Bright spots called white-matter hyperintensities (WMHs) often appear on MRI scans of people with familial or sporadic Alzheimer’s disease, and they tend to intensify as the disease progresses. Some scientists think they reflect cerebrovascular disease. However, researchers led by Jasmeer Chhatwal at Massachusetts General Hospital in Charlestown offer a different explanation. In the October 16 JAMA Neurology, they reported that WMHs worsened most in people with extensive neurodegeneration, amyloid plaques, or cerebral microbleeds, a sign of cerebral amyloid angiopathy (CAA), while WMH severity did not correlate with vascular risk. They concluded that WMHs are driven by AD pathology.
- White-matter hyperintensities bloom as Alzheimer’s disease progresses.
- People with rampant amyloid and neurodegeneration were most affected.
- WMHs did not track with cardiovascular health.
“Conventional wisdom that white-matter disease is solely representative of vascular brain injury in older people is proven not to be the case,” Charles DeCarli at the University of California, Davis, told Alzforum. He said the data was convincing that neurodegeneration leads to WMHs, though he was less sure about plaques or CAA driving damage in all cases. Costantino Iadecola, Weill Cornell Medical College, New York, does think that amyloid’s assault on vessels underlies some of the pathology and that this work may refocus minds. “These results will get researchers out of the rut of thinking that hypertension and diabetes are the only things that damage the blood vessels in Alzheimer’s,” Iadecola said.
First author Zahra Shirzadi compared the total volume of WMHs to cardiovascular risk, as measured by the Framingham Heart Study cardiovascular disease risk score, and to the amount of amyloid, be it plaques or CAA. She drew data from clinical records and almost 4,000 brain scans of 1,141 people from three longitudinal cohorts: the Harvard Aging Brain Study, the Alzheimer’s Disease Neuroimaging Initiative, and the Dominantly Inherited Alzheimer Network. Participants included 252 carriers of pathogenic APP, PSEN1, and PSEN2 variants, average age 38; 458 healthy controls, averaging 72 years old; and 431 adults with MCI or AD, average age 73. Almost all were Caucasian and had better-than-average cardiovascular health for their age. Each had at least two structural MRI and amyloid PET scans over an average of three to five years.
At baseline, WMH volume was greatest among those who were oldest, had the least gray matter, the highest amyloid burden, or who had two or more cerebral microbleeds, a commonly used indicator of CAA that can only be diagnosed at autopsy. Over time, WMHs worsened more among these people than among their respective controls.
Amyloid and WMHs. MRI scans from people with a high amyloid load (left) predict more white-matter damage (red) than do scans from people with little amyloid (right). [Courtesy of Shirzadi et al., JAMA Neurology, 2023.]
Larger WMH volume might signify CAA before cerebral microbleeds do, the authors propose. Among the 527 older adults without such microbleeds at baseline, those with above-average WMH volume were 2.6 times likelier to develop microbleeds after six years than people with below-average WMH volume. Shirzadi had also seen WMHs worsen before microbleeds appeared in people who developed Dutch CAA, an autosomal-dominant form of the disease caused by a point mutation within the Aβ sequence of APP (Shirzadi et al., 2022). These results suggest that enlarged WMHs are an early sign of CAA.
To Iadecola, both studies fit with the idea that amyloid constricts blood vessels. He and others have found that soluble Aβ slowed cerebral blood flow in wild-type and amyloidosis mice and that vascular injury can be prevented if reactive oxygen species (ROS) scavengers are administered before the peptide settles into vessels as CAA. ROS are a major cause of vessel damage by Aβ (Mar 2011 news; Park et al., 2014). Iadecola thinks a similar window of opportunity for early intervention might exist in people with WMHs but no microbleeds. “By the time you see a single microbleed, it's probably too late to save those damaged blood vessels,” he said.
Did vascular health factor into WMH severity? Surprisingly, the amount of WMHs had no correlation with cardiovascular risk score after accounting for age, gray-matter volume, amyloid burden, and cerebral microbleeds. The authors concluded that amyloid and gray-matter atrophy, i.e., neurodegeneration, drives the brain lesions rather than small-vessel disease.
Others partially agreed. DeCarli thinks amyloid may be to blame in the young, heart-healthy DIAN cohort but that there is insufficient evidence to exclude concurrent vascular disease causing WMHs in the older ADNI and HABS participants.
Adam Brickman of Columbia University, New York, shared similar sentiments. “Showing that WMHs are not related to vascular risk factors and that they are related to aspects of AD pathophysiology tells us two things: that WMHs are not due exclusively to (modifiable) risk factors and that there is a relationship between WMHs and other markers of AD,” he wrote (comment below). “But do these observations prove the etiology of WMHs? I do not think that question has been settled.”—Chelsea Weidman Burke
- Shirzadi Z, Yau WW, Schultz SA, Schultz AP, Scott MR, Goubran M, Mojiri-Forooshani P, Joseph-Mathurin N, Kantarci K, Preboske G, Wermer MJ, Jack C, Benzinger T, Taddei K, Sohrabi HR, Sperling RA, Johnson KA, Bateman RJ, Martins RN, Greenberg SM, Chhatwal JP, DIAN Investigators. Progressive White Matter Injury in Preclinical Dutch Cerebral Amyloid Angiopathy. Ann Neurol. 2022 Sep;92(3):358-363. Epub 2022 Jun 25 PubMed.
- Park L, Koizumi K, El Jamal S, Zhou P, Previti ML, Van Nostrand WE, Carlson G, Iadecola C. Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke. 2014 Jun;45(6):1815-21. Epub 2014 Apr 29 PubMed.
- Shirzadi Z, Schultz SA, Yau WW, Joseph-Mathurin N, Fitzpatrick CD, Levin R, Kantarci K, Preboske GM, Jack CR Jr, Farlow MR, Hassenstab J, Jucker M, Morris JC, Xiong C, Karch CM, Levey AI, Gordon BA, Schofield PR, Salloway SP, Perrin RJ, McDade E, Levin J, Cruchaga C, Allegri RF, Fox NC, Goate A, Day GS, Koeppe R, Chui HC, Berman S, Mori H, Sanchez-Valle R, Lee JH, Rosa-Neto P, Ruthirakuhan M, Wu CY, Swardfager W, Benzinger TL, Sohrabi HR, Martins RN, Bateman RJ, Johnson KA, Sperling RA, Greenberg SM, Schultz AP, Chhatwal JP, Dominantly Inherited Alzheimer Network and the Alzheimer’s Disease Neuroimaging Initiative. Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease. JAMA Neurol. 2023 Oct 16; PubMed.