The overall aim of this pilot study is to investigate the development of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) markers after cerebral amyloid angiopathy (CAA)-related and hypertensive arteriopathy (HA)-related intracerebral hemorrhage (ICH) in relation to cognitive decline. The results from this pilot trial will be used to design a larger cohort study to investigate underlying mechanisms of cognitive decline after ICH. The study population consists of 32 patients; 16 patients with CAA-related ICH and 16 patients with HA-related ICH who are 55 years or older. Data will be collected at four measuring points: at baseline (during hospital admission for the ICH or at the outpatients clinic within one month of presentation with an acute ICH), after three months, after six months and after 12 months. Premorbid cognitive functioning will be assessed with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) to select participants without pre-existing cognitive impairment.
Dementia is a major contributor of dependence and disability in the ageing population and is mainly caused by neurodegenerative and cerebrovascular disease. Vascular cognitive impairment (VCI) occurs in at least 10% of patients who recover from an intracerebral hemorrhage (ICH) and has a major impact on post ICH recovery. In the acute phase of ICH, cognitive impairment may be caused directly by the hemorrhage damaging the brain parenchyma. In the chronic phase, however, further cognitive decline is also prevalent. Cognitive decline after ICH might be caused by the underlying etiology of the ICH. The most frequent underlying small vessel diseases (SVD) that cause ICH are cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). CAA and HA have their own radiological signatures of SVD markers which allow for in vivo tracking of disease progression using MRI. Although the initial clinical presentation these two types of SVD differs - CAA classically presents with a lobar ICH, whereas HA causes deep ICH - both groups of patients are at risk of developing dementia. However, it has recently been shown that patients with lobar ICH develop new onset dementia twice as often as patients with deep ICH. Whether underlying CAA pathology causes this increase, remains unclear. In addition, whether ICH accelerates the process of vascular damage and if cognitive decline can be predicted by certain disease markers is uncertain. Understanding the underlying mechanisms for cognitive decline after ICH helps to improve knowledge of prognosis and clinical management of patients who are recovering from ICH. The overall aim is to study cognitive decline in patients who recover from ICH and the relation with SVD markers. The results will be used to design a larger cohort study. The study population are patients with ICH that have no family history of hereditary forms of ICH such as hereditary CAA (HCHWA-D) and no cognitive impairment before the ICH. Patients will be aged ≥ 55y, since the radiological Boston criteria for CAA-related ICH only include patients ≥ 55y. At baseline, the premorbid functional status will be assessed with the modified Rankin Scale (mRS) and Barthell index. A 3Tesla MRI will be performed to assess the most likely underlying cause of the ICH (patients with either CAA or HA-related ICH will be included). Stroke severity will be assessed with the National Institutes of Health Stroke Scale (NIHSS) and a neurologic exam will be performed. Participants will undergo an extensive interview on life-style, vascular risk factors and medication, and will undergo a blood withdrawal. Neuropsychological testing will be performed and questionnaires will be used for screening for depression, anxiety and psychopathology. In addition, participants will be asked to undergo a lumbar puncture to collect cerebrospinal fluid (CSF). After three months, neurological examination, and neuropsychological testing will be repeated. After six and 12 months, the neurological examination, the 3 Tesla MRI and neuropsychological testing will be repeated. Additionally, participants will be asked for a lumbar puncture at these two time points. The main parameters are cognitive decline (according to the neuropsychological assessment) at 12 months. Secondary outcomes are burden of SVD markers on MRI and CSF markers at baseline, at six months and 12 months.
Study Type
OBSERVATIONAL
Enrollment
2
Leiden University Medical Center
Leiden, South Holland, Netherlands
Cognitive decline (according to the neuropsychological assessment)
New onset cognitive impairment and dementia will be determined according to the Mini-Mental State Examination (MMSE) and compared between CAA-related and HA-related ICH.
Time frame: 12 months after ICH
Burden of SVD markers on MRI markers at baseline, at six months and at 12 months
The presence and number of microbleeds (MBs), cortical superficial siderosis (cSS), white matter hyperintensities (WMH), chronic subarachnoid hemorrhage (cSAH), enlarged perivascular spaces (ePVS), microinfarcts, intragyral hemorrhages, cortical atrophy and other new and known small vessel biomarkers will be assessed on 3T and scored according to the STRIVE-criteria. These SVD markers will be added up to form a total MRI small vessel disease score. This total MRI small vessel disease score will be compared in patients at baseline, at six months and after twelve months.
Time frame: Baseline, at six months and at 12 months
Concentrations of p-tau181 in CSF at baseline, at six months and at 12 months
Concentrations of p-tau181 (in pg/ml) will be determined in the CSF of each patient at baseline, at six months and at 12 months. Changes in concentration will be calculated in each patient. Linear regression analysis will be used to examine associations of CSF markers primarily with the MMSE.
Time frame: Baseline, at six months and at 12 months
Concentrations of Aβ40 in CSF at baseline, at six months and at 12 months
Concentrations of Aβ40 (in pg/ml) will be determined in the CSF of each patient at baseline, at six months and at 12 months. Changes in concentration will be calculated in each patient. Linear regression analysis will be used to examine associations of CSF markers primarily with the MMSE.
Time frame: At baseline, at six months and at 12 months
Concentrations of Aβ42 in CSF at baseline, at six months and at 12 months
Concentrations of Aβ42 (in pg/ml) will be determined in the CSF of each patient at baseline, at six months and at 12 months. Changes in concentration will be calculated in each patient. Linear regression analysis will be used to examine associations of CSF markers primarily with the MMSE.
Time frame: At baseline, at six months and at 12 months
Concentrations of t-tau in CSF at baseline, at six months and at 12 months
Concentrations of t-tau will be determined in the CSF of each patient at baseline, at six months and at 12 months. Changes in concentration will be calculated in each patient. Linear regression analysis will be used to examine associations of CSF markers primarily with the MMSE.
Time frame: At baseline, at six months and at 12 months
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