Reduced Cerebrovascular CO ₂ Reactivity in CADASIL

Abstract

Background and Purpose-Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in Notch3. Cerebral microvessels show an accumulation of granular osmiophilic material in the vicinity of degenerating vascular smooth muscle cells. To study cerebrovascular function in CADASIL, we performed measurements on cerebral hemodynamics by using transcranial Doppler sonography. Methods-Middle cerebral artery (MCA) mean blood flow velocity (MFV), cerebrovascular CO 2 reactivity, and the resistance index were measured by bilateral transcranial Doppler sonography in 29 CADASIL individuals (mean age, 49.0Ϯ2.4 years) and an equal number of age-and sex-matched control subjects. T he clinical, pathological, and genetic spectrum of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) has recently been characterized by several comprehensive studies. 1-8 Clinical manifestations include recurrent ischemic episodes (TIAs and strokes) (70% to 80%), cognitive deficits (30% to 50%), and migraine (20% to 40%), mostly with aura, as well as psychiatric disorders (20% to 30%) and epileptic seizures (6% to 10%). 1-3 Onset of ischemic symptoms is usually in mid adulthood. [1][2][3] MRI reveals a microangiopathic pattern of signal abnormalities: diffuse white matter T2-signal hyperintensities and small cystic lesions compatible with lacunes. 4 These changes are caused by a distinctive angiopathy characterized by granular osmiophilic material within the vascular basal membrane, often located in close contact with degenerating vascular smooth muscle cells (VSMC). 6,9 The disease is caused by mutations within the Notch3 gene. 10 Notch3 codes for a large transmembrane receptor that is physiologically expressed in VSMC. In the brains of CADASIL patients there is a dramatic accumulation of the extracellular domain of Notch3 within arteries, capillaries, and venules. This accumulation takes place at the cell surface of VSMC. 11 So far, information on microvascular function and hemodynamic parameters in CADASIL is limited. Using SPECT, Mellies et al 12 found a reduction of cerebral blood flow (CBF) that correlated with the amount of MRI white matter abnormalities. Chabriat et al 13 used PET to study 2 CADASIL individuals (1 asymptomatic, 1 demented). CBF was reduced both in the symptomatic case and the asymptomatic case, thus suggesting a role of CBF reduction early in the disease. Results-ComparedTo investigate microvascular function in CADASIL, we studied 3 hemodynamic parameters by using transcranial Doppler sonography (TCD): CO 2 reactivity, middle cerebral artery (MCA) mean blood flow velocity (MFV), and resistance index (RI). range, 20 to 84 years) were enrolled into this study. CADASIL individuals were derived from 21 families. In all CADASIL cases, the diagnosis had been confirmed by the identification of a mutation in the Notch3 gene (nϭ24) or by skin biopsy (nϭ14). 7,8,14,15 All CADASIL individuals received a ...

Arterial Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Relation to Pathogenesis of Diffuse Myelin Loss of Cerebral White Matter

“…10 The pathological findings of the white matter of this case, such as the diffuse myelin loss and atrophy with mild gliosis and sparing of the subcortical U fibers and no evidence of leukodystrophy, are also compatible with this deduction. The significance of arterial SMC loss with respect to hemodynamic derangement in CADASIL is supported by the reduced cerebrovascular CO 2 reactivity associated with this disease 11 ; it has been shown that CO 2 reactivity is significantly lower in disabled than in nondisabled CADASIL individuals. This suggests that the severity and extent of SMC loss in the cerebral arteries progress at the shift from the nonsymptomatic to the symptomatic state.…”

“…This suggests that the severity and extent of SMC loss in the cerebral arteries progress at the shift from the nonsymptomatic to the symptomatic state. In addition, it has been reported that there is a reduction in blood flow to the cerebrum 4 and in the middle cerebral artery 11 in CADASIL, but these findings may merely reflect the final devastated state of the brain. Cerebrovascular reactivity to fluctuations not only in CO 2 but also in systemic blood pressure during the clinical course of CADASIL should be examined further.…”

Consensus statement for diagnosis of subcortical small vessel disease

“…46 Functional neuroimaging studies have provided evidence of compromised cerebral hemodynamics in CADASIL patients; studies of cerebrovascular reactivity, as determined by measurement of CBF changes after exposure to inhaled CO 2 or injected acetazolamide, indicate that cerebral blood vessels are dysfunctional in CADASIL patients. 70,71 Notably, an association was reported between a lower cerebrovascular reactivity at baseline and a larger increase in WMHs at follow-up, suggesting a role for impaired cerebrovascular reactivity in progression of whitematter lesions. Positron emission tomography studies have documented a significant decrease in CBF in the white matter, consistent with a chronic ischemia of white matter or decreased demand for oxygen and blood supply consequent upon having fewer normal cells to supply.…”

Characteristic Features of in vivo Skin Microvascular Reactivity in CADASIL

“…At the cerebral level, they are presumably responsible for a decrease in basal perfusion and reduction of hemodynamic reserve (Chabriat et al, 2000;Pfefferkorn et al, 2001). In vitro, abnormal vasoconstrictor responses to angiotensin II and noradrenaline have been detected in arteries of CADASIL patients (Hussain et al, 2004).…”