James Nicoll and Delphine Boche send their dispatch from Cerebral Amyloid Angiopathy: Emerging Concepts, a conference held August 8-11 in Iceland.
Earlier this month, a select band of investigators with a particular interest in cerebral amyloid angiopathy (CAA) were warmly welcomed to the University of Iceland at Reykjavik by the Icelandic hosts of a small conference to discuss and advance the current state of knowledge on this condition. CAA is not only a risk factor for hemorrhagic stroke, but also directly influences brain function and the development of several forms of dementia, including Alzheimer disease (AD). There were presentations on CAA from all perspectives, including clinical aspects, genetics, human neuropathology, mouse models, and molecular mechanisms. There are several peptides that can accumulate in the cerebral vasculature as amyloid, but the major focus at this meeting was on Aβ and cystatin C.
Cystatin C amyloid angiopathy is Iceland’s own form of CAA. It was first described in 1935, and occurs due to a point mutation (L68Q) in the cystatin C gene that is found in 13 families originating from the west of the country. Astridur Palsdottir, University of Iceland, Reykjavik, gave a fascinating presentation of the epidemiology of this disorder. This insight is made possible by accurate knowledge of the Viking-derived population in Iceland from the Book of Icelanders and from death certificates and parish records. These sources enabled age at death of obligatory mutation carriers to be determined from the year 1800 onwards. One notable finding is that the average life span of obligatory carriers shrank progressively and dramatically during the nineteenth century, from about 65-70 to 30 years around the year 1900. Curiously, it has remained unchanged since. The Icelandic diet changed in the middle of the nineteenth century as imports led to an increase in salt and sugar intake, and the reduced survival of people with hereditary cystatin C amyloid angiopathy was tentatively attributed to this environmental change.
Masahito Yamada, University Graduate School of Medicine in Kanazawa, Japan, highlighted the scale of CAA-associated problems. The prevalence of CAA in AD is 87 percent, and 35 percent in elderly people without AD. In a population-based study, CAA was found in 23 percent of people aged 40 years or older. An attempt at a comprehensive study of CAA throughout Japan identified 794 patients with CAA-related intracerebral hemorrhage over 5 years, giving an estimate of nearly 3,000 patients with hemorrhage in the whole country. This work has resulted in an impressive cohort of patients available for study. Steven Greenberg, Harvard Medical School, and Mark Van Buchem, Leiden University Medical Center, The Netherlands, highlighted the problem that there is as yet no in-vivo imaging system in humans that is capable of specifically identifying CAA. This shortcoming limits the ability to study the disorder and its consequences from a clinical point of view. Jonathan Rosand, Massachusetts General Hospital, Boston, highlighted the importance of identifying CAA in vivo in humans. CAA is a risk factor for cerebral hemorrhage in patients who have received anticoagulation medication, for example, elderly people who are at high risk for thromboembolic stroke due to atrial fibrillation. The ability to identify CAA in such populations would allow the risk/benefit of anticoagulant therapy to be assessed more accurately in individual patients.
Delphine Boche, University of Southampton, U.K., presented data from neuropathological follow-up of Alzheimer patients in the Elan-Wyeth AN-1792 trial of active Aβ42 immunization. The findings suggest that as the immune system clears plaques from the brain, there is evidence of an increase in severity of CAA, which may subsequently resolve. Roxana Carare and Roy Weller, University of Southampton, provided experimental data to support their hypothesis that the brain has a perivascular drainage pathway analogous to the lymphatics of other organs, which is an important route for clearance of solutes, including Aβ. They propose that age-related vascular disease impairs clearance of Aβ by this route, leading to accumulation of Aβ as CAA and as parenchymal plaques.
Mathias Jucker, Hertie Institute in Tuebingen, Germany, described elegant studies in transgenic mouse models of CAA, showing that the relative distribution of Aβ accumulation in plaques and blood vessels can be altered by shifting the ratio of neuronally produced Aβ40 and Aβ42. Aβ42 favors the production of parenchymal amyloid plaques, while shifting the ratio towards Aβ40 favors accumulation in the vasculature as CAA (Herzig et al., 2004). Seth Love, University of Bristol, U.K., presented evidence that the Aβ-degrading enzyme neprilysin is decreased in the walls of Aβ-laden cerebral blood vessels, suggesting that this may contribute to the pathogenesis of CAA.
Brian Bacskai, Massachusetts General Hospital, provided evidence of the physiological dysfunction resulting from CAA in a transgenic mouse model. Accumulation of amyloid in the vessel wall renders the wall more rigid and damages the smooth muscle cells. It has long been postulated that the consequence of this would be impairment of the exquisitely precise matching of perfusion of the cerebral cortex to local neuronal metabolic demand that occurs on a microscopic scale. The application of elegant new technology of laser speckle flowmetry has allowed non-invasive mapping of flow in the network of cortical vessels in response to several stimuli including hypercapnia (i.e., excess carbon dioxide in blood), whisker stimulation, cortical spreading depression, and anesthetics. These studies show that there is an age-related impairment of vascular reactivity that is further worsened by the presence of Aβ amyloid, rather than soluble Aβ peptide, in the walls of the blood vessels.
Conference attendants took the opportunity to sample the geographical, geological, biological, and culinary delights of this spectacular country. For example, the conference dinner was preceded by bathing in the geothermally heated waters of the Blue Lagoon. A Friday evening boat trip from Reykjavik harbor allowed us to see puffins, Minke whales, and an impressive Humpback whale. A Saturday afternoon trip took us to Thingvellir. This spectacular rift valley between the American and Eurasian continental plates is where the early Viking settlers met each year for the purposes of government and to settle disputes. Overall, this meeting offered a valuable opportunity to focus on CAA and the multiple ways in which it contributes to brain dysfunction in aging, and also gave us a chance to strengthen collegial ties.—James Nicoll and Delphine Boche.
James Nicoll and Delphine Boche are at University of Southampton, U.K.
- Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Stürchler-Pierrat C, Bürki K, van Duinen SG, Maat-Schieman ML, Staufenbiel M, Mathews PM, Jucker M. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci. 2004 Sep;7(9):954-60. PubMed.