. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease. JAMA Neurol. 2014 Jul 1;71(7):878-83. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. This recent analysis by Ringman and colleagues at the UCLA Alzheimer’s Disease Research Center teases out the clinical and pathological features conferred by advanced cerebral amyloid angiopathy (CAA) in the setting of Alzheimer’s disease (AD). The authors used data from the National Alzheimer’s Coordinating Center Uniform Data Set to compare 232 autopsied brains with neuropathologic diagnosis of AD (by NIA-Reagan Institute criteria) and no CAA, to 193 brains with AD plus severe CAA (defined as intensely amyloid-positive parenchymal and meningeal vessels in two or more brain regions).

    One set of findings from this analysis falls under the rubric of confirming that CAA causes ischemic and hemorrhagic brain injury. CAA brains had a higher prevalence of cortical microinfarcts than controls (20.7 percent vs. 12.9 percent), subcortical leukoencephalopathy (20.5 percent vs. 12.1 percent), and cerebral hemorrhages (9.3 percent vs. 3.5 percent).  Severe CAA also associated with a history of transient ischemic attacks (12.5 percent vs. 6.1 percent for non-severe CAA), though, as the authors point out, these symptoms might alternatively reflect the non-ischemic, transient neurologic symptoms that can occur in association with sulcal bleeding (Charidimou et al., 2012).  A related finding is that CAA brains had lower diffuse plaque scores.  Although there are various ways to interpret this finding, one possibility is that less severe AD pathology combined with severe CAA might be sufficient to impair cognition. Given the wide body of literature demonstrating that vascular- plus AD-related brain injury produce more severe clinical impairment than either pathology on its own (Snowdon et al., 1997; Schneider et al., 2007), it is reasonable to consider these patients with AD and severe CAA as suffering from mixed dementia.  

    A second set of findings relate to the link between CAA and the apolipoprotein E (APOE) ε4/ε4 genotype (28.5 percent of the severe CAA brains vs. 8.8 percent of the no CAA brains) or at least one ε4 allele (60.6 percent vs. 41.2 percent). Although APOE ε4 is well known to increase both AD and CAA, these data strengthen the evidence that particularly the homozygous genotype tilts the balance towards severe CAA pathology.  This result is perhaps most relevant to the observation that amyloid-related imaging abnormalities (ARIA) in trials of anti-amyloid immunotherapy occur with greatest frequency in APOE ε4 carriers (Salloway et al., 2014), adding further evidence for the importance of vascular amyloid in generating ARIA.

    Finally, there was at least one unexpected association: the link between severe CAA and Hispanic ethnicity (6.8 percent vs. 1.3 percent).  Racial or ethnic predilections for CAA have not been consistently identified; the association with Hispanic ethnicity could thus be a false positive due to multiple hypothesis testing or differential pathology grading across centers.  If confirmed, however, the finding would add an entirely new perspective to the pathogenesis of this challenging disorder.

    References:

    . Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy: multicentre magnetic resonance imaging cohort study and meta-analysis. Stroke. 2012 Sep;43(9):2324-30. Epub 2012 Jul 12 PubMed.

    . Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997 Mar 12;277(10):813-7. PubMed.

    . Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007 Dec 11;69(24):2197-204. PubMed.

    . Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 23;370(4):322-33. PubMed.

  2. This very interesting clinicopathological study identifies a number of risk factors for cerebral amyloid angiopathy (CAA) that, together with associated vascular lesions in the brain, may aid the clinical diagnosis of patients with CAA. Furthermore, the study highlights the close and complex relationship between CAA and cerebrovascular disease. As summarized below, cerebrovascular disease, and particularly arteriosclerosis, appears to play very important role in the pathogenesis of CAA. However, CAA may also be responsible for cerebrovascular lesions in the brain.

    The evidence supplied in the manuscript by Ringman et al. suggests that some steps in the mechanism of development of CAA may be different in the presence of ApoE ε3, compared with ApoE ε4. We have demonstrated that interstitial fluid and soluble Aβ are cleared from the brain along the basement membranes of capillary and artery walls, analogous to the lymphatics of other organs (Carare et al., 2008; Hawkes et al., 2011). Observations in human brains and experimental studies suggest that with increasing age and in the presence of ApoE ε4, there is a failure of elimination of soluble Aβ from the brain (Hawkes et al., 2012; Carare et al., 2013; Hawkes et al., 2013). Our mathematical models suggest that pulsations, together with biochemical interactions, provide the biophysical force necessary for the clearance of Aβ along the cerebral vascular basement membranes (Schley et al., 2006). The present neuropathological study provides substantive evidence that cerebrovascular disease is a pathological entity that leads to CAA. Recent experimental evidence suggests that the interaction between Aβ and ApoE ε4 is weaker compared to ApoE ε3 (Ulrich et al., 2013).

    Collectively, the experimental data and the present postmortem study of human CAA provide strength to the working hypothesis that: In the presence of ApoE ε4, the biochemical interactions of Aβ with lipoproteins within the extracellular space result in a failure of the clearance of Aβ across the endothelium and along the basement membranes of capillaries and arteries (Tai et al., 2014; Thal et al., 2009; Deane et al., 2008); a failure that contributes to the pathogenesis of CAA. 

     

    References:

    . Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008 Apr;34(2):131-44. Epub 2008 Jan 16 PubMed.

    . Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 2011 Apr;121(4):431-43. PubMed.

    . Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele. PLoS One. 2012;7(7):e41636. PubMed.

    . Cerebral amyloid angiopathy, Prion angiopathy, CADASIL and the spectrum of Protein Elimination-Failure Angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol. 2013 Mar 13; PubMed.

    . Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Aging Cell. 2013 Apr;12(2):224-36. PubMed.

    . Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol. 2006 Feb 21;238(4):962-74. PubMed.

    . In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol Neurodegener. 2013;8:13. PubMed.

    . Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk. Mol Neurodegener. 2014 Jan 4;9:2. PubMed.

    . Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol Aging. 2009 Dec;30(12):1936-48. PubMed.

    . apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008 Dec;118(12):4002-13. PubMed.