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Histopathological Correlates of Lobar Microbleeds in False-Positive Cerebral Amyloid Angiopathy Cases
Valentina Perosa1, Corinne A Auger2, Maria Clara Zanon Zotin1,3
1J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Objective:
A definite diagnosis of cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid β in walls of cerebral small vessels, can only be obtained through pathological examination. A diagnosis of probable CAA during life relies on the presence of hemorrhagic markers, including lobar cerebral microbleeds (CMBs). The aim of this project was to study the histopathological correlates of lobar CMBs in false-positive CAA cases.
Methods:
In 3 patients who met criteria for probable CAA during life, but showed no CAA upon neuropathological examination, lobar CMBs were counted on ex vivo 3T magnetic resonance imaging (MRI) and on ex vivo 7T MRI. Areas with lobar CMBs were next sampled and cut into serial sections, on which the CMBs were then identified.
Results:
Collectively, there were 25 lobar CMBs on in vivo MRI and 22 on ex vivo 3T MRI of the analyzed hemispheres. On ex vivo MRI, we targeted 12 CMBs for sampling, and definite histopathological correlates were retrieved for 9 of them, of which 7 were true CMBs. No CAA was found on any of the serial sections. The "culprit vessels" associated with the true CMBs instead showed moderate to severe arteriolosclerosis. Furthermore, CMBs in false-positive CAA cases tended to be located more often in the juxtacortical or subcortical white matter than in the cortical ribbon.
Interpretation:
These findings suggest that arteriolosclerosis can generate lobar CMBs and that more detailed investigations into the exact localization of CMBs with respect to the cortical ribbon could potentially aid the diagnosis of CAA during life. ANN NEUROL 2023;94:856-870.
Insights
Arteriolosclerosis, not cerebral amyloid angiopathy (CAA), can cause lobar cerebral microbleeds (CMBs) in some patients. Identifying CMB location may improve in-life diagnosis of CAA.
Area of Science:
- Neuropathology
- Neuroradiology
- Vascular Neurology
Background:
- Cerebral amyloid angiopathy (CAA) diagnosis relies on pathological examination, with probable diagnosis during life based on hemorrhagic markers like lobar cerebral microbleeds (CMBs).
- Distinguishing true CAA from conditions mimicking it is crucial for accurate clinical management.
Purpose of the Study:
- To investigate the histopathological underpinnings of lobar CMBs in individuals falsely diagnosed with probable CAA.
- To determine if arteriolosclerosis, rather than amyloid-beta deposition, underlies CMBs in these cases.
Main Methods:
- Analysis of 3 patients with probable CAA who lacked pathological evidence of CAA.
- Ex vivo 3T and 7T MRI to count lobar CMBs, followed by targeted tissue sampling and histopathological examination of identified CMBs.
- Serial sectioning and detailed microscopic analysis to identify CMBs and associated vascular pathology.
Main Results:
- No evidence of CAA was found in the examined brain tissue.
- Seven out of nine sampled CMBs were confirmed histopathologically.
- The vessels associated with these confirmed CMBs exhibited moderate to severe arteriolosclerosis, not amyloid deposition.
- CMBs in these false-positive cases were predominantly located in juxtacortical or subcortical white matter.
Conclusions:
- Arteriolosclerosis is a significant contributor to the formation of lobar CMBs, particularly in cases misdiagnosed as probable CAA.
- Precise localization of CMBs, especially in relation to the cortical ribbon, may enhance the accuracy of in-life CAA diagnosis.
- This study highlights the importance of considering arteriolosclerotic changes in the differential diagnosis of lobar CMBs.
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