The general aim of this study is to implement validated markers for CAA in asymptomatic individuals with CMBs, to investigate whether presence of CMBs signifies early CAA.
ID
Source
Brief title
Condition
- Vascular haemorrhagic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) Measurement of cerebrovascular reactivity to physiological stimuli using
fMRI.
Previous studies using functional transcranial Doppler (fTCD) to measure the
flow velocity in the posterior cerebral artery after visual stimulation, showed
a slower and lower peak response to visual stimulation in subjects with CAA
compared to normal subjects. The preference of fMRI use over fTCD in this
current study is due to less operator dependency and the additional spatial
information fMRI provides.
2) PiB- retention measured in regions of interest.
PiB, a radioactive ligand, binds to vascular and plaque b-Amyloid. PiB-PET
imaging is used to measure the PiB retention and distribution in regions of
interests. Previous studies have reported on increased retention of PiB in
non-demented subjects with CAA compared to normal controls. Retention was
mainly seen in posterior brain regions, reflecting the predilection of CAA for
the occipital cortex.
Secondary outcome
The assessment of the following neuropsychological tests will take place after
fMRI; CAMCOG, MMSE, Wechsler memory test, trial making test, Stroop test, and
word learning test. Though both case and control subjects are neurologically
asymptomatic and do not suffer from apparent cognitive impairment on study
entry, these cognitive tests are applied in order to detect and adjust for
subtle differences when present.
Background summary
Although it often goes unrecognized during life, cerebral amyloid angiopathy
(CAA) is a common age-related brain pathology, with severe complications such
as brain hemorrhage and dementia. CAA is a disease of the cerebral small
vessels, affecting capillaries, arterioles, and small arteries of the cerebral
cortex and leptomeninges and largely sparing vessels outside corticosubcortical
regions such as basal ganglia and brainstem. The primary constituent of the
vascular deposits is the ß-amyloid peptide. In moderate to severely advanced
CAA, the vascular ß-amyloid deposits are accompanied by loss of vascular smooth
muscle cells, microaneurysms, and paravascular accumulations of
hemosiderin-laden macrophages, the pathological correlate of cerebral
microbleeds (CMBs).
Radiographically, CMBs present as well-demarcated round hypo-intense lesions on
magnetic resonance imaging (MRI). In CAA patients, microbleeds are almost
invariably present in lobar brain regions. Yet, previous studies by our group
have shown that CMBs - especially those in a lobar location- are also highly
prevalent in neurologically asymptomatic individuals from the general
population. Overall, microbleeds are present in up to 23.5% of persons aged 60
years and over, with more than half of these CMBs occurring in strictly lobar
locations, i.e. locations suggestive of CAA. However, whether lobar microbleeds
in these asymptomatic individuals indeed indicate CAA as underlying pathology
remains unknown. Data from population-based autopsy studies suggest a high
prevalence of preclinical CAA pathology of up to 50% in elderly persons, but
there are to date no non-invasive studies during life to corroborate this. At
present, neuroimaging markers to detect early CAA are being validated in
well-defined patients with known CAA. We will apply these validated
non-invasive markers to a group of asymptomatic individuals with lobar
microbleeds, for whom the presence of CAA is uncertain. This will provide
evidence whether microbleeds in asymptomatic persons may reflect early CAA.
Clinical- pathological correlation studies suggest that approximately 74% of
lobar ICH and approximately 34% of all primary ICH in the elderly may be due to
advanced CAA. Overall outcome of lobar ICH is poor, with mortality ranging up
to 30%, severe disability in approximately 40%, and recurrence rate of ICH of
20% in 2 years. Advanced CAA however is known to have a long prodromal phase,
and it remains unclear if all individuals with early CAA will progress to
advance CAA and eventually face clinical consequences. Therefore, identifying
microbleeds as a potential MRI marker for early CAA would have implications to
identify and follow up subjects with early CAA before clinical symptoms occur.
The primary focus of this current proposal is to investigate whether
microbleeds in asymptomatic individuals reflect early CAA. We will do so by
applying recently validated methods for detection of early CAA. Secondly, our
results can be extrapolated to provide insight in the burden of early CAA in
the asymptomatic elderly population. This is important information in light of
ongoing investigations into prevention of CAA progression and CAA-related
complications.
Study objective
The general aim of this study is to implement validated markers for CAA in
asymptomatic individuals with CMBs, to investigate whether presence of CMBs
signifies early CAA.
Study design
An observational cross-sectional diagnostic study
Study burden and risks
This is a non-therapeutic group relatedness study. Study enrolment indicates
that participants will undergo fMRI, a PiB-PET scan, and a number of
standardized cognitive tests. All tests have negligible health consequences.
fMRI does not involve exposure to harmful radiation or other side effects in
persons screened eligible to undergo MRI (without contra-indications). PiB-PET
includes intravenous injection of radioactive 11-C-PiB ligand, which leads to a
limited amount of radiation exposure, amounting to an effective radiation dose
of 1.75 mSv (which is less than a year of background radiation).
Contra-indications will be carefully investigated per subject to minimize the
risks. Burden will be kept at a bear minimum by using short protocols.
's Gravendijkwal 230
Rotterdam 3015CE
NL
's Gravendijkwal 230
Rotterdam 3015CE
NL
Listed location countries
Age
Inclusion criteria
1) One or more strictly lobar CMB on previously performed 3D T2*-weighted GRE MRI
2) Ability and willingness to provide written informed consent
3) Age >=60. There is no upper age limit or restriction on race or gender for study participation.
Exclusion criteria
1) Other definite cause of microbleeds of hemorrhage. Exclusion causes are excessive anticoagulation (INR >3.0), antecedent head trauma or ischemic stroke, CNS tumor, vascular malformation, vasculitis, and blood dyscrasia
2) History of symptomatic hemorrhagic stroke
3) Microbleeds outside lobar or cerebellar brain regions (e.g. basal ganglia, thalamus, brainstem) demonstrated by neuroimaging. The presence of additional cerebellar CMBs is not an exclusion criterium, as CAA can affect the cerebellum.
4) Dementia
5) Contra-indication to MRI (e.g. cranial metallic implant, cardiac pacemaker, severe claustrophobia)
6) Specific contraindications to fMRI, i.e.:
a. History of diabetes, ischemic stroke, transient ischemic attack, carotid/intracranial artery stenosis
b. Current tobacco use
c. Change in antihypertensive medication within the previous three months.
d. Seizure within prior year
e. Noncorrectable visual impairment
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL41378.078.12 |