High Frequency Imaging in Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is defined as the deposition of β-amyloid in the walls of small cortical cerebral vessels. It is very common in the elderly population with prevalence rates up to 60% and is associated with Alzheimer´s disease. Intracerebral lobar macrohemorrhages (ICH) are the most devastating presentation of CAA and the main cause of morbidity and mortality. In addition to developing clinically manifest strokes, CAA patients may also suffer from transient neurological symptoms and progressive cognitive impairment ultimately resulting in dementia.

Apart from ICH, typical MRI signs of CAA include multiple cerebral microbleeds (CMB) in a cortical-subcortical localization, white matter hyperintensities on T2-weighted images and supratentorial cortical superficial siderosis (cSS). Main risk factors for recurrence of CAA-related ICH are apolipoprotein E ε2 or ε4 alleles, previous ICHs and CMB on follow-up imaging. Recently, cSS emerged as an additional, major independent risk factor for ICH and disability.

In CAA, siderosis affects the convexity of the cerebral hemispheres, and thus is termed cortical superficial siderosis (cSS). This is in contrast to infratentorial superficial siderosis, which is not linked to CAA. CSS is likely caused by recurrent non-traumatic, focal convexity subarachnoid hemorrhages (fSAH). There are causes of fSAH and cSS other than CAA, and these causes seem to vary depending on age: in younger patients (< 60 years of age) fSAH and cSS are most commonly seen in the context of trauma, vasculitis and reversible cerebral vasoconstriction syndrome, while CAA seems to be the by far most common cause in subjects above 60 years of age. cSS is common (> 60%) in patients with histologically proven CAA, and may be the only hemorrhagic imaging sign on MRI.

Lesions on diffusion-weighted imaging, i.e. areas of restricted diffusion, are a very frequent finding in CAA. These diffusion restrictions can be found in 25% to 50% of CAA patients when performing a single MRI. One recent study even suggests a spatial relationship with cSS. The clinical significance of these lesions is not yet fully established. The most likely pathophysiology behind these lesions is acute ischemia, or to be more precise cytotoxic edema after brain ischemia/infarction. However, subcortical infarcts as detected through a diffusion-restricted lesion can have vastly different fates, ranging from disappearance to complete brain tissue loss (cavitation). An important step in the understanding of these lesions is the precise estimation of prevalence and tissue consequences. A critical point in this endeavour is that these diffusion restricted lesions are typically only visible for a few weeks. Thus, they can remain completely undetected in studies using conventional study designs with follow-up intervals as long as 6 months, one year or even longer.

While small subcortical and cortical ischemic lesions (detectable as diffusion restrictions) are a common finding in CAA patients, their exact prevalence and relevance for disease progression are unclear. Overall, temporal dynamics of the processes leading to hemorrhagic and ischemic manifestations of CAA as well as their interrelationships are insufficiently understood. These critical aspects can be addressed by a novel study design with serial, monthly magnetic resonance imaging. The study design is inspired by a recent high-frequency serial imaging study in patients with sporadic, non-amyloid cerebral small vessel disease conducted at Nijmegen (Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort - Investigating The origin and Evolution of cerebral small vessel disease, RUN DMC - InTENse).

The primary aim of this study is to prospectively evaluate the development and temporal evolution of incident and prevalent fSAH \& cSS in CAA patients.

Secondary aims are i) to assess the monthly incidence of acute ischemic lesions (diffusion restrictions) in CAA patients with cSS/fSAH and to compare the incidence with lobar ICH survivors, and ii) to assess the inter-relationship between hemorrhagic lesions (fSAH/cSS/CMB) and acute ischemic lesions as well as the association between these lesions and cerebrovascular event rates and functional status.