To perform a targeted pathological examination aided by ex vivo MRI in the second reported case of the Piedmont form of hereditary cerebral amyloid angiopathy (CAA).

Patients with CAA often present with hemorrhagic lesions, including symptomatic intracerebral hemorrhages and silent cortical microbleeds, and microinfarcts. However, mechanisms of small and large blood vessel rupture remain largely undetermined. Hereditary forms of CAA associated with mutations in amyloid precursor protein (APP) have provided important insights into mechanisms underlying deposition of β-amyloid in cerebral vessels and mechanisms of brain injury.

A 62-year-old woman with a family history of intracerebral hemorrhages presented with multiple large lobar hemorrhages in rapid succession. She had no cognitive impairment and quickly returned to her baseline after each intracerebral hemorrhage until her terminal event. She was found to have a mutation in the β-amyloid coding sequence of APP (Leu705Val), termed the Piedmont type mutation.

Pathological examination revealed severe CAA mainly involving the leptomeningeal vessels and, to a far lesser extent, cortical vessels, with no amyloid plaques or neurofibrillary tangles. Ex vivo MRI scans of an intact hemisphere revealed 51 cortical microbleeds, and targeted pathological examination of these regions demonstrated that vessels associated with cortical microbleeds did not contain β-amyloid, similar to findings in prior studies of sporadic CAA. Our examination also suggested the presence of fewer chronic microinfarcts than in sporadic CAA. Each identified microinfarct had an associated feeding vessel with severe β-amyloid deposition. 

The leptomeningeal pattern of β-amyloid deposition coupled with multiple large hemorrhages demonstrated by this individual with Piedmont type hereditary CAA suggest an association between leptomeningeal CAA and larger intracerebral hemorrhages. The finding of fewer microinfarcts than in sporadic CAA appeared to result from the relative lack of β-amyloid within cortical vessels. We hypothesize that this pattern may contribute to cognitive sparing in Piedmont type hereditary CAA.