Apolipoprotein A‐1 Deficiency in Older Adults with Spontaneous Cerebral Lobar Hemorrhage

Abstract

An 80-year-old woman was admitted to the Stroke Unit at Sant'Andrea Hospital (La Spezia, Italy) for spontaneous right cerebellar hemorrhage (Figure 1A); she complained of cognitive impairment and had a cerebellar hemorrhage 1 year before. Angio-computed tomography (CT) of the intracranial vessels did not show any vascular malformations. Her apolipoprotein A-1 (apoA-1) plasma level was 92 mg/dL (normal range 105–205 mg/dL) and her high-density lipoprotein cholesterol (HDL-C) was 29 mg/dL. An 82-year-old woman with diabetes mellitus and hypertension, treated with metformin and ramipril, presented a spontaneous hemorrhage in the right temporal and occipital lobes (Figure 1B). She was admitted to the Neurosurgery Unit, where she underwent digital subtraction angiography of intracranial vessels, which was normal. Her apoA-1 plasma concentration was 91 mg/dL, and her HDL-C was 70 mg/dL. An 86-year-old woman with hypertension and severe cognitive deficits, receiving treatment with furosemide, was admitted to the emergency department for a sudden-onset left hemiparesis; CT scan showed intraparenchymal right frontal hemorrhage (Figure 1C). Angio-CT of the intracranial vessels was normal. Her apoA-I plasma level was 79 mg/dL, and her HDL-C was 29 mg/dL. ApoA-1 is a 28-KDa protein synthesized by the liver and small intestine. It plays a critical role in the formation, metabolism, and catabolism of HDL-C, a plasma lipoprotein whose levels are highly linked to protection against the development of cardiovascular disease.1 As expected, gene deletion of apoA-1 results in extremely low levels of HDL-C in mice, which are significantly more likely to develop atherosclerosis. Hepatic overexpression of apoA-1 significantly raises HDL-C levels and inhibits the progression of and even regresses atherosclerosis in mice. Thus, upregulation of endogenous apoA-I expression is widely considered to be one of the most promising approaches in HDL-C-related therapies.2 Mutated apoA-1 causes rare forms of late-onset familial amyloidosis that are inherited in an autosomal-dominant manner and are characterized by asymptomatic cholestatic hepatopathy and nephropathy, the latter presenting with slowly progressive renal failure without proteinuria due to selective tubular involvement. In a subset of individuals, a progressive cardiomyopathy leading to heart failure may be observed. Skin, peripheral nerves, and the larynx are also frequently involved.3 None of the women described above had clinical or laboratory signs of systemic amyloidosis. The accumulation of amyloid in the walls of small and medium-sized cerebral arteries causes cerebral amyloid angiopathy (CAA). In most cases, the accumulated amyloid is composed of the amyloid-beta peptide, the same found in the plaques of individuals with Alzheimer's disease (AD). Amyloid deposition in cerebral blood vessels can have several clinical consequences. First, it can remain asymptomatic, as suggested by the neuropathological observation that, during normal aging, approximately 50% of individuals aged 80 and older have CAA. Second, it can weaken the vessel wall, causing vessel rupture and intracerebral hemorrhage. Finally, it can obliterate the vessel lumen, leading to ischemia.4 CAA-related hemorrhage is a major cause of spontaneous cerebral lobar hemorrhages in older adults with normal or high blood pressure.5 A recent study demonstrated that apoA-1 significantly decreased amyloid-beta toxicity against brain vascular smooth cells in transgenic mice. It concluded that lack of apoA-1 aggravates memory deficits along with significantly greater CAA.6 In another study, an oral apoA-1 mimetic peptide was administered in a mouse model of AD and showed improvement of cognitive function and reduction of amyloid burden.7 We hypothesized that low plasma concentrations of apoA-1 would favor amyloid angiopathy and the consequent lobar hemorrhages in older adults. We report three patients with spontaneous and lobar hemorrhages low plasma levels of apoA-1. This sample is too small to draw any conclusion, but if this finding is confirmed in a larger sample, plasma levels of apoA-1 could become a useful diagnostic test in older adults with amyloid angiopathy at risk of hemorrhagic strokes. In addition, oral administration of apoA-1 mimetic peptides could be studied not only in the treatment of atherosclerotic vascular diseases, but also in preventing amyloid deposition in cerebral blood vessels. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Massimiliano Godani: Study concept and design. Cesare Capellini: Acquisition, analysis and interpretation of CT data. Massimo Del Sette: Supervision of the manuscript. Sponsor's Role: None.