Neuropathological correlates of cortical superficial siderosis in cerebral amyloid angiopathy

Abstract

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.

Recurrent Lobar Hemorrhages and Multiple Cortical Superficial Siderosis in a Patient of Alzheimer's Disease With Homozygous APOE ε2 Allele Presenting Hypobetalipoproteinemia and Pathological Findings of 18F-THK5351 Positron Emission Tomography: A Case Report

“…These findings suggest that 18 F-THK5351 accumulates in lesions where astrogliosis occurs and that 18 F-THK5351 PET can be an imaging modality to visualize and quantify astrogliosis, as recently demonstrated in patients with a cerebral infarction or neurological disorders ( 49 – 51 ). In our case, 18 F-THK5351 retentions were observed in some, but not all, regions with cSS, presumably because this effect might depend on severity of cSS and the degree of astrogliosis that is correlated with the extent of hemosiderin deposition ( 52 ). 18 F-THK5351 retentions were observed only in some areas rather than all peripheral regions at the lobar hemorrhage in this patient.…”

Micro-MRI improves the accuracy of clinical diagnosis in cerebral small vessel disease

“…This result was in line with those of a recent cSS study. 24 However, some unique findings were revealed in our patient. A bilinear track-like appearance of the cSS on the ex vivo MRI was compatible with iron deposition on the pia matter and within cortical layers II–III.…”

Deep learning assisted quantitative assessment of histopathological markers of Alzheimer’s disease and cerebral amyloid angiopathy

“…The reliability of the Aβ and iron models were assessed by comparing the AI-assisted quantitative measures (percentage area of cortical and leptomeningeal CAA, percentage area of cortical parenchymal Aβ-plaques, and density of cortical iron positive cells) with previously obtained semiquantitative scores [ 10 , 31 ]. For this purpose, a subset of 68 sections were used, derived from a total number of 17 CAA and non-CAA cases (7 females, 10 males; mean age at death [standard deviation] 76.53 [10.10] years) from the MGH cohort (see [ 11 ] for more details). These sections included standard sampled areas from the frontal, parietal, temporal, and occipital lobes.…”

“…Other histopathological observations, such as iron deposition (indicative of hemorrhage and siderosis) [ 7 , 9 ], reactive astrocytes and microglia (indicative of neuroinflammation) [ 19 ], and fibrin accumulation in the walls of small vessels and surrounding cells (indicative of blood–brain-barrier [BBB] leakage) [ 12 , 16 ] are also crucial to understand complex disease mechanisms. These markers have so far mainly been quantified using visual semiquantitative scores [ 11 ] or manual count [ 15 , 32 ]. Even when the scores are well-defined and their reliability assessed by inter-rating [ 32 ], they remain subjective and time-consuming to standardize across centers [ 24 ].…”