eMedicine Specialties > Neurology > Neuro-vascular Diseases

Cerebral Amyloid Angiopathy

Author: Ravi S Menon, MD, Clinical Fellow in Stroke Diagnostic and Therapeutics, National Institute of Health, National Institute of Neurological Disorders and Stroke
Coauthor(s): Jose G Merino, MD, Medical Director, Suburban Hospital Stroke Program; Vladimir C Hachinski, MD, MSc, DSc, FRCP(C), Professor, Departments of Medicine, Physiology, London Health Sciences Center, University of Western Ontario, Canada
Contributor Information and Disclosures

Updated: Aug 20, 2008

Introduction

Background

Cerebral amyloid angiopathy (CAA) refers to the deposition of b -amyloid in the media and adventitia of small- and mid-sized arteries (and less frequently, veins) of the cerebral cortex and the leptomeninges. It is a component of any disorder in which amyloid is deposited in the brain, and it is not associated with systemic amyloidosis. CAA has been recognized as one of the morphologic hallmarks of Alzheimer disease (AD), but it is also often found in the brains of elderly patients who are neurologically healthy. While often asymptomatic, CAA may lead to dementia, intracranial hemorrhage (ICH), or transient neurologic events. ICH is the most recognized result of CAA.

Pathophysiology

Amyloid damages the media and adventitia of cortical and leptomeningeal vessels, leading to thickening of the basal membrane, stenosis of the vessel lumen, and fragmentation of the internal elastic lamina. These processes result in fibrinoid necrosis and microaneurysm formation, predisposing to hemorrhage. Some evidence suggests that the amyloid is produced in the smooth muscle cells of the tunica media as a response to damage of the vessel wall (perhaps by arteriosclerosis or hypertension). CAA-related brain changes include lobar cerebral and cerebellar hemorrhage, leukoencephalopathy, small cortical ischemic infarcts, and plaque deposition. Leukoencephalopathy may be related to chronic hypoperfusion of deep WM (meningo-cortical segments of long perforators).

Amyloid deposition is complex; several key processes are involved: production of amyloid precursor proteins (APP), processing of precursor proteins, aggregation of protein, and fibril formation. Impaired elimination and accumulation of soluble and insoluble β-amyloid peptide may underlie the pathogenesis of CAA and explain the link between CAA and AD. Amyloid fibrils may deposit in cerebral vessels, as in β-amyloid CAA, or form senile plaques in brain parenchyma.

Neuropathologically, mild CAA primarily affects a relatively smaller proportion of the leptomeningeal and superficial cortical vessels, in contrast to the diffuse, significant deposition of amyloid in small arteries and arterioles seen in severe CAA. Medium-sized leptomeningeal arteries are affected with amyloid deposition in the outer portion of tunica media to tunica adventitia. Frequently, complete erosion occurs with only endothelium surrounding the deposit, predisposing to hemorrhage. Electron microscopy demonstrates fibrils of amyloid in the outer basement membrane in the initial stage of CAA. As the disease progresses, significant amyloid accumulation leads to tunica media degeneration, capillary and arteriolar infiltration, and formation of dystrophic neuritic plaques.

Many types of amyloid protein are present in the body, but some are unique to the brain. β-amyloid is a unique cerebrovascular amyloid protein that is immunohistochemically similar in patients without dementia and in patients with Alzheimer dementia. CAA and AD coexist pathologically at rates greater than predicted by chance. Arterial β-amyloid in CAA is nearly identical to senile plaque β-amyloid. Other amyloid proteins co-localize and may play a role in creating the phenotypic changes seen in CAA. No clear known correlation exists between the distribution of brain CAA and senile plaques and neurofibrillary tangles.

Different cerebrovascular amyloid proteins have been characterized, with some clinical correlates. For example, Worster-Drought syndrome, also known as familial British dementia, has protein ABri encoded by novel gene BRI. Sporadic CAA of β-amyloid is most commonly associated with Alzheimer disease.

Frequency

United States

The true incidence and prevalence of cerebral amyloid angiopathy are hard to specify, as definite CAA is a pathologic diagnosis typically obtained postmortem. However, estimates can be made based on autopsy series and the incidence of lobar ICH. A series of 400 autopsies found evidence of CAA in the brains of 18.3% of men and 28% of women aged 40-90 years. In a series of 117 brains of patients with confirmed AD, 83% had evidence of CAA.¹ The prevalence of CAA increases with advancing age; some autopsy series have found CAA in 5% of individuals in the seventh decade but in 50% of those older than 90 years. In patients with Alzheimer disease, the incidence in several studies and meta-analyses ranges from about 80-90%.

CAA is estimated to account for up to 15% of all ICH in patients older than 60 years and up to one half of nontraumatic lobar ICH in patients older than 70 years (approximately 15-20 cases per 100,000 people per year). CAA and CAA-related hemorrhage are particularly common in elderly individuals with AD and Down syndrome.

Mortality/Morbidity

Intracranial hemorrhage

• The most consistent clinical effect of cerebral amyloid angiopathy is lobar ICH. Lobar ICH is associated with a lower mortality rate (11-32%) and a better functional outcome than hypertensive deep ganglionic bleeds.
• Of individuals with CAA-related hemorrhage, 25-40% have a recurrence, with the highest risk in the first year. Recurrent hemorrhages can occur simultaneously or several years later. They are associated with a high mortality rate (up to 40%).
• Patients with a previous hemorrhage are at greater risk for subsequent hemorrhages than those with no history.
• Hypertension may exacerbate the tendency to CAA-related hemorrhage and vice versa.
• Cortical petechial hemorrhage can be epileptogenic.

Dementia

• Cognitive impairment is a common feature of CAA.
• CAA is the most significant microscopic abnormality in 10-15% of patients diagnosed with AD by clinical criteria.
• More than 40% of patients with ICH-related hemorrhage have some degree of dementia. In some cases, the cognitive changes can precede the ICH.
• The relationship between CAA and AD is close. CAA, present in 80-85% of patients with AD, is severe in one-third to two-thirds of these patients. 
• Vascular lesions can play a significant pathophysiologic role and can contribute to the development of dementia in AD. The severity of CAA is correlated with the presence of ischemic or hemorrhagic lesions in the brains of patients with AD, and CAA is associated with gross strokes but not with subcortical lacunae.
• Although CAA may contribute to the neurodegeneration of AD, a direct causal link between the 2 disorders has not been established: the association could be due to shared risk factors such as the presence of apolipoprotein (ApoE) e4.
• Some patients with CAA present with a progressive dementia, involving rapid cognitive decline over days or weeks. This rapid progression could be due to the additive effects of severe vascular amyloid, cortical hemorrhages and infarctions, white matter destruction, and accumulation of neuritic plaques.

Vasculitis

• Few cases of vasculitis of various types (giant cell arteritis, rheumatoid vasculitis, primary angiitis of the CNS) associated with CAA have been reported. No consensus exists as to whether the pathologic abnormalities are related causally or whether the appearance of vasculitis is a reaction to CAA-induced angiopathic changes.

Sex

Upon autopsy, cerebral amyloid angiopathy may be found more commonly in women than men; however, the incidence of ICH is the same in women and men.

Age

• The severity of cerebral amyloid angiopathy is age related; more than 50% of patients in the tenth decade of life have evidence of CAA. Increasing age and the presence of AD are the only identified risk factors for CAA.
• Sporadic CAA-related ICH occurs in patients aged 60 years or older.
• Familial forms of CAA are associated with hemorrhage at younger ages, by the third or fourth decade in the Icelandic form and by the sixth decade among the Dutch kindreds.
• Hemorrhage occurs at the same age in men and women.

Clinical

History

Cerebral amyloid angiopathy (CAA) is frequently asymptomatic. However, it can manifest as one of several clinicopathologic entities. The most frequent are intracranial hemorrhage (ICH) and dementia.

• CAA most often comes to clinical attention because of ICH. Symptoms may range from transient weakness to coma, depending on the size and location of the hemorrhage. Patients may have recurrent episodes.
  • The most common symptom at onset is headache (60-70% of patients). Frontal hematomas produce bifrontal headache pain; parietal bleeds, usually unilateral temple pain; temporal hematomas, ipsilateral eye and ear pain; and occipital bleeds, ipsilateral eye pain.
  • Vomiting (in 30-40%) tends to occur early.
  • Seizures occur at onset in 16-36% of patients. Seizures are most commonly partial, with symptoms determined by the location of the ICH. As many as half of the patients present in status epilepticus.
  • Coma at presentation has been reported in a small proportion of patients (0.4-19%). Decreased level of consciousness, related to the size and location of the hematoma, results from compression of the contralateral hemisphere or brain stem or increased intracranial pressure.
• Dementia may manifest as several patterns of cognitive dysfunction. Some cognitively normal patients present with rapid progression to profound dementia in a couple of years. Other patients can have a more protracted course, commonly seen in AD.
• Stereotyped transient neurologic events commonly consist of focal weakness, paresthesias, or numbness. In some cases, these events may be prodromes to larger hemorrhages.
  • The symptoms spread to contiguous body parts over 2-10 minutes, and they may involve areas in several vascular territories. These events are probably due to small cortical petechial hemorrhages that lead to focal seizures. The rate of spread is akin to that seen in migraine; some have proposed that these episodes may represent spreading depression of neuronal activity.
  • Some patients present with transient confusion or episodes of visual misperceptions.
• Uncommon presentations of CAA
  • CAA can be associated with ischemic strokes; in some of these patients, a coexistent vasculitis can be found. The causal relationship with CAA is unclear.
  • CAA is found in patients with autosomal dominant dementia, spasticity, and ataxia without ICH.
  • CAA is reported in patients with vascular malformations, postirradiation necrosis, spongiform encephalopathies, and dementia pugilistica.
  • CAA can present as a mass lesion, such as an amyloidoma with accumulation of amyloid in the brain parenchyma, or to edema and gliosis that result from the vascular lesion.
  • CAA can manifest as a reversible leukoencephalopathy with rapid progression of symptoms and imaging abnormalities followed by dramatic improvement.²

Physical

Physical findings depend on the disease process associated with cerebral amyloid angiopathy in a particular patient.

• The features of ICH depend on the location of the bleed. Strict isolation of features from each lobe is frequently not possible because of extension of hematoma to other lobes, mass effect, and increased intracranial pressure.
  • Frontal: Depending on the size and location, frontal ICH may present with any symptoms from weakness of one limb to impaired consciousness with contralateral hemiparesis, hemisensory loss, and horizontal gaze palsy. Left hemispheric lesions can present with aphasia, and more anterior lesions lead to an abulic state with frontal release signs.
  • Parietal: Hemisensory loss, homonymous hemianopsia, hemi-inattention, and apraxia are all signs of parietal ICH.
  • Temporal: Dominant hemisphere hematomas lead to aphasia and hemianopia; nondominant hemisphere hematomas produce a confusional state.
  • Occipital: Unilateral hemianopia or quadrantanopia and visual hallucinations often accompany occipital ICH.

Causes

• Most cases of cerebral amyloid angiopathy are sporadic, although genetic predispositions exist (eg, ApoE subtypes confer different risk profiles).
• Most cases of CAA-related ICH are spontaneous, but they may be related to vessel wall injury by atherosclerosis and hypertension. The risk of intracranial bleeding following head trauma and neurosurgical procedures is increased in patients with CAA. Some evidence suggests that CAA has a role in a substantial proportion of anticoagulant- and thrombolytic-related hemorrhages.
• Hereditary forms of CAA are due to specific gene mutations.
• Hereditary cerebral hemorrhage with amyloidosis-Dutch type is an autosomal-dominant disorder with complete penetrance.
  • Of those affected, 87% have ICH and 13% have infarcts (deep).The age of onset of ICH is in the sixth decade (mean, 55 y).
  • Some patients develop dementia without ICH.
  • Amyloid deposits are found in cortical and leptomeningeal vessels; parenchymal neurofibrillary tangles are not seen. Deposited amyloid protein in these patients is identical to the amyloid protein seen in sporadic cases, and the likely genetic defect is in the amyloid protein precursor protein (APP) gene on chromosome 21.
• Hereditary cerebral hemorrhage with amyloidosis-Icelandic type is also autosomal dominant.
  • Patients present with their first episode of ICH in the third or fourth decade, with some patients dying from ICH as young as 15 years. One case report has identified a family with late-onset dementia with and without ICH.
  • The amyloid angiopathy is more widely distributed in this type than in other types, involving arteries in the cerebrum, cerebellum, and brain stem.
  • The amyloid protein is a mutant of the cysteine protease inhibitor cystatin C.
• Severity of angiopathy and fibrinoid necrosis closely correlate with the occurrence of ICH.
• The Boston Cerebral Amyloid Angiopathy Group has elaborated guidelines for the diagnosis of CAA associated with ICH. Four levels of certainty in the diagnosis of CAA are considered: definite, probable with supporting pathological evidence, probable, and possible. The first 3 require that no other cause of hemorrhage has been identified.
  • Definite CAA: Full postmortem examination reveals lobar, cortical, or corticosubcortical hemorrhage and evidence of severe CAA.
  • Probable CAA with supporting pathological evidence: The clinical data and pathological tissue (evacuated hematoma or cortical biopsy specimen) demonstrate a hemorrhage with the aforementioned characteristics and some degree of vascular amyloid deposition.
  • Probable CAA: Clinical data and MRI findings (in the absence of a pathological specimen) demonstrate multiple hematomas (as described above) in a patient older than 60 years.
  • Possible CAA: This is considered if the patient is older than 60 years, and clinical and MRI data reveal a single lobar, cortical, or corticosubcortical hemorrhage without another cause, multiple hemorrhages with a possible but not a definite cause, or some hemorrhage in an atypical location.

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