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Original Paper

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

Hooghiemstra A.M.a · Bertens A.S.b,c · Leeuwis A.E.a · Bron E.E.d · Bots M.L.e · Brunner-La Rocca H.-P.f · de Craen A.J.M.c · van der Geest R.J.g · Greving J.P.e · Kappelle L.J.h · Niessen W.J.d,i · van Oostenbrugge R.J.j · van Osch M.J.P.k · de Roos A.b · van Rossum A.C.l · Biessels G.J.h · van Buchem M.A.b · Daemen M.J.A.P.m · van der Flier W.M.a,n · on behalf of the Heart-Brain Connection Consortium

Author affiliations

aAlzheimer Center & Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
bDepartment of Radiology, Leiden University Medical Center, Leiden, the Netherlands
cDepartment of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
dBiomedical Imaging Group Rotterdam, Departments of Medical Informatics and Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
eJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
fDepartment of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands
gDivision of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
hDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
iImaging Physics, Applied Sciences, Delft University of Technology, Delft, the Netherlands
jDepartment of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands
kC.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
lDepartment of Cardiology, VU University Medical Center, Amsterdam, the Netherlands
mDepartment of Pathology, Academic Medical Center, Amsterdam, the Netherlands
nDepartment of Epidemiology, VU University Medical Center, Amsterdam, the Netherlands

Corresponding Author

A.M. Hooghiemstra

VU University Medical Center, Alzheimer Center

PO Box 7057, NL–1007 MB Amsterdam (The Netherlands)

E-Mail a.hooghiemstra@vumc.nl

Related Articles for ""

Cerebrovasc Dis Extra 2017;7:140–152

Abstract

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 Alz­heimer 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.

© 2017 The Author(s). Published by S. Karger AG, Basel


Introduction

With the rapid aging of the population, the prevalence of cognitive decline and dementia increases [1-4]. Although Alzheimer disease is the most common cause of dementia, vascular disease is increasingly recognized as an independent contributor to cognitive impairment [1]. The term vascular cognitive impairment (VCI) has been introduced to describe the complete spectrum of cognitive disorders (mild and major) associated with and due to cerebrovascular disease [1, 5-8]. VCI can be the result of irreversible structural damage to the vascular system in the brain [9]. Based on that view, treatment for VCI is often restricted to secondary prevention by treating risk factors, such as high blood pressure [10]. Recent findings suggest that cerebral hypoperfusion can also hinder the function of the brain before structural damage occurs [9]. The latter is supported by the finding that nondemented patients with cardiovascular disease show cognitive decline [11] and that in patients with heart failure (HF) cognitive functioning can be enhanced by improving cardiac function [12-14]. Furthermore, the observation of cognitive impairment in carotid occlusive disease (COD) suggests a relationship between reduced cerebral blood flow (CBF) and cognitive functioning [15]. Thus, cardiac and (cerebro-)vascular pathology affecting CBF might influence cellular functions in the brain before structures are altered. Exploring the contribution of cardiac and (cerebro-)vascular pathology to brain alterations is important, because it could identify treatment targets for patients with cognitive impairment due to this type of pathology in the foreseeable future. Medication that improves hemodynamics, such as antihypertensive medication, is available at this moment. However, trials assessing the efficacy of such therapies in VCI are currently lacking. This is due to an incomplete understanding of the mechanisms involved and to the lack of research that identifies patients who will benefit most [1, 16, 17]. Since health care and research are usually organized in a monodisciplinary way, cardiovascular status tends to be neglected in patients presenting with cognitive impairment in memory clinics and, vice versa, cognitive disorders are often neglected in patients presenting with cardiovascular disease in cardiology or vascular medicine departments. Moreover, guidelines for diagnostic protocols that provide a combined comprehensive assessment of the cardiovascular and cerebral structure and function are lacking. The Heart-Brain Study is part of a larger Heart-Brain Connection consortium (www.heart-brain.nl) [18], covering preclinical, experimental, and clinical trial research (Textbox 1). The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain is an important, but underestimated cause of VCI. We aim to assess the association between (cardio-)vascular and hemodynamic factors in the heart and the brain in relation to cognitive function. Our objectives are to assess (1) the association between cardiovascular parameters and cognitive function, (2) the association between cardiovascular parameters and brain structure and perfusion, and (3) the association between brain structure and perfusion and cognitive function. We study these objectives in patients with HF, COD, and VCI, both cross-sectionally as well as longitudinally. By studying the complete heart-brain axis in patient groups that present themselves with complaints attributed to specific parts of the heart-brain 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. Here, we describe the design and study protocol of this multidisciplinary study, in which cardiologists, epidemiologists, neurologists, neuropsychologists, radiologists, image processing experts, and MR physicists work together to study the hemodynamic status of the heart and the brain as an important, but underestimated determinant of VCI.

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Methods

Study Design

The Heart-Brain Study is a prospective study with a follow-up measurement after 2 years. Five Dutch university medical centers collaborate: Erasmus Medical Center (ErasmusMC) in Rotterdam, Leiden University Medical Center (LUMC) in Leiden, Maastricht University Medical Center (MUMC) in Maastricht, University Medical Center Utrecht (UMCU) in Utrecht, and VU University Medical Center (VUmc) in Amsterdam. Participants have been enrolled from September 2014 onwards. For an overview of the data collection see Table 1.

Table 1.

Overview of data collection per assessment moment

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Participants

Patients with VCI, COD, and HF are recruited from cardiology, memory, and neurology outpatient clinics from four sites: LUMC, MUMC, UMCU, and VUmc. In each patient group, 175 patients are recruited, yielding a total sample size of 525 patients. In addition, 120 controls undergo the same study procedures as patients. Eligible participants are selected according to the inclusion and exclusion criteria (Table 2). Written informed consent is obtained prior to participation in the study.

Table 2.

Inclusion and exclusion criteria of patients with VCI, COD, and HF and controls for the Heart-Brain Study

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Baseline Assessment

Clinical Data and Assessment

The following measures are collected and saved as a core clinical dataset:

  • Sociodemographic factors, including age, sex, educational level, and social situation.

  • Vascular risk factors including hypertension, diabetes, hyperlipidemia, smoking, overweight, and extensive alcohol use.

  • Medical, neurologic, cardiovascular, and family history.

  • Current medication.

  • Physical examination with particular attention to clinical signs of volume overload (e.g., pitting edema, rales) and heart murmur.

  • Duplicate blood pressure measurement on one occasion (sitting, lying, and standing).

  • Resting 12-lead electrocardiography.

  • Anthropometry, physical performance, and physical activity [19, 20].

Cognitive Functioning

All participants undergo an extensive and standardized neuropsychological assessment, based on the Dutch Parelsnoer Initiative [21]. This test battery covers global cognitive functioning and four major cognitive domains including memory, language, attention-psychomotor speed, and executive functioning (Table 3). All test scores are standardized into z-scores and subsequently combined into cognitive domains. We rate a cognitive domain as impaired when the z-score is below –1.5. Patients are classified as cognitively normal when no domains are impaired, with minor cognitive impairment with one domain impaired, and with major cognitive impairment with more than one domain impaired.

Table 3.

Neuropsychological assessment and measures of neuropsychiatry and general functioning

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In addition to cognitive functioning, we assess general functioning, activities of daily living, depressive symptoms, and apathy (Table 3).

MRI

MRIs are acquired on Philips Ingenia 3T scanners at LUMC and UMCU, a Philips Achieva 3T scanner at MUMC, and a Philips Gemini 3T PET-MR scanner at VUmc (Philips, Best, The Netherlands). The MRI protocol consists of a cardiac, vascular, and brain protocol (Table 4). The brain protocol includes T1-weighted, fluid-attenuated inversion recovery (FLAIR) images and susceptibility-weighted imaging (SWI). Cerebral perfusion is measured with arterial spin labeling [22] and phase-contrast flow measurements. The sequences measuring perfusion are performed in the same scan session as the structural sequences. The heart protocol includes short-axis multislice cine steady-state free precision (SSFP), aorta QFlow images, and phase-contrast mitral flow measurements. Scans are screened by local radiologists for clinically relevant incidental findings.

Table 4.

MRI protocol

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Blood and Cerebrospinal Fluid Markers

We investigate systemic and organ-specific blood biomarkers that relate to functional or structural abnormalities in components of the heart-brain axis. For systemic biomarkers, we assess biomarkers related to processes involved in HF, atherosclerosis, and VCI. We focus on abnormalities in lipid metabolism, insulin resistance/dysglycemia, inflammation, and anemia. For markers reflecting pathogenic processes in organ-specific components of the heart-blood vessels-brain axis, we assess markers of HF and cardiac fibrosis, and remodeling of blood vessel pathology and of Alzheimer-type pathology.

Cerebrospinal fluid is collected for patients with VCI in the routine clinical setting in VUmc for determination of amyloid-beta 1–42, total tau, and hyperphosphorylated tau-18 [23]. Participants are asked to give separate informed consent for DNA storage for future genetic analyses.

Echocardiography

We use standard clinical Doppler-echocardiographic equipment to measure the complete standard clinical array including structures as well as systolic and diastolic function of both ventricles, atrial dimensions, and valve function, as recommended by the European and American Societies of Echocardiography [24, 25]. Transthoracic echocardiography is performed in standard parasternal, apical, and subcostal views. Echocardiography is performed in MUMC and VUmc.

24-Hour Ambulatory Blood Pressure Monitoring

24-hour ambulatory blood pressure monitoring is performed, using validated blood pressure monitors from Microlife (Microlife Corporation Europe, Widnau, Switzerland). 24-hour blood pressure measurements have been shown to be of better prognostic value for cardiovascular events and more reproducible than conventional office BP measurements [26]. 24-hour ambulatory blood pressure is performed in MUMC, UMCU, and VUmc.

Follow-Up Assessment

Two years after baseline assessment, all participants are invited for a second visit which includes neuropsychological testing, brain MRI, and collection of blood samples. Echocardiography is included when performed at baseline. In addition, clinical data on disease incidence and admission to hospital or nursing home between the first and last visit are collected by history taking. For participants with cognitive problems or when the history of the participant is considered less reliable, additional history is obtained from next of kin and/or the general practitioner. For deceased participants, the cause of death is obtained from Central Agency for Statistics Netherlands (CBS) and general practitioners. Patients with VCI additionally undergo follow-up of neuropsychological testing after 1 year. We evaluate cognitive decline based on the difference in the cognitive domain z-scores (for more information, see section Cognitive Functioning above).

Data Collection, Processing, and Storage

We use centralized state-of-the-art storage platforms for clinical (OpenClinica, LLC, Waltham, MA, USA) and imaging data (Extensible Neuroimaging Archive Toolkit [XNAT]). Imaging data are processed centrally with automated standardized pipelines. For an elaborate description, see online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000480738).

Sample Size Considerations

With a sample size of 175 patients in each patient cohort we can detect associations in which the determinant explains 4% or more of the variance in the dependent variable (i.e., the equivalent of a correlation coefficient of 0.2 or more with alpha 0.05, power 90%), taking 10–20 relevant covariates into account. Assuming that the dropout rate will not exceed 25% over 2 years, we have 80% power to detect associations of the same strength at follow-up.

Statistical Analysis

Cross-Sectional Relations

Regression analyses are used to investigate the independent associations between measures of cerebral perfusion and blood flow, structural brain abnormalities (brain atrophy, white matter hyperintensities, infarcts, and microbleeds), and cognitive performance. Also, regression analyses are used to investigate the relationship between cardiovascular parameters (cardiac output, systolic and diastolic function of the ventricle, blood pressure, pulse wave velocity, aortic and carotid stiffness) and cerebral perfusion and blood flow (arterial spin labeling and phase-contrast flow measurements) at baseline.

Prospective Relations

To investigate prospective relations of baseline cardiovascular and cerebral perfusion and flow measures with change in brain MRI abnormalities and cognitive functioning, we use regression models with brain volume and change in cognitive performance at follow-up as the dependent variables and cardiovascular parameters and brain perfusion and blood flow at baseline as the independent variables.

Since the main analyses have an etiologic focus, appropriate adjustment for confounding factors is performed. All abovementioned associations are examined in each patient cohort (VCI, COD, or HF) separately, comparing groups with controls. Finally, we pool all data and perform linear regression analyses, taking into account potential effect modifications by cohort [27].

Ethical Considerations

The Medical Ethics Review Committee of the LUMC performed central approval of the Heart-Brain Study (number P.14.002). Subsequently, local boards of the UMCs approved the local performance of the study. The Heart-Brain Study is performed in accordance with the declaration of Helsinki (version 2013) and the Medical Research Involving Human Subjects Act (WMO).

Current Status and Time Line

The first participant was included in September 2014, the inclusion period finalizes in 2017, and the last follow-up measurement will be in 2018. The first baseline results are expected in 2017, the longitudinal results in 2019.

Results and Conclusion

The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain are important, but underestimated determinants of VCI. Previous studies have investigated components of the heart-brain axis in (prospective cohorts of) healthy people [28-33], patients with HF [12, 13, 34-39], and COD [40-43]. These studies have found circumstantial evidence that cardiac and cardiovascular pathology affecting CBF and perfusion in the brain may influence brain function before structures are irreversibly damaged. It is currently unknown how often hemodynamic changes based on cardiovascular pathology occur in patients with cognitive impairment. Various cardiovascular factors, such as cardiac output, blood pressure, pulse wave velocity, and aortic and carotid stiffness, may influence CBF. On the other hand, in VCI a lower CBF could also be related to a decreased need of blood by an already affected brain. Little is known about how these factors, separate or in concert, influence cognitive performance. The Heart-Brain Study is unique because of the integrated approach that we use to investigate relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment, in three patient groups that represent components of the heart-brain axis. While zooming in on one component of the heart-brain axis we assess the other components and how they are interconnected. This way, we assess both clinical and subclinical manifestations of disorders of the heart, vascular system, and brain, with hemodynamic status as a possible binding factor along the heart-brain axis. This integrated approach may show light on the mechanisms involved in these relationships. To study the relationships as clearly as possible we chose to exclude patients with current atrial fibrillation at the time of inclusion, since atrial fibrillation may lead to unpredictable hemodynamic changes. This exclusion might lead to limited generalizability of this study. However, the patient groups mainly function as a model of specific parts of the heart-brain axis, i.e., hemodynamic components possibly leading to chronic cerebral hypoperfusion.

We perform extensive phenotyping using a comprehensive and standardized MRI protocol that has been developed to measure structure and function of both the heart and the brain. Alongside, a platform for data storage and image processing is developed in which both automatic and manual quality assessment procedures are implemented. Quantification of imaging biomarkers of the heart, brain, and cerebropetal arteries is performed with existing and newly developed automated software. With this study, we provide a foundation for an interdisciplinary collaborative network for the study of the heart-brain axis that will lead to a true multidisciplinary and consensus-based approach of clinical management of cognitive impairment in patients with HF, COD, and VCI. The close collaboration between departments of cardiology and neurology opens possibilities for future heart-brain clinics, through which implementation of newly developed diagnostic tools and treatment options can be optimized. With this approach we meet the clinical and research need for centers of excellence with transdisciplinary programs within and between centers [1, 16, 17].

In addition to the Heart-Brain Study, in the Heart-Brain Connection consortium [18] we perform preclinical, experimental, and clinical trial studies that further increase the understanding of the mechanisms underlying the relationship between hemodynamic status and cognitive functioning (Textbox 1).

In conclusion, in the Heart-Brain Study we test the hypothesis that the hemodynamic status of the heart and the brain is an important, but underestimated cause of VCI offering promising opportunity for treatment. Moreover, we develop a novel, clinically feasible diagnostic protocol including a comprehensive MRI protocol that assesses the heart, the vascular system, and the brain. This protocol can be used for identifying patients suitable for future trials as well as monitoring treatment effects. Finally, we provide a foundation for an interdisciplinary collaboration for the study of VCI that will lead to a true multidisciplinary and consensus-based approach of the clinical management of VCI.

Acknowledgements

We acknowledge the contribution of Heart-Brain Study researchers and employees. For an overview of Heart-Brain Connection consortium members, see online supplementary material.

We acknowledge the support of the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation (CVON 2012-06 Heart Brain Connection), Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences.

Disclosure Statement

W.J. Niessen is cofounder, part-time Chief Scientific Officer, and stock holder of Quantib BV. Other authors declare that there are no competing interests. None of the authors have direct or indirect relationships with the Netherlands CardioVascular Research Initiative.


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  50. Van der Elst W, Van Boxtel MPJ, Van Breukelen GJP, Jolles J: Normative data for the Animal, Profession and Letter M Naming verbal fluency tests for Dutch speaking participants and the effects of age, education, and sex. J Int Neuropsychol Soc 2006; 12: 80–89.
  51. Luteijn F, van der Ploeg FAE: Handleiding Groninger Intelligentie Test (Manual Groningen Intelligence Test). Lisse, Swets & Zeitlinger, 1983.
  52. van der Elst W, van Boxtel MPJ, van Breukelen GJP, Jolles J: The Letter Digit Substitution Test: normative data for 1,858 healthy participants aged 24–81 from the Maastricht Aging Study (MAAS): influence of age, education, and sex. J Clin Exp Neuropsychol 2006; 28: 998–1009.
  53. Morris JC: Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997; 9: 173–178.
    External Resources
  54. Sikkes S, de Lange-de Klerk E, Pijnenburg Y, Gillissen F, Romkes R, Knol DL, et al: A new informant-based questionnaire for instrumental activities of daily living in dementia. Alzheimers Dement 2012; 8: 536–543.
  55. Gelinas I, Gauthier L, McIntyre M, Gauthier S: Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther 1999; 53: 471–481.
  56. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al: Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1983; 17: 37–49.
  57. Starkstein SE, Jorge R, Mizrahi R, Robinson RG: A prospective longitudinal study of apathy in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2006; 77: 8–11.
  58. Ikram MA, van der Lugt A, Niessen WJ, Koudstaal PJ, Krestin GP, Hofman A, et al: The Rotterdam Scan Study: design update 2016 and main findings. Eur J Epidemiol 2015; 30: 1299–1315.
  59. Poulet R, Gentile MT, Vecchione C, Distaso M, Aretini A, Fratta L, et al: Acute hypertension induces oxidative stress in brain tissues. J Cereb Blood Flow Metab 2006; 26: 253–262.
  60. Carnevale D, Mascio G, Ajmone-Cat MA, D’Andrea I, Cifelli G, Madonna M, et al: Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging 2012; 33: 19–29.
  61. Gentile MT, Poulet R, Pardo AD, Cifelli G, Maffei A, Vecchione C, et al: Beta-amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging 2009; 30: 222–228.
  62. Carnevale D, Mascio G, D’Andrea I, Fardella V, Bell RD, Branchi I, et al: Hypertension induces brain beta-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension 2012; 60: 188–197.
  63. Leeuwis AE, Hooghiemstra AM, Amier R, Ferro DA, Franken L, Nijveldt R, et al: Study design: the effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment. Alzheimers Dement Transl Res Clin Interv 2017; 3: 157–165.

Author Contacts

A.M. Hooghiemstra

VU University Medical Center, Alzheimer Center

PO Box 7057, NL–1007 MB Amsterdam (The Netherlands)

E-Mail a.hooghiemstra@vumc.nl


Article / Publication Details

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Abstract of Original Paper

Received: November 10, 2016
Accepted: August 18, 2017
Published online: October 10, 2017
Issue release date: September – December

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Number of Figures: 0
Number of Tables: 4


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  50. Van der Elst W, Van Boxtel MPJ, Van Breukelen GJP, Jolles J: Normative data for the Animal, Profession and Letter M Naming verbal fluency tests for Dutch speaking participants and the effects of age, education, and sex. J Int Neuropsychol Soc 2006; 12: 80–89.
  51. Luteijn F, van der Ploeg FAE: Handleiding Groninger Intelligentie Test (Manual Groningen Intelligence Test). Lisse, Swets & Zeitlinger, 1983.
  52. van der Elst W, van Boxtel MPJ, van Breukelen GJP, Jolles J: The Letter Digit Substitution Test: normative data for 1,858 healthy participants aged 24–81 from the Maastricht Aging Study (MAAS): influence of age, education, and sex. J Clin Exp Neuropsychol 2006; 28: 998–1009.
  53. Morris JC: Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997; 9: 173–178.
    External Resources
  54. Sikkes S, de Lange-de Klerk E, Pijnenburg Y, Gillissen F, Romkes R, Knol DL, et al: A new informant-based questionnaire for instrumental activities of daily living in dementia. Alzheimers Dement 2012; 8: 536–543.
  55. Gelinas I, Gauthier L, McIntyre M, Gauthier S: Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther 1999; 53: 471–481.
  56. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al: Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1983; 17: 37–49.
  57. Starkstein SE, Jorge R, Mizrahi R, Robinson RG: A prospective longitudinal study of apathy in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2006; 77: 8–11.
  58. Ikram MA, van der Lugt A, Niessen WJ, Koudstaal PJ, Krestin GP, Hofman A, et al: The Rotterdam Scan Study: design update 2016 and main findings. Eur J Epidemiol 2015; 30: 1299–1315.
  59. Poulet R, Gentile MT, Vecchione C, Distaso M, Aretini A, Fratta L, et al: Acute hypertension induces oxidative stress in brain tissues. J Cereb Blood Flow Metab 2006; 26: 253–262.
  60. Carnevale D, Mascio G, Ajmone-Cat MA, D’Andrea I, Cifelli G, Madonna M, et al: Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging 2012; 33: 19–29.
  61. Gentile MT, Poulet R, Pardo AD, Cifelli G, Maffei A, Vecchione C, et al: Beta-amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging 2009; 30: 222–228.
  62. Carnevale D, Mascio G, D’Andrea I, Fardella V, Bell RD, Branchi I, et al: Hypertension induces brain beta-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension 2012; 60: 188–197.
  63. Leeuwis AE, Hooghiemstra AM, Amier R, Ferro DA, Franken L, Nijveldt R, et al: Study design: the effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment. Alzheimers Dement Transl Res Clin Interv 2017; 3: 157–165.
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