SPECT study of a German CADASIL family

Mellies, J. K.; Bäumer, Tobias; Muller, J; Tournier‐Lasserve, Elisabeth; Chabriat, Hugues; Knobloch, O.; Hackelöer, H. J.; Goebel, Hans H.; Wetzig, L.; Haller, Peter

doi:10.1212/wnl.50.6.1715

Cited by 66 publications

(43 citation statements)

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“…36 Assuming a constant diameter of the MCA, the MFV reduction in our CADASIL cases may essentially reflect reduced CBF. In fact, a reduction of CBF has been suggested recently by SPECT, 12 PET, 13 and MRI studies 20 in CADA-SIL. It seems reasonable to assume that the changes in MFV and CBF are related to the morphological alterations within small blood vessels, in particular small arteries and capillaries.…”

Section: Discussionmentioning

confidence: 96%

Reduced Cerebrovascular CO ₂ Reactivity in CADASIL

Pfefferkorn

Stuckrad-Barre

Herzog

et al. 2001

Stroke

113

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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 ...

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Section: Discussionmentioning

confidence: 96%

Reduced Cerebrovascular CO ₂ Reactivity in CADASIL

Pfefferkorn

Stuckrad-Barre

Herzog

et al. 2001

Stroke

113

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 However, there are some phenocopies in which such a mutation is not recognized but in which deposition of GOM has been noted pathologically. 4 Therefore, the origin of CADASIL seems to be genetically heterogeneous. Neuropathologically, diffuse myelin loss, atrophy of the cerebral white matter with sparing of the subcortical U fibers, and small infarcts in the subcortical gray matter are all characteristic of CADASIL but not specific to it; these pathological signs are also seen in association with acute carbon monoxide poisoning, a potential hazard of general anesthesia such as in accidents of artificial ventilation, amyloid angiopathy, and Binswanger's disease.…”

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confidence: 99%

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

Okeda

Arima

Kawai

2002

Stroke

104

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Background and Purpose-There is little information regarding the pathogenesis underlying diffuse myelin loss in the cerebral white matter and sparing of the U fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of systemic arteries are characteristically involved. We sought to examine the precise extent and severity of changes in the cerebral arteries in an autopsy case of CADASIL in relation to pathogenesis of the diffuse myelin loss. Methods-We reconstructed 1000 serial sections of the frontal cerebral medullary arteries of an autopsy subject, which was the first identified Japanese case of CADASIL, as confirmed by the presence of ultrastructural deposits of granular osmiophilic material in the media of some visceral arteries and by genetic analysis. Results-We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin loss and atrophy of the white matter with sparing of the U fibers. All of these showed complete loss of medial smooth muscle cells over their entire length and severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present, luminal occlusion was scarce. These changes were also observed in the small and large arachnoidal arteries but were relatively mild in the latter and in the cortical and subcortical medullary arteries. Conclusions-These arterial changes resulted in transformation of the cerebral arteries, in particular almost all the medullary arteries, to a so-called earthen pipe state. This supports the reported findings of a reduction in vascular reactivity to fluctuations in CO 2 levels and systemic blood pressure in CADASIL.

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“…A reduction of cerebral blood flow (CBF) has been documented in the cortex and white matter in CADASIL patients using PET (31), SPECT (32), and MRI bolus tracking (33). We measured resting CBF in awake TgNotch3 R169C mice and control TgNotch3 WT and nontransgenic littermate mice by quantitative autoradiography using a diffusible radiolabeled tracer, which provides a measure of local tissue perfusion through brain microvascularization (Supplemental Figure 6 and Supplemental Table 1).…”

Section: Figurementioning

confidence: 99%

Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease

Joutel¹,

Monet-Leprêtre²,

Gösele³

et al. 2010

J. Clin. Invest.

310

380

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Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Dominant mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic archetype of cerebral ischemic SVD. Progress toward understanding the pathogenesis of this disease and developing effective therapies has been hampered by the lack of a good animal model. Here, we report the development of a mouse model for CADASIL via the introduction of a CADASIL-causing Notch3 point mutation into a large P1-derived artificial chromosome (PAC). In vivo expression of the mutated PAC transgene in the mouse reproduced the endogenous Notch3 expression pattern and main pathological features of CADASIL, including Notch3 extracellular domain aggregates and granular osmiophilic material (GOM) deposits in brain vessels, progressive white matter damage, and reduced cerebral blood flow. Mutant mice displayed attenuated myogenic responses and reduced caliber of brain arteries as well as impaired cerebrovascular autoregulation and functional hyperemia. Further, we identified a substantial reduction of white matter capillary density. These neuropathological changes occurred in the absence of either histologically detectable alterations in cerebral artery structure or blood-brain barrier breakdown. These studies provide in vivo evidence for cerebrovascular dysfunction and microcirculatory failure as key contributors to hypoperfusion and white matter damage in this genetic model of ischemic SVD.

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SPECT study of a German CADASIL family

Abstract: We describe a CADASIL phenotype that is characterized by the absence of focal neurologic symptoms and present the first SPECT study of this disorder.

Cited by 66 publications

References 0 publications

Reduced Cerebrovascular CO ₂ Reactivity in CADASIL

Reduced Cerebrovascular CO ₂ Reactivity in CADASIL

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

Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease

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SPECT study of a German CADASIL family

Abstract: We describe a CADASIL phenotype that is characterized by the absence of focal neurologic symptoms and present the first SPECT study of this disorder.

Cited by 66 publications

References 0 publications

Reduced Cerebrovascular CO 2 Reactivity in CADASIL

Reduced Cerebrovascular CO 2 Reactivity in CADASIL

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

Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease

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Reduced Cerebrovascular CO ₂ Reactivity in CADASIL

Reduced Cerebrovascular CO ₂ Reactivity in CADASIL