Quantitative MRI in CADASIL

Dichgans, Martin; Filippi, Massimo; Brüning, R.; Iannucci, Giuseppe; Berchtenbreiter, Christian; Minicucci, L.; Uttner, Ingo; Crispin, Alexander; Ludwig, Harald; Gasser, Thomas; Yousry, Tarek

doi:10.1212/wnl.52.7.1361

Cited by 105 publications

(62 citation statements)

References 27 publications

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“…Both deletions are predicted to result in the loss of one cysteine residue. In conjunction with the missense mutations reported here and previously 17,22,23 these deletions substantiate the pivotal role of an odd number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of this disorder. The mechanisms by which mutations in CADASIL become pathogenic are currently unknown.…”

Section: Discussionsupporting

confidence: 86%

“…This adds to previous clinical and neuroimaging evidence indicating, that the Notch3 genotype has no major influence on the phenotype. 3,22 In conclusion we have found a number of new mutations including two small in-frame deletions. These deletions are relevant in that they substantiate the pivotal role of an odd number of cysteine residues within EGF-like repeat domains in the pathogenesis of CADASIL.…”

Section: Discussionmentioning

confidence: 70%

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Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3v EGF-like repeat domains

Dichgans¹,

Ludwig²,

Müller‐Höcker

et al. 2000

Eur J Hum Genet

113

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CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 70%

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3v EGF-like repeat domains

Dichgans¹,

Ludwig²,

Müller‐Höcker

et al. 2000

Eur J Hum Genet

113

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“…Similarly, there was a strong correlation between age and volume of lesions appearing hyperintense on dual-echo scans, as expected from previous studies. 35,36 In contrast, there was no significant correlation between the number of MBs and volume of lesions when age is introduced as a covariate. These findings are in keeping with the chronic nature of the underlying angiopathy and its proposed role in causing 2 largely independent complications: ischemic lesions and petechial hemorrhages.…”

Section: Dichgans Et Al Cerebral Microbleeds In Cadasil 69mentioning

confidence: 83%

Cerebral Microbleeds in CADASIL

Dichgans

Holtmannspötter

Herzog

et al. 2002

Stroke

241

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Background and Purpose-An increased frequency of clinically silent microbleeds (MB) has recently been observed in patients with sporadic small-vessel disease related to vascular amyloid deposition or hypertension. In this study, we searched for cerebral MBs in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a unique type of small-vessel disease caused by mutations in the Notch3 gene. Our purposes were (1) to determine the frequency, extent, and pattern of MBs in CADASIL; (2) to analyze the relationship between MBs and T2-hyperintense lesions; and (3) to evaluate the histopathology of brain tissue affected by MBs. Methods-Gradient-echo, T2/PD-weighted dual-echo, and T1-weighted MRI scans of the brain were obtained from 16 consecutive CADASIL subjects and 16 age-matched control subjects. T2-lesion volume measurements were made with a semiautomated segmentation technique based on local thresholding. Postmortem examinations were performed on the brains of 7 additional CADASIL subjects. Results-Focal areas of signal loss on gradient-echo images suggesting past MBs were found in 11 CADASIL individuals (69%) and no control subjects (PϽ0.001). The average number of MBs was 5.9Ϯ7.3 (range, 0 to 22) in individual CADASIL patients. MBs were associated with age (rϭ0.71, Pϭ0.002) and total lesion volume (rϭ0.75, Pϭ0.001). However, after correction for age, the correlation with lesion volume was no longer significant. MBs were located simultaneously in various parts of the brain with a preference for cortical-subcortical regions (38%), white matter (20%), thalamus (13%), and brainstem (14%). Eighty-two percent of the MBs were located outside areas appearing hyperintense on T2-weighted images. Postmortem examination revealed focal accumulations of hemosiderin-containing macrophages in 6 of the 7 brains (86%). They were always found outside ischemic lesions. Key Words: angiopathy Ⅲ CADASIL Ⅲ echo-planar imaging Ⅲ intracerebral hemorrhage C erebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease of small blood vessels caused by mutations in the Notch3 gene. 1,2 Clinical manifestations include recurrent ischemic episodes, cognitive deficits, and migraine mostly with aura, as well as psychiatric disorders. 3,4 There have been single reports of intracerebral hemorrhages (ICHs), 5,6 but the meaning of these observations remains unclear given the absence of ICH in large patient series. 3,4 MRIs show lacunar infarcts and less well demarcated subcortical T2 hyperintensities that may show different degrees of hypointensity on T1-weighted scans. 7-9 These alterations are caused by a unique type of nonarteriosclerotic, amyloid-negative angiopathy involving small arteries and capillaries primarily in the brain but also in other organs. 10 Ultrastructural examination reveals characteristic granular osmiophilic material within the vascular basal lamina, which is often seen in close association with vascular smooth muscle ...

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“…7,11 Although areas of hypointense signal on T1-weighted images correspond to areas where demyelination, axonal loss, and prominent reactive gliosis have occurred, 44 the assessment of these abnormalities is highly operator dependent and does not provide a quantitative measure of tissue damage within individual lesions. On the contrary, MTR is a quantitative and operator-independent measure, which has been shown to correlate strongly with the degree of axonal and myelin loss.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Such arteriopathic changes have been documented in virtually all organs of patients with CADASIL, but they are more pronounced in the brain, where they can result in small circumscribed subcortical infarcts and confluent areas of diffuse white matter abnormalities. 4 As shown by a number of MRI studies, [5][6][7][8][9][10][11] conventional T2-weighted scans of the brain are very sensitive in detecting the presence of such lesions in the brain from individuals with CADASIL. However, conventional MR scanning allows only limited quantification of the degree of tissue destruction.…”

mentioning

confidence: 99%

Correlations Between Clinical Findings and Magnetization Transfer Imaging Metrics of Tissue Damage in Individuals With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Iannucci

Dichgans

Rovaris

et al. 2001

Stroke

Self Cite

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Background and Purpose-We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance. Methods-Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced. Results-All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment. Conclusions-PD

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Quantitative MRI in CADASIL

Abstract: This study demonstrates correlations between MRI lesion volume and clinical characteristics in CADASIL. Longitudinal studies are now warranted to investigate whether quantitative MRI could be used as an adjunct outcome measure in future therapeutic trials in CADASIL.

Cited by 105 publications

References 27 publications

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3v EGF-like repeat domains

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3v EGF-like repeat domains

Cerebral Microbleeds in CADASIL

Correlations Between Clinical Findings and Magnetization Transfer Imaging Metrics of Tissue Damage in Individuals With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

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