (VCI) present themselves with complaints attributed to specific parts of the heart-brain axis, but hemodynamic changes often go beyond the part of the axis for which they primarily seek medical advice. The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain is an important but underestimated cause of VCI. We investigate this by studying to what extent hemodynamic changes contribute to VCI and what the mechanisms involved are. Here, we provide an overview of the design and protocol. METHODS: The Heart-Brain Study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling. In subsets of participants we assess Alz-heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines. RESULTS AND CONCLUSIONS: The Heart-Brain Study investigates relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment. By studying the complete heart-brain axis in patient groups that represent components of this axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system and brain, with hemodynamic status as a possible binding factor.

Gait Speed and Grip Strength Reflect Cognitive Impairment and Are Modestly Related to Incident Cognitive Decline in Memory Clinic Patients With Subjective Cognitive Decline and Mild Cognitive Impairment: Findings From the 4C Study.

BACKGROUND: Prospective studies in the general population show that slow gait speed is associated with cognitive decline and clinical progression to dementia. However, longitudinal studies in memory clinic populations are mostly lacking. We aimed to study the association between gait speed and grip strength and cognitive functioning at baseline and cognitive decline over time in memory clinic patients with subjective cognitive decline and mild cognitive impairment. METHODS: We included 309 patients (age 70 ± 9 years, 108 [35%] women, Mini-Mental State Examination 27 ± 3 points). Baseline gait speed was assessed over 15 feet, grip strength with a hydraulic hand dynamometer. Cognitive functioning was assessed annually with a comprehensive test battery during 3 years. RESULTS: Age- and gender-adjusted linear mixed models showed that slower gait speed was related to worse baseline attention, memory, information processing speed, and verbal fluency. Longitudinally, gait speed was related to decline in information processing speed and executive functioning. Weaker grip strength was related to worse baseline information processing speed and executive functioning but there were no longitudinal associations. Cox proportional hazards models revealed no significant associations with clinical progression. CONCLUSIONS: Our findings suggest that markers of physical performance are related to current cognitive status and modestly related to cognitive decline but are seemingly not useful as an early marker of incident clinical progression.

Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer's disease.

INTRODUCTION: We examined the association between decreased cerebral blood flow (CBF) and cognitive impairment in Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD). METHODS: We included 161 AD, 95 MCI, and 143 SCD patients from the Amsterdam Dementia Cohort. We used 3-T pseudo-continuous arterial spin labeling to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and five cognitive domains. Associations were investigated using linear regression analyses. RESULTS: In the whole sample, reduced overall and regional CBF was associated with impairment in all cognitive domains. We found significant interactions between diagnosis and CBF for language and between diagnosis and parietal CBF for global cognition and executive functioning. Stratification showed that decreased CBF was associated with worse performance in AD patients but not in MCI or SCD. DISCUSSION: Our results suggest that CBF may have potential as a functional marker of disease severity.

The rest-activity rhythm and physical activity in early-onset dementia.

BACKGROUND: A substantial part of elderly persons with dementia show rest-activity rhythm disturbances. The rest-activity rhythm is important to study in people with early-onset dementia (EOD) for rest-activity rhythm disturbances are predictive of institutionalization, and caregivers of young patients suffer from high distress. OBJECTIVE: The aim of this study was to study (1) whether EOD patients have more rest-activity rhythm disturbances compared with cognitively intact adults; and (2) which factors contribute to a disturbed rhythm. METHODS: We included 61 patients with EOD [mean age 61.9 (4.9) y, 41 (67%) men] and 68 cognitively intact adults [mean age 61.6 (4.5) y, 28 (41%) men]. Rest-activity rhythm was assessed by actigraphy. RESULTS: EOD patients tended to have higher intradaily variability [0.46 (0.16) and 0.39 (0.10), P=0.03]. EOD patients also lay for a longer time in bed [time in bed: 08:49 (0:51) h and 08:07 (0:47) h, P<0.001] and needed more time to fall asleep [sleep onset latency: 23 (22) min and 15 (15) min, P=0.02]. Disturbances in the rest-activity rhythm were predicted by a low level of physical activity, use of antidepressants and central nervous system neurological medications, and being male. CONCLUSIONS: EOD patients showed more variability in the rest-activity rhythm compared with cognitively intact adults. The main predictor for rest-activity rhythm disturbances was a low level of physical activity.

Study protocol: EXERcise and cognition in sedentary adults with early-ONset dementia (EXERCISE-ON).

BACKGROUND: Although the development of early-onset dementia is a radical and invalidating experience for both patient and family there are hardly any non-pharmacological studies that focus on this group of patients. One type of a non-pharmacological intervention that appears to have a beneficial effect on cognition in older persons without dementia and older persons at risk for dementia is exercise. In view of their younger age early-onset dementia patients may be well able to participate in an exercise program. The main aim of the EXERCISE-ON study is to assess whether exercise slows down the progressive course of the symptoms of dementia. METHODS/DESIGN: One hundred and fifty patients with early-onset dementia are recruited. After completion of the baseline measurements, participants living within a 50 kilometre radius to one of the rehabilitation centres are randomly assigned to either an aerobic exercise program in a rehabilitation centre or a flexibility and relaxation program in a rehabilitation centre. Both programs are applied three times a week during 3 months. Participants living outside the 50 kilometre radius are included in a feasibility study where participants join in a daily physical activity program set at home making use of pedometers. Measurements take place at baseline (entry of the study), after three months (end of the exercise program) and after six months (follow-up). Primary outcomes are cognitive functioning; psychomotor speed and executive functioning; (instrumental) activities of daily living, and quality of life. Secondary outcomes include physical, neuropsychological, and rest-activity rhythm measures. DISCUSSION: The EXERCISE-ON study is the first study to offer exercise programs to patients with early-onset dementia. We expect this study to supply evidence regarding the effects of exercise on the symptoms of early-onset dementia, influencing quality of life. TRIAL REGISTRATION: The present study is registered within The Netherlands National Trial Register (ref: NTR2124).