Diagnosis, pathomechanisms and therapy of cerebral amyloid angiopathy-related inflammation (CAA-ri)

Research of the past years has refined our perception of cerebral amyloid angiopathy-related inflammation (CAA-ri) as a subacute autoimmune encephalopathy, which is presumably caused by elevated CSF concentrations of anti-amyloid β (Aβ) autoantibodies. A broad understanding of the pathophysiological mechanisms and diagnostic criteria of CAA-ri may lay the foundation for improved immunosuppressive treatment of the disease.

Spontaneous CAA-ri mainly occurs in elderly patients but might also be evoked iatrogenically by modern treatment with amyloid-modifying therapies in Alzheimer's disease (AD). On a histopathological level, CAA-ri is characterized by microglial activation and the formation of vasogenic edemas. Clinically, the disease frequently presents with progressive cognitive decline, focal neurological deficits, headache and epileptic seizures. While brain biopsy has formerly represented the gold standard in the diagnosis of CAA-ri, its importance has been increasingly replaced by clinical as well as radiological diagnostic criteria and the relevance of anti-Aβ autoantibodies in the CSF of affected patients. Though relevant progress has been achieved in immunosuppressive treatment of CAA-ri, the protocols lack standardization as well as decision criteria for the choice of the respective immunosuppressive agent.

CAA-ri gains increasing interest as a spontaneous human model of iatrogenic edematous amyloid-related imaging abnormalities (ARIA-E) in the context of amyloid-modifying therapies. In near future, screening of AD patients for the presence of CAA-ri using CSF anti-Aβ autoantibodies might play a decisive role in the risk stratification as well as dosage finding of amyloid-modifying therapies, as they show high specificity for CAA-ri. The clinical and radiological diagnostic criteria by Auriel et al. allow diagnosis of probable resp. possible CAA-ri with high accuracy. Though only tested in small, specialized patient cohorts to date, additional imaging modalities (¹¹C-PK11195 PET) might play a future role in the clinical monitoring of CAA-ri. Therapy of CAA-ri frequently encompasses initial steroid treatment, whereby different schemes, dosages as well as substances are used. Choice of immunosuppressive agents with higher potency still requires objective decision criteria, which should be established in future studies involving larger CAA-ri patient cohorts.