In a society with increased life expectancy, the economic, social and personal burden of dementia increases. Dementia is often caused by a combination of neurovascular and neurodegenerative diseases. Impaired brain clearance is suggested to be closely related to dementia development, as waste products (e.g. amyloid beta) accumulate in the brain, leading to neurodegeneration. Cerebral small vessel disease (SVD) is the most common neurovascular disease that even contributes to about 45% of dementia pathophysiology in patients with a diagnosis of Alzheimer's dementia. White matter hyperintensities of presumed vascular origin (WMH) are the key brain MRI manifestation of cerebral SVD. There is evidence that the currently known and MRI-visible WMH are landmarks of an already progressed stage of the underlying pathology. The pathophysiology of WMH has been attributed to multiple underlying mechanisms, such as hypoperfusion, defective cerebrovascular reactivity and blood-brain barrier dysfunction. Furthermore, different anatomical locations and different types of WMH are related to different underlying pathological changes. Using ultra-high field 7T MR imaging techniques WMH lesions can be detected with a higher sensitivity and resolution than on 3T MRI. The hypothesis is that different pathological mechanisms of cerebral SVD lead to variations in WMH shape. Moreover, the brain clearance ('glymphatic') system of the brain appears to be tightly connected to dementia pathology. Thus, novel markers of glymphatic activity could aid to describe and understand the pathology.
Admitted to the memory or the geriatric clinic of the LUMC, the Alrijne Hospital Leiden or the Haga Hospital the Hague
From 65 years of age
Eligible for MRI
Native-level Dutch speaker
Claustrophobia
Contraindications for MRI such as metal implants and pacemaker
Use of benzodiazepines
Initiated treatment with antidepressants less than 6 weeks prior to inclusion
We will prospectively include patients with memory complaints and/or vascular brain abnormalities (n=50; over 65 years of age) from the memory clinic at one of their first visits, prior to any diagnosis, at the Leiden University Medical Center, the Alrijne Hospital Leiden or the Haga Hospital the Hague. If not enough eligible patients are available from the memory clinic, we will include participants from the geriatric clinic.
Case-only
Prospective
3T MRI scan
Other interventionConventional (3T) brain MRI scans will be used to determine global and functional markers of cerebral SVD, like WMH volume and presence of lacunes, microbleeds and superficial siderosis (3D T1, 3D FLAIR, SWI, DWI), hemodynamics (arterial spin labelling \& flow territory mapping) and white matter structural integrity (diffusion tensor imaging (DTI)). Furthermore, we want to measure structural integrity with a novel MR fingerprinting sequence and an inhomogeneous magnetization transfer (ihMT) MRI scan. We also want to apply a fMRI scan technique to measure CSF fluctuations in the 4th ventricle as a measure of brain glymphatics. Also the flow-territory mapping sequence is a non-standard sequence. Heart rate and respiratory signal will be measured during the scans (3T and 7T MRI) with standard vendor-supplied equipment.
7T MRI scan
Other interventionUltra-high field (7T) brain MRI scans will be used to determine WMH shape and other markers of cerebral SVD in or surrounding the WMH, like local enlarged perivascular spaces, (cortical) microinfarcts and microbleeds (T1, T2, FLAIR and T2\*) and vascular pulsatility (phase contrast MRI). Moreover, a recently implemented MRI technique to measure glymphatic flow in perivascular spaces will be used.
Neuropsychological assessment
Behavioral* Mini-mental state examination * Clock drawing * 15-Word Verbal Learning Test, immediate and delayed * Visual Association Test * Stroop Color Word Test, 40 item version * Trail Making Test A\&B * Letter Digit Substitution Test * Animal fluency test * Hospital anxiety and depression scale * Informant Questionnaire on Cognitive Decline in the Elderly
General baseline data
Other interventionBaseline data, such as age, sex, psychiatric comorbidity and medication lists will be extracted from the patient files. Age (Year of birth); Years of education; BMI (height \& weight); Sex; Verhage scale (education); Smoking status; Blood values; Sleep habits; Waste-hip ratio; Blood pressure; Current/general cardiovascular health; Psychiatric comorbidity; medical history related to cardiovascular health.
WMH shape
The investigators will use an in-house developed analysis pipeline to calculate WMH shape on 3T and 7T brain MRI scans. Associations between WMH shape and other SVD markers and cognition will be investigated with linear and logistic regression (at least corrected for age and sex).
Brain clearance
Measured on brain MRI as a marker of glymphatic activity.
Perivascular space volume
This marker will be measured on brain MRI.
WMH subtypes
Based on WMH parameters the investigators will study if subtypes of WMH can be identified.
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Leiden University Medical Center
Lead sponsor
Alzheimer Nederland
Collaborator
