Predicting cerebral amyloid angiopathy-related intracerebral hemorrhages and other cerebrovascular disorders in Alzheimer's disease

Abstract

Cerebral amyloid angiopathy (CAA) of amyloid β-protein (Aβ) type is common in Alzheimer's disease (AD). Aβ immunotherapies have been reported to induce CAA-related intracerebral hemorrhages (ICH) or vasogenic edema. For the purpose of developing a method to predict CAA-related ICH and other cerebrovascular disorders in AD, the biomarkers, and risk factors are reviewed. The biomarkers include (1) greater occipital uptake on amyloid positron emission tomography imaging and a decrease of cerebrospinal fluid Aβ40 levels as markers suggestive of CAA, and (2) symptomatic lobar ICH, lobar microhemorrhages, focal subarachnoidal hemorrhages/superficial siderosis, cortical microinfarcts, and subacute encephalopathy (caused by CAA-related inflammation or angiitis) as imaging findings of CAA-related ICH and other disorders. The risk factors include (1) old age and AD, (2) CAA-related gene mutations and apolipoprotein E genotype as genetic factors, (3) thrombolytic, anti-coagulation, and anti-platelet therapies, hypertension, and minor head trauma as hemorrhage-inducing factors, and (4) anti-amyloid therapies. Positive findings for one or more biomarkers plus one or more risk factors would be associated with a significant risk of CAA-related ICH and other cerebrovascular disorders. To establish a method to predict future occurrence of CAA-related ICH and other cerebrovascular disorders in AD, prospective studies with a large number of AD patients are necessary, which will allow us to statistically evaluate to what extent each biomarker or risk factor would increase the risk. In addition, further studies with progress of technologies are necessary to more precisely detect CAA and CAA-related cerebrovascular disorders.

Keywords: Alzheimer’s disease; amyloid β-protein; biomarker; cerebral amyloid angiopathy; cerebrovascular disorders; dementia; intracerebral hemorrhage; risk factor.

Figure 1

Pathophysiology of cerebral amyloid angiopathy (CAA)-related disorders. Aβ shows parenchymal or vascular deposition, depending on dominance of Aβ42 or Aβ40, respectively, in elderly individuals and patients with Alzheimer’s disease (AD). Cerebrovascular amyloid deposition, CAA, is related to stroke and dementia.

Figure 2

The spectrum of cerebral Aβ amyloidosis.

Figure 3

The distribution of the severity of CAA in elderly individuals (n = 201; age, 85.9 ± 8.0 years) with and without Alzheimer’s disease (AD), based on an autopsy series including AD (n = 82; age, 86.1 ± 7.9 years) and non-AD cases (n = 119; age, 85.7 ± 8.0 years). Frequencies are shown in the percentages in each of the AD and non-AD group (The modified data from the previous report; Yamada, 2002).

Figure 4

(A) Cerebral microhemorrhages with lobar distribution in a patient with Alzheimer’s disease (AD) on gradient-echo T2* imaging. (B,C) A patient with AD had presented with multiple, old focal subarachnoid hemorrhages (superficial siderosis; arrows) on T2-weighted MRI at the time of the diagnosis of AD (B). The patient later developed a large intracerebral hemorrhage in the left frontal lobe as shown on CT (C), probably related to CAA (by courtesy of Dr. Toshiya Fukui, Showa University).