CAA and ARIA revisited

Dr. Steven Greenberg is most likely the most knowledgeable expert in the world concerning cerebral amyloid angiopathy (CAA) and the vascular pathology associated with Alzheimer’s disease. Earlier this week, I had the honor of joining him by Zoom in speaking at the National Institute of Neurological Disease and Stroke’s Clinical Neuroscience Grand Rounds about amyloid-related imaging abnormalities (ARIA) caused by anti-amyloid therapy. I began by presenting my own case of severe ARIA associated with aducanumab in a clinical trial. I have previously written about these events in chapter 13 of A Tattoo on my Brain: A Neurologist’s Personal Battle against Alzheimer’s Disease,  and Dr. Gil Rabinovici and his group at UCSF wrote a detailed case study published in Alzheimer’s & Dementia. 

This MRI of my brain was done about a week after the onset of my symptoms. Panel A demonstrates MRI-FLAIR images in which water in the brain appears white.  All of the fluffy white areas are edema, swelling of the brain. All lobes of the cortex had evidence of edema, so-called ARIA-e. Panel B is a sequence sensitive to iron in blood.  The tiny dark dots on both sides of the brain are micro-hemorrhages, ARIA-h.  Panel C was taken after injection of iv contrast demonstrating tiny white dots due to leakage of fluid in the same areas as the microhemorrhages.

These FLAIR MRI done over a sixth month period show a slight increase in brain swelling between January 12 and January 29.  High dose iv steroids were than administered, and my symptoms of headache and trouble reading gradually improved along with the MRI scans until I was back to baseline within 6 months. Note how my MOCA score (Montreal Cognitive Assessment) was essentially normal at baseline, dropped to an abnormal 22 at the peak of brain swelling, and finally returned to normal at six months. 

After my 20-minutes case presentation, Dr. Greenberg took over and spoke eloquently for the next hour on how CAA overlaps with Alzheimer’s disease. In CAA, beta-amyloid invades the smooth muscle in the walls of small, cerebral blood vessels increasing the chances of getting microhemorrhages indistinguishable from ARIA-h as well as large hemorrhages. CAA is one of the major causes of brain bleeding in the elderly. At autopsy, most but not all brains with CAA pathology, amyloid in the walls of small blood vessels and inflammation of the brain, also show signs of Alzheimer’s disease, amyloid plaques and neurofibrillary tangles.  The opposite is also true: most brains showing Alzheimer’s pathology at autopsy also have evidence of CAA.  There is a strong overlap. In fact, the serious cases of ARIA during treatment with anti-amyloid monoclonal antibodies like aducanumab, lecanumab and donanemab, both edema and microhemorrhages, may be due to weakened smooth muscle in small brain blood vessels caused by CAA. For more on this fascinating topic, I strongly recommend reading Dr. Greenberg’s review paper: Greenberg SM, et al. Cerebral amyloid angiopathy and Alzheimer disease – one peptide, two pathways. Nat Rev Neurol. 2020 Jan;16(1):30-42.