The role of Arteriolosclerosis in Cerebral Amyloid Angiopathy – shedding light on the understudied role of white matter vasculopathy in a cortical vascular pathology

• Applicant: Dr. Johanna Rotta
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564272236

The proposed project aims to investigate the role of arteriolosclerosis in the context of cerebral amyloid angiopathy. Cerebral amyloid angiopathy (CAA) is one of the most common forms of cerebral small vessel disease. In patients with CAA, cortical and leptomeningeal vessels are affected by the deposition of amyloid beta. It is one of the leading causes of intracerebral hemorrhage, a condition that leads to high morbidity and disability in its survivors. There is currently no effective treatment option for CAA. Arteriolosclerosis is another pathology of the brain’s small vessels that can cause intracerebral bleeding. It manifests as thickening of the wall of the smallest arterial vessels in the brain, the arterioles, which then leads to a reduction of the vessel’s lumen. Arteriolosclerosis is a common condition in the elderly and associated with arterial hypertension. Both brain pathologies have been attributed to different parts of the human brain: While cerebral amyloid angiopathy is found in cortical brain regions, arteriolosclerosis has been described in the region below the cortex, the white matter. Paradoxically, CAA also leads to white matter injury, an area far away from the deposition of amyloid beta. These white matter injuries occur as much as 10 to 15 years before the brain hemorrhages in CAA and are strongly linked to cognitive impairment. Arteriolosclerosis and CAA can co-occur. Still, the role of arteriolosclerosis in the development of white matter injury in CAA has not yet been studied. This project aims to close this knowledge gap by characterizing arteriolosclerosis and its relationship with amyloid beta deposition/CAA and white matter injury. By doing so, early biomarker of CAA disease progression and potential therapeutic targets to prevent cognitive impairment and intracerebral hemorrhage could be identified. To achieve this aim, we will, 1) use advanced in vivo magnetic resonance imaging (MRI) to assess presence and severity of arteriolosclerosis and its effect on white matter injury in patients with and without CAA. 2) assess the severity of arteriolosclerosis and its relationship with white matter injury histopathologically on brain autopsy samples of CAA patients and controls 3) demonstrate the presence of CAA and arteriolosclerosis in different portions of the same vessel using three dimensional histology. We hypothesize that arteriolosclerosis is highly prevalent in the subcortical white matter of CAA patients and that it induces white matter injury.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Valentina Perosa, Ph.D.