Patients with cerebral amyloid angiopathy (CAA) — but not Alzheimer’s disease or mild cognitive impairment (MCI) — may have reduced cerebrovascular reactivity, a small study suggested.
Blood oxygen level dependent (BOLD) signal amplitudes were 29% lower in CAA patients than healthy controls in a visual response task, while MCI and Alzheimer’s BOLD amplitudes did not differ from controls, reported Eric Smith, MD, MPH of the University of Calgary, Canada and coauthors in Neurology. A reduced BOLD signal suggests reduced cerebrovascular reactivity.
In contrast, visual evoked potential tests, which correlate with measures of brain metabolic activity, showed no group differences in amplitude or latency between any group and healthy controls.
“Our study is the first to compare cerebrovascular reactivity in patients with CAA to patients with Alzheimer’s disease without CAA-related microbleeds,” Smith and coauthors wrote. The findings suggest cerebrovascular reactivity is more impaired in CAA, they noted.
“Preserved visual evoked potentials amplitudes in CAA suggest that occipital metabolic activity is preserved, which implies that the reduced BOLD responses are due to lower blood flow from impaired cerebrovascular reactivity,” they added.
“Decreased occipital lobe cerebrovascular reactivity may be a feature that is unique to CAA,” they continued. “Prior studies that detected lower cerebrovascular reactivity in patients with Alzheimer’s disease may have instead been detecting changes related to comorbid CAA.”
The researchers “conclude that occipital cerebrovascular reactivity decline results from vascular rather than parenchymal Aβ,” noted Stefanie Schreiber, MD, PhD, of the Otto-von-Guericke University in Magdeburg, Germany, and Jacopo DiFrancesco, MD, PhD, of the ASST San Gerardo Hospital, University of Milano-Bicocca in Monza, Italy, in an accompanying editorial.
This approach could “add value in distinguishing between vascular and parenchymal β-amyloid in the occipital lobe — even on a single-subject level — and thereby complement current β-amyloid-detecting methods such as PET and body fluid measures (which are still limited with regard to differ[ences] between individuals with CAA and Alzheimer’s disease pathology),” they added.
This study’s paradigm consisted of distinguishing vascular versus parenchymal-metabolic impairments of cerebrovascular reactivity by comparing change in BOLD signal amplitude on functional MRI (fMRI) with a measure of parenchymal-metabolic integrity (visual evoked potentials, which correlate with measures of brain metabolic activity). In healthy controls, globally or focally stimulated brain parenchyma with good metabolic capability demands more oxygen, requiring increased blood flow, and reactive vasculature flexibly meets the demand. How these factors change in different diseases may give insights into mechanisms, with diagnostic, prognostic, and therapeutic implications.
CAA is present in a large majority (82% to 98%) of people with Alzheimer’s, and both conditions are associated with impaired vascular reactivity. While CAA involves posterior-dominant amyloid deposition in vasculature with posterior microbleeds, vascular cognitive impairment, and decreased BOLD response to visual stimulus, Alzheimer’s involves amyloid deposition in brain parenchyma and also leads to cognitive impairment. Alzheimer’s vascular reactivity studies have given conflicting results on the basis for blood flow changes and have not controlled for the very frequent presence of CAA with Alzheimer’s.
The author’s previous study of 18 participants with CAA showed decreased BOLD response amplitudes to a visual stimulus despite normal neuronal function as measured by visual evoked potentials. “The current study, adding 22 additional CAA participants, showed consistent results in a larger sample size,” they wrote.
In the present study, Smith and colleagues analyzed fMRI data in 40 CAA, 22 AD, 27 MCI, and 25 control participants without stroke or dementia. Non-CAA group members had no CAA findings (including no CAA-related microbleeds) on MRI. Alzheimer’s patients had mild dementia. Adjusted analysis included age and hypertension as covariates.
During fMRI scans, participants viewed four repetitions of 40-second blocks of an 8-Hz contrast-reversing black and white checkerboard visual stimulus, followed by 40 seconds of a grey screen with a central fixation cross. A subset of patients in each group had occipital lobe visual evoked potential tests (the group stopped obtaining visual evoked potentials when analysis showed they were not changed in CAA).
Participant age and sex by group were, respectively: control 68 years, 60% female; MCI 72 years, 44% female; Alzheimer’s 70 years, 40% female; and CAA 74 years, 64% female.
The area in primary visual cortex activated by visual stimulus on fMRI was significantly smaller for all groups compared with controls, with reduction greatest for CAA, then MCI, then Alzheimer’s.
Compared with controls, CAA and Alzheimer’s, but not MCI, showed an increase in white matter hyperintensity volume. Only the CAA group showed a relationship between BOLD response and white matter hyperintensity volume: for each 0.1% lower BOLD response amplitude, white matter hyperintensity volume was 9.2% higher.
“Higher white matter hyperintensity volumes were associated with lower BOLD response amplitudes only in patients with CAA,” the authors wrote. “This suggests that impaired cerebrovascular reactivity leading to ischemia may cause white matter hyperintensity in CAA, a vascular disease, whereas other mechanisms (such as inflammation, altered blood brain permeability, or microembolic disease) may be at play in Alzheimer’s disease, MCI, and healthy brains.”
“In this study, we targeted activation of the occipital lobe by visual stimulation because CAA preferentially affects posterior brain regions,” they added. “A drawback of this approach is that one can only investigate brain regions that are strongly activated by tasks.”
“Future studies should investigate whether cerebrovascular reactivity can be measured using a global stimulus such as carbon dioxide inhalation, which dilates arteries through the entire brain,” they continued. “This would allow investigation of regional associations between impaired vascular reactivity and vascular lesions (not limited to white matter hyperintensity but also including microbleeds, cortical superficial siderosis, microinfarcts, and large perivascular spaces) in finer detail at higher spatial resolution.”
Other limitations include a small sample of Alzheimer’s participants. In addition, amyloid-PET was not used to correlate amyloid deposition with vascular reactivity or other measures.
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Patients with cerebral amyloid angiopathy (CAA) — but not Alzheimer’s disease or mild cognitive impairment (MCI) — may have reduced cerebrovascular reactivity, as shown by reduced blood oxygen level dependent (BOLD) signals on functional MRI when patients engaged in a visual response task.
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Decreased cerebrovascular reactivity may be a feature unique to CAA; prior studies that detected lower cerebrovascular reactivity in patients with Alzheimer’s disease may have instead been detecting changes related to comorbid CAA, the researchers suggested.
Paul Smyth, MD, Contributing Writer, BreakingMED™
This study was supported by the Canadian Institutes of Health Research, Brain Canada, Canadian Stroke Network, Heart and Stroke Foundation of Canada, and Alzheimer Society of Canada.
Smith reports grant funding from the Canadian Institutes of Health Research and Brain Canada; is an Assistant Editor for Stroke and member of the Editorial Board for Neurology and the Journal of the American Heart Association Up to Date.
The editorialists report no disclosures relevant to the manuscript.
Cat ID: 33
Topic ID: 82,33,404,485,730,33,361,192,925
