Cerebral amyloid angiopathies (CAA)

Cerebral amyloid angiopathies are defined as a heterogeneous group of angiopathies characterized by the presence of amyloid protein deposits in the walls of cerebral vessels.

They are common in elderly individuals and are considered one of the main causes of hemorrhagic and ischemic strokes. Traditionally, no specific treatments were available, and recommendations were limited to managing cardiovascular risk factors and general measures. However, recently identified inflammatory forms, though rare, are amenable to treatment.

Epidemiology

The prevalence of the condition is high and increases with age based on pathological studies:

• 30% at 60 years (2% if considering only moderate to severe lesions)
• 90% at >85 years (12% if considering only moderate to severe lesions).

Risk factors include Alzheimer's disease (80% of patients with Alzheimer's disease present with cerebral amyloid angiopathy based on pathological studies), Down syndrome, and a slight female predominance.

Their role in clinically evident cerebrovascular pathologies is difficult to establish due to the very high prevalence of other vascular risk factors. They are better documented for the hemorrhagic aspect of the disease, where they represent the second leading cause of intracerebral hemorrhages (~30% of cases) in the general population and the leading cause, alongside hypertension, in those over 70 years of age.

Pathophysiology

There is a progressive accumulation of amyloid protein deposits around the smooth muscle cells of the media and adventitia, leading to the destruction of the muscular layer, architectural disorganization with thickening, and hyaline degeneration of the vessel walls. These abnormalities weaken the vascular wall, leading to microaneurysms, fibrinoid necrosis, and vascular stenoses.

These lesions promote both hemorrhage and ischemia (vascular occlusions).

Classification

Sporadic Aβ forms account for the vast majority of cerebral amyloid angiopathies. Hereditary forms are exceptionally rare and are all autosomal dominant.

• Cerebral Aβ Amyloid Angiopathies
  • Sporadic Forms
    • Affect small and medium-sized arteries, cortical, and leptomeningeal veins, as well as cortical capillaries to a lesser extent.
    • All vascular locations are possible, but white matter and spinal cord vessels are generally relatively spared.
  • Hereditary Forms
    • Dutch Type
    • Flemish Type
    • Italian Type
    • Iowa Type
• Hereditary Cystatin C Cerebral Amyloid Angiopathy (Icelandic Type)
• Gelsolin Amyloidosis (Finnish Familial Amyloidosis Type)
• Transthyretin Cerebral Amyloid Angiopathy (Familial Oculoleptomeningeal Amyloidosis)
• Prion Protein Cerebral Amyloid Angiopathy
• Amyloid Angiopathies of Unknown Biochemical Nature: Worster-Drought Amyloid Angiopathy (British Type), Danish Familial Amyloid Angiopathy, etc.
• Rare Secondary Forms (Systemic Amyloidoses)
  • Neurological manifestations are generally overshadowed by other organ involvement (++ renal involvement).

Recently, amyloid angiopathies have been further divided into non-inflammatory forms and those associated with an inflammatory response ("vasculitic," potentially responsive to immunosuppressive therapy). These inflammatory forms represent a very small minority of cases (though data is limited—potentially underestimated prevalence?).

Clinical Presentation

Cerebral amyloid angiopathies are generally considered asymptomatic (discovered at autopsy).

For symptomatic presentations in sporadic forms:

• Stroke (Often Recurrent)
  • Hemorrhagic
    • Account for ~30% of intraparenchymal hemorrhages (second leading cause) and are the leading cause, alongside hypertension, in those over 70 years of age.
    • Typically occur after age 55.
    • Hemorrhages are often lobar, frequently frontal (despite the posterior predominance of lesions) but can affect all lobes. There is a relative sparing of deep white matter, basal ganglia, and brainstem. Cerebellar hematomas are rare.
    • Possible subarachnoid and/or subdural hemorrhages, either spontaneous or associated with underlying hematomas. Intraventricular hemorrhages are rare.
    • Generally have a favorable spontaneous evolution but pose a high risk of hemorrhagic recurrence if surgical intervention is undertaken.
  • Ischemic
    • Multiple small cortical infarcts and/or transient ischemic attacks.
  • Nonspecific diffuse leukoencephalopathy (due to chronic hypoperfusion?).
    • Rarely present with a "pseudo-tumoral" clinico-radiological form → diagnosis by biopsy; inflammatory amyloid angiopathy should be considered.
    • Rarely present with a clinico-radiological form (symptoms of subacute evolution + asymmetric leukoencephalopathy on FLAIR/T2) suggestive of inflammatory (peri)vascular involvement.
  • Dementia syndromes due to multiple strokes + leukoencephalopathy + significant association with Alzheimer's disease.
    • Exclude central nervous system vasculitis in cases of rapidly progressive dementia.
  • May predispose to partial epileptic seizures.

The occurrence of transient neurological symptoms (transient ischemic attacks, partial epileptic seizures) often precedes or accompanies hematoma formation. A clinical history of subacute cognitive disturbances, chronic headaches, or partial epileptic seizures should prompt consideration of inflammatory amyloid angiopathy.

Additional Examinations

The purpose of imaging is to rule out differential diagnoses, highlight positive diagnostic arguments, and identify any potential inflammatory nature of the lesions.

Biopsy - Pathology

A biopsy confirms the diagnosis of cerebral amyloid angiopathy (CAA) and allows for the exclusion of differential diagnoses. It can reveal the presence of vasculitic infiltrates in inflammatory cerebral amyloid angiopathies (sensitivity/specificity unknown). However, it is rarely performed due to the absence of specific treatment for non-inflammatory forms, a theoretically increased surgical hemorrhagic risk (not proven), advances in brain imaging, and because patients are often elderly and debilitated.

It should be systematically performed in cases of symptomatic surgery for intraparenchymal hemorrhage with clinical suspicion. It should be considered in cases of pseudo-tumoral leukoencephalopathies or when associated with vasculitis.

Injected Cerebral CT-Scan

Main utility: to rule out the main differential diagnoses. It is not very sensitive to micro-hemorrhages. It can show non-specific leukoencephalopathy, lacunar infarcts, and sequelae of lobar hematomas.

Angio-MRI

• Common but non-specific anomalies: cortico-subcortical atrophy, periventricular leukopathy, superficial siderosis.
• Contribution to positive diagnosis: requires a T2*-weighted gradient echo sequence, which is the most sensitive for detecting the presence of diffuse micro-hemorrhages with a cortico-subcortical predominance (= microbleeds, punctate hypointensities of 2 to 5 mm corresponding to hemosiderin-rich macrophage accumulation near small vessels) of varying ages (thus also allowing an estimation of the disease’s progression).
• FLAIR and T2 sequences are useful for identifying white matter abnormalities (++ FLAIR hyperintense areas), essential for characterizing any associated leukoencephalopathy. Asymmetric areas with associated mass effect (obliteration of cortical sulci) suggest inflammatory angiopathy (diffusion sequences showing vasogenic edema provide additional support).

Radiological features suggesting inflammatory angiopathy: lesions involving U-fibers, asymmetric areas with mass effect, leptomeningeal or parenchymal contrast enhancement, vasculitis images (very rare), hyperintense areas on FLAIR/T2 without diffusion restriction, hydrocephalus.

Conventional Arteriography

It is considered a gold standard in the workup but is rarely used (MRI is increasingly efficient, invasive nature of the procedure). It is not useful for positive diagnosis but is valuable for ruling out differential diagnoses (arteriovenous malformations, dural fistula, vasculitis, etc.).

Moreover, even in the subgroup of potentially reversible inflammatory leukoencephalopathies, arteriography rarely shows signs of vasculitis.

PET-CT Scanner

Although not very specific, hypermetabolic images can support a suspicion of the inflammatory nature of the lesions.

Biology and Lumbar Puncture

An elevated ESR in blood tests and/or hyperproteinorachia, pleocytosis, or oligoclonal bands in cerebrospinal fluid testing argue for an inflammatory form.

Diagnosis

In clinical practice, the diagnosis is difficult and relies on a combination of clinical and radiological arguments. Diagnostic criteria have been developed:

• Definite CAA: Autopsy showing cortical or cortico-subcortical lobar hemorrhage + severe amyloid angiopathy + no other diagnosis.
• Probable CAA with Pathological Evidence: Pathology showing cortical or cortico-subcortical lobar hemorrhage + presence of amyloid + no other diagnosis.
• Probable CAA Based on Clinical and MRI Evidence: Patient > 55 years old + multiple cortical or cortico-subcortical lobar hemorrhages + no other diagnosis.
• Possible CAA Based on Clinical and MRI Evidence: Patient > 55 years old + single cortical or cortico-subcortical lobar hemorrhage or unusual location (brainstem, etc.) + no other diagnosis.

These criteria should be considered with caution as they are primarily based on the hemorrhagic manifestations of the disease and do not distinguish inflammatory forms, which are the only real therapeutic concern.

Therapeutic Management - Treatments

There is no specific treatment... in general, the focus is on:

• Controlling vascular risk factors, particularly hypertension, smoking, and dyslipidemia.
• No absolute contraindication but avoid antiplatelets and anticoagulants if possible.
• Traditionally, neurosurgical indications were restricted. However, recent data do not show increased mortality in these patients compared to the general population when hematoma evacuation is performed.
• In case of cognitive impairment: usual paramedical measures (home evaluation by the attending physician, referral to a social worker, etc.).

In selected cases, when an inflammatory component is suspected, a therapeutic trial may be conducted:

• Indications:
  • To be discussed based on a combination of clinical-radiological (exceptionally on the basis of a biopsy) and biological arguments: unexplained inflammatory syndrome, inflammatory cerebrospinal fluid, rapidly progressive dementia, history of seizures, series of closely occurring vascular accidents. Consider also the age and dependency level of the patient (it is generally unrealistic to expect significant improvement in a completely bedridden patient), MRI findings (see above).
• Modalities:
  • Corticosteroid therapy (e.g., 1 g/day IV for 5 days followed by oral therapy), cyclophosphamide, methotrexate.
  • Clinical and/or radiological improvement at 1 month?

Bibliography

Greenberg SM, Cerebral amyloid angiopathy, UpToDate, 2022

Meschia JF et al., Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association, Stroke, 2014 Dec, 45(12):3754-832