Introduction

Steven Greenberg and Mathias Jucker led this live discussion on 12 March 2003. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

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Background

Background Text
By Steven Greenberg and Mathias Jucker

As a neuropathological entity, cerebral amyloid angiopathy (CAA) is no stranger to the AD community. Defined as deposition primarily of Ab in the walls of small and medium-sized vessels of the cerebral cortex and leptomeninges, CAA occurs in moderate or severe forms in approximately 25 percent of AD brains. Indeed, nearly all AD brains contain some evidence of mild CAA, which appears to develop at roughly the same pace as the senile plaques and other pathological changes of AD. More recent studies have defined vascular amyloid deposition as also occurring in transgenic mouse models of AD.

But does the vascular amyloid actually do anything? CAA also occurs in the normal elderly and is a common cause of hemorrhagic stroke, but this is generally a problem for stroke neurologists rather than AD investigators. Though CAA-related hemorrhagic stroke may be more common in AD, it nonetheless occurs in only a small proportion of AD patients and, thus, by itself is likely not a significant contributor to AD pathogenesis.

The topic we propose to address is: Does CAA play a broader role in AD? Recently, two potential niches have received experimental support. First, CAA might contribute to dementia in AD and second, CAA possibly plays a role in the response to immune-based therapy.

Does CAA Contribute to Dementia?
The strongest evidence for a role of CAA in AD pathogenesis and dementia has come from large clinical-pathological studies, in which patients are tested during life and their brains examined neuropathologically after death. In the Honolulu-Asia Aging Study, for example, cognition scores were significantly lower in AD patients whose brains demonstrated CAA at postmortem than in those without CAA. The difference persisted after controlling for age, education, ApoE genotype, and senile plaque and neurofibrillary tangle counts (Pfeifer et al., 2002). A similar, independent contribution of CAA to cognitive impairment has been reported with normal aging in the MRC Cognitive Function and Aging Study (Paul Ince, personal communication) and in several forms of hereditary CAA (Natte et al., 2001; Grabowski et al., 2001; Vidal et al., 1999).

Potential mechanisms linking vascular amyloid and AD dementia might be divided into the "direct" and "indirect" vascular hypotheses.

The "direct" vascular hypotheses suggest that CAA is part of AD pathogenesis and either potentiates or even triggers the dementia ( Kalaria, 1997; de la Torre, 1999). Experimental support comes from recent transgenic mouse work suggesting that vascular and parenchymal amyloid may have a common neuronal origin and that vascular amyloid is the result of abnormal drainage of parenchymal Ab (Calhoun et al., 1999; Van Dorpe et al., 2000; Weller et al., 1998). Moreover, in transgenic mice, virtually identical amyloid-associated pathologies develop as a consequence of parenchymal amyloid and dyshoric (i.e., perivascular) amyloid (Calhoun et al., 1999; Van Dorpe et al., 2000).

The "indirect" vascular hypotheses do not posit a direct connection between CAA and the pathogenesis of AD, per se, but instead argue that CAA affects cognition by impairing cerebral perfusion and generating discrete brain infarctions or diffuse ischemic injury. In conjunction with AD neuropathology, such ischemic lesions would lead to greater degrees of cognitive impairment than would occur from either AD or ischemic damage on its own. The evidence supporting an association between CAA and cerebral ischemia has grown increasingly convincing. Case-control studies showing greater prevalence of CAA in brains with infarctions than those without (Olichney et al., 1995; Cadavid et al., 2000) have more recently been supplemented by demonstration of a quantitative relationship between CAA severity and diffuse white matter injury or "leukoaraiosis." (Haglund et al., 2002; see also Paul Ince, personal communication). An investigation of patients with CAA-related hemorrhagic stroke found leukoaraiosis to be both common and highly correlated with the presence of dementia (Smith et al., 2003).

Regardless of the mechanistic pathway, CAA appears increasingly likely to account for a substantial burden of cognitive impairment. Preventing its appearance or its pathogenic effects on vascular function or AD pathogenesis would thus be rational approaches to treatment of cognitive decline in the elderly. A clinical trial of a candidate treatment for CAA known as Cerebril^TM has recently been initiated in North America under joint funding from the National Institute of Neurological Diseases and Stroke and the biopharmaceutical company Neurochem, Inc. (St. Laurent, Quebec).

CAA and AD Immunotherapy
The past few years have seen the inflammatory response to Ab undergo an image makeover. Anti-Ab inflammation had for years been implicated as part of the AD pathogenic cascade and thus a potential target for drug treatment, an idea supported by epidemiologic evidence of a protective role for antiinflammatory agents. This model was essentially turned on its head by the observation first by Dale Schenk and colleagues (Schenk et al., 1999) of protection from plaque formation by immunization with Ab. The ongoing story of this potential treatment, including the discontinuation of immunization in the phase II trial after about 15 patients developed a type of meningoencephalitis, has been widely reported (see Alzforum discussion).

There are several reasons for considering whether the inflammatory response generated to coincident CAA might have important implications for how patients respond to immune-based anti-amyloid therapy. A naturally occurring inflammatory response has been identified in a subset of CAA patients, with accumulation of monocytes and T-lymphocytes surrounding amyloid-laden vessels (Eng et al., 2003).

These patients typically demonstrate subacute cognitive decline and strikingly abnormal white matter on MRI, a syndrome that may be similar to the meningoencephalitis associated with vaccination. Similarly, a subset of transgenic mice with CAA develop CAA-associated endovasculitis (Winkler et al., 2001). It is also notable that the antibodies generated to Ab vaccination readily recognize vascular Ab (see ARF related news story). That these antibodies might disrupt the integrity of the amyloid-laden vessel wall was suggested by studies in which passive immunization of transgenic mice with CAA resulted in an increase in both the number and size of hemorrhagic lesions (see ARF related news story).

The possibility that either of these types of inflammatory response to vascular Ab occurs in immunized patients places CAA in the middle of the Ab vaccine discussion. This consideration emphasizes the importance of defining noninvasive methods for identifying the presence and severity of CAA in living subjects, a goal that has thus far eluded the Ab-studying community.

Let's Discuss These Questions (and More)

• Can we define the term CAA? Nearly all AD brains contain at least a few amyloid-laden vessels. At what point does this become meaningful to AD?
• What next? Given current knowledge, what methods should be brought to bear to understand the contribution of CAA to cognitive decline?
• Does CAA arise early or late in AD pathogenesis?
• In what way should future vaccination approaches incorporate CAA?
• How important is CAA relative to other contributing factors in AD?
• Mechanistically, what are the most likely links between CAA, AD, and dementia?

References:
Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology 2002;58(11):1629-1634. Abstract

Natte R, Maat-Schieman ML, Haan J, Bornebroek M, Roos RA, van Duinen SG. Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann Neurol 2001;50(6):765-772. Abstract

Grabowski TJ, Cho HS, Vonsattel JPG, Rebeck GW, Greenberg SM. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Annals of Neurology 2001;49(June):697-705. Abstract

Vidal R, Frangione B, Rostagno A, Mead S, Revesz T, Plant G, et al. A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 1999;399(6738):776-781. Abstract

Kalaria RN. Cerebrovascular degeneration is related to amyloid-beta protein deposition in Alzheimer's disease. Annals of the New York Academy of Sciences 1997;826(263):263-271. Abstract

de la Torre JC. Critical threshold cerebral hypoperfusion causes Alzheimer's disease? Acta Neuropathol (Berl) 1999;98(1):1-8. Abstract

Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, et al. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci U S A 1999;96(24):14088-14093. Abstract

Van Dorpe J, Smeijers L, Dewachter I, Nuyens D, Spittaels K, Van Den Haute C, et al. Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons. Am J Pathol 2000;157(4):1283-1298. Abstract

Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE. Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol 1998;153(3):725-733. Abstract

Olichney JM, Hansen LA, Hofstetter CR, Grundman M, Katzman R, Thal LJ. Cerebral infarction in Alzheimer's disease is associated with severe amyloid angiopathy and hypertension. Archives of Neurology 1995;52(7):702-708. Abstract

Cadavid D, Mena H, Koeller K, Frommelt RA. Cerebral beta amyloid angiopathy is a risk factor for cerebral ischemic infarction. A case control study in human brain biopsies. J Neuropathol Exp Neurol 2000;59(9):768-773. Abstract

Haglund M, Englund E. Cerebral amyloid angiopathy, white matter lesions and Alzheimer encephalopathy - a histopathological assessment. Dement Geriatr Cogn Disord 2002;14(3):161-166. Abstract

Smith EE, Eng JA, Rosand J, Greenberg SM. Presence of leukoaraiosis predicts recurrent lobar hemorrhage. Stroke (abs) 2003;34(1):242.

Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400(6740):173-177. Abstract

Eng JA, Frosch MP, Greenberg SM. Cerebral amyloid angiopathy-related inflammation, subacute cognitive decline, and reversible white matter changes. Stroke (abs) 2003;34(1):275.

Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci 2001;21(5):1619-1627. Abstract

Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, et al. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med 2002;8(11):1270-1275. Abstract

Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, et al. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 2002b;298(5597):1379. Abstract

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References

News Citations

1. The Alzheimer's Vaccination Story, Continued 22 Nov 2002
2. Mini-strokes from Passive Immunization? 22 Nov 2002

Webinar Citations

1. CAA: We All Know It's There, But Just What Is It Doing in Alzheimer's? 12 Mar 2003

Paper Citations

1. Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology. 2002 Jun 11;58(11):1629-34. PubMed.
2. Natté R, Maat-Schieman ML, Haan J, Bornebroek M, Roos RA, van Duinen SG. Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann Neurol. 2001 Dec;50(6):765-72. PubMed.
3. Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol. 2001 Jun;49(6):697-705. PubMed.
4. Vidal R, Frangione B, Rostagno A, Mead S, Révész T, Plant G, Ghiso J. A stop-codon mutation in the BRI gene associated with familial British dementia. Nature. 1999 Jun 24;399(6738):776-81. PubMed.
5. Kalaria RN. Cerebrovascular degeneration is related to amyloid-beta protein deposition in Alzheimer's disease. Ann N Y Acad Sci. 1997 Sep 26;826:263-71. PubMed.
6. de la Torre JC. Critical threshold cerebral hypoperfusion causes Alzheimer's disease?. Acta Neuropathol. 1999 Jul;98(1):1-8. PubMed.
7. Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):14088-93. PubMed.
8. Van Dorpe J, Smeijers L, Dewachter I, Nuyens D, Spittaels K, Van den Haute C, Mercken M, Moechars D, Laenen I, Kuiperi C, Bruynseels K, Tesseur I, Loos R, Vanderstichele H, Checler F, Sciot R, Van Leuven F. Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons. Am J Pathol. 2000 Oct;157(4):1283-98. PubMed.
9. Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE. Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol. 1998 Sep;153(3):725-33. PubMed.
10. Olichney JM, Hansen LA, Hofstetter CR, Grundman M, Katzman R, Thal LJ. Cerebral infarction in Alzheimer's disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol. 1995 Jul;52(7):702-8. PubMed.
11. Cadavid D, Mena H, Koeller K, Frommelt RA. Cerebral beta amyloid angiopathy is a risk factor for cerebral ischemic infarction. A case control study in human brain biopsies. J Neuropathol Exp Neurol. 2000 Sep;59(9):768-73. PubMed.
12. Haglund M, Englund E. Cerebral amyloid angiopathy, white matter lesions and Alzheimer encephalopathy - a histopathological assessment. Dement Geriatr Cogn Disord. 2002;14(3):161-6. PubMed.
13. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999 Jul 8;400(6740):173-7. PubMed.
14. Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci. 2001 Mar 1;21(5):1619-27. PubMed.
15. Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med. 2002 Nov;8(11):1270-5. PubMed.
16. Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. PubMed.

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