Cynthia Tsai, MD, PhD: AD typically presents with both brain amyloid and tau pathologies, while showed limited/no vascular insults. CAA is typically characterized by vascular amyloid-ß deposition but not tau pathology. Both the amyloid plaque in AD (mostly parenchyma) and CAA (mostly vascular) could be imagined using amyloid PET scans.
Therefore, we operationally defined pure CAA as a group of patients without tau pathology who show CAA-related vascular lesions as those in the Boston criteria, have positive amyloid PET but negative tau PET, and pure AD as a group of patients with typical A(+)T(+) on PET scans but show no vascular insults on MRI. This is our maximal effort to exclude patients with between-conditions overlap as these 2 age-related diseases (CAA and AD) commonly overlap.
Between patients with CAA and AD, what were the key findings regarding regional uptake patterns in the occipital, frontal, and posterior cingulate cortex?
As CAA tends to involve occipital area most frequently and probably most pronouncedly, we hypothesized that occipital lobe may show a higher relative uptake (to the whole cortex) in CAA than in AD, as suggested by several previous works by others. However, despite our strict patient selection, we still could not detect a significant difference (but only a trend) showing high relative occipital uptake in CAA.
This could be related to a small effect size that requires larger sample size to confirm, while it also implicates limited clinical diagnostic utility applying amyloid PET in differentiating CAA and AD. As for frontal and posterior cingulate cortex uptake, the amyloid burden was higher in AD than in CAA as these regions are affected by Alzheimer pathology early in the disease stage.
In the assessment of diagnostic utility, were there any unexpected challenges or limitations encountered in determining cutoffs for SUVR and visual assessments?
The most unexpected challenges and results probably came from our investigation into amyloid PET diagnostic utility using visual analysis to differentiate CAA and AD. We have included 2 experienced nuclear medicine specialists who had more than 5 years of amyloid scan reading experiences (mostly for identifying patients with AD clinically). They have been instructed to categorize each scan as typical or atypical AD pattern. However, using visual scans could only yield low sensitivity (22-30%) and moderate specificity (52-62%) in differentiating AD from CAA.
SUVR cutoffs yielded slightly better, but still limited accuracy. This suggested the fact that during clinical practice, the visual pattern or regional uptakes characteristics of amyloid PET may have little role in improving our diagnostic certainty when determining the diagnosis CAA or AD. We may need other approaches to enhance the clinical utility of this tool (for example, a voxel-wise approach, combining with other biomarker, etc.)
Given the prevalence of incipient AD pathology in older individuals, how did the study address potential confounding factors or overlaps that might influence the identification of a specific regional uptake pattern for CAA?
This is of course our major limitation as we don’t have available pathological data in our samples. We have maximized our efforts using dual amyloid and tau PET scan, and adopted a strict criteria selecting negative tau PET patients in CAA—to minimize our possibility of selecting patients with overlap AD. In addition, we have performed subgroup analysis for patients CAA who had ICH and patients with CAA who had cognitive impairment, as those who presented with cognitive impairment may have a higher probability of concomitant AD. The results were not presented at ISC—but will be in our submitted paper thats currently under review—basically these findings were unchanged even in the comparisons between AD and CAA-cognitive impairment.
What implications does the study have for the clinical utility of amyloid PET in differentiating between CAA and AD, and are there potential areas for further research?
Overall, amyloid PET has limited diagnostic utility in differentiating CAA and AD in our study, not to mention probably even lower in those with overlap conditions (AD plus CAA). We are exploring other approaches. Future area of research could include a voxel-wise approach to identity CAA-specific brain area/amyloid uptake pattern, or to combine with other biomarker (CSF, plasma, other imaging modality, etc.) to enhance our diagnostic ability.
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REFERENCES
1. Gatti L, Tinelli F, Scelzo E, et al. Understanding the Pathophysiology of Cerebral Amyloid Angiopathy. Int J Mol Sci. 2020;21(10):3435. Published 2020 May 13. doi:10.3390/ijms21103435
2. Charidimou A, Farid K, Baron JC. Amyloid-PET in sporadic cerebral amyloid angiopathy: A diagnostic accuracy meta-analysis. Neurology. 2017;89(14):1490-1498. doi:10.1212/WNL.0000000000004539
3. Baron JC, Pasi M, Liu CJ, et al. Differentiating Cerebral Amyloid Angiopathy (CAA) From Alzheimer Disease (AD) Using Dual Amyloid PET and Tau PET. Presented at: International Stroke Conference; February 7-9, 2024; Abstract LBP56.
