Small Vessel Diseases of the Brain Hereditary causes of Hemiparesis

Background Hereditary, unrelated to arteriosclerosis or hypertensive disease Cerebral autosomal dominant ateriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form Leads to cognitive decline and dementia from multiple small ischaemic lesions and lacunar infarcts Yamamoto Y, Craggs L, Baumannt M, Kalimo H, Kalaria RN. Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathology and Applied Neurobiology. 2011;37:94-113.

Pathophysiology Mutation in one of 4 different genes: NOTCH3, HTRA1, TREX1, COL4A1 Sucortical lesions Diffuse white matter changes Lacunes Microinfarction Yamamoto Y, Craggs L, Baumannt M, Kalimo H, Kalaria RN. Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathology and Applied Neurobiology. 2011;37:94-113.

Pathophysiology continued… Affects intracerebral small vessels including: arteries, arterioles, capillaries, and small veins Arteriolar narrowing Thickened arterial walls with fibrosis Accumulation of eosinophilic material Pericyte degeneration Loss of vascular smooth muscle cells Arterial changes lead to reduction in cerebral blood flow and blood volume in affected areas Yamamoto Y, Craggs L, Baumannt M, Kalimo H, Kalaria RN. Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathology and Applied Neurobiology. 2011;37:94-113.

Signs & Symptoms Mean age of onset (first stroke) is 46 y/o May be preceded by migraines Cognitive changes: deficits in attention, processing speed, and executive function Dementia by the sixth decade of life Prognosis for disability and death worse for men > women by 6 years Yamamoto Y, Craggs L, Baumannt M, Kalimo H, Kalaria RN. Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathology and Applied Neurobiology. 2011;37:94-113.

Diagnostic tests and Imaging T2 weighted MRI Neuroimaging Yamamoto Y, Craggs L, Baumannt M, Kalimo H, Kalaria RN. Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathology and Applied Neurobiology. 2011;37:94-113.

Small vessel disease compared to large vessel disease Reference: Yamamoto Y, Craggs L, Baumannt M, Kalimo H, Kalaria RN. Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathology and Applied Neurobiology. 2011;37:94-113.

Types of Small Vessel Disease with hemiplegia Hereditary Small Vessel Disease of the Brain (SVDB) – Autosomal Dominant - Age of onset: 36-52 y/o - Duration of disease: > 5 years - Key clinical features: Hemiplegia, motor and sensory deficits, memory impairments - Neuroimaging findings: diffuse white matter changes, deep cerebral infarcts, degeneration of pyramidal tract, and multiple micro bleeds Reference: Yamamoto Y, Craggs L, Baumannt M, Kalimo H, Kalaria RN. Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathology and Applied Neurobiology. 2011;37:94-113.

Types of Small Vessel Disease with hemiplegia COL4A1-related disorder (stroke syndrome) – Autosomal dominant - Age of onset: 14-49 y/o - Duration of disease: > 8 years - Key clinical features: infantile hemiparesis, migraines, intracerebral hemorrhages, seizures, Raynaud phenomenon, dementia - Neuroimaging findings: diffuse white matter changes, dilated perivasular changes, subcortical infarcts, microbleeds, and absence of porencephaly cavities Reference: Yamamoto Y, Craggs L, Baumannt M, Kalimo H, Kalaria RN. Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathology and Applied Neurobiology. 2011;37:94-113.