Cortical superficial
siderosis is an established haemorrhagic neuroimaging marker of
cerebral amyloid angiopathy. In fact, cortical superficial
siderosis is emerging as a strong independent risk factor for future lobar intracerebral haemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cortical superficial
siderosis remain elusive. Here we use an in vivo MRI, ex vivo MRI, histopathology approach to assess the neuropathological correlates and vascular pathology underlying cortical superficial
siderosis. Fourteen autopsy cases with
cerebral amyloid angiopathy (mean age at death 73 years, nine males) and three controls (mean age at death 91 years, one male) were included in the study. Intact
formalin-fixed cerebral hemispheres were scanned on a 3 T MRI scanner. Cortical superficial
siderosis was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, 11 representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI-defined cortical superficial
siderosis. In addition, samples were taken from predefined standard areas of the brain, blinded to MRI findings. Serial sections were stained for haematoxylin and
eosin and Perls'
Prussian blue, and immunohistochemistry was performed against
amyloid-β and GFAP. Cortical superficial
siderosis was present on ex vivo MRI in 8/14 cases (57%) and 0/3 controls (P = 0.072). Histopathologically, cortical superficial
siderosis corresponded to
iron-positive haemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic
bleeding events originating from the leptomeningeal vessels. Increased severity of cortical superficial
siderosis was associated with upregulation of reactive astrocytes. Next, cortical superficial
siderosis was assessed on a total of 65 Perls'-stained sections from MRI-targeted and untargeted sampling combined in
cerebral amyloid angiopathy cases. Moderate-to-severe cortical superficial
siderosis was associated with concentric splitting of the vessel wall (an advanced form of
cerebral amyloid angiopathy-related vascular damage) in leptomeningeal vessels (P < 0.0001), but reduced
cerebral amyloid angiopathy severity in cortical vessels (P = 0.048). In terms of secondary tissue injury, moderate-to-severe cortical superficial
siderosis was associated with the presence of microinfarcts (P = 0.025), though not microbleeds (P = 0.973). Collectively, these data suggest that cortical superficial
siderosis on MRI corresponds to
iron-positive deposits in the superficial cortical layers, representing the chronic manifestation of
bleeding episodes from leptomeningeal vessels. Cortical superficial
siderosis appears to be the result of predominantly advanced
cerebral amyloid angiopathy of the leptomeningeal vessels and may trigger secondary ischaemic injury in affected areas.