CADASIL - Molecular and Cellular Mechanisms

CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene and the most common monogenic cause of stroke and vascular dementia. CADASIL has evolved as a unique 'model' to study stroke mechanisms in small vessel disease and vascular dementia. Our research focuses on interventional and MR-imaging studies investigating the structural and functional correlates underlying vascular cognitive impairment. Another main focus is on the molecular and cellular mechnisms underlying CADASIL and includes work in animal models. This work involves strong collaborations with other research groups in Munich.

Projects

Transgenic Mouse Models
Aggregation properties of wt and mutant Notch3 Receptor (in vitro studies)
Antiapoptotic effects of Notch3
Genetic Modifyers in CADASIL
Structural and Functional Correlates underlying Vascular Dementia (see Imaging)

Diagnostics

We offer molecular genetic testing by direct sequencing of the NOTCH3-gene. We further offer Ultrastructural examination of skin biopsy samples for vascular osmiophilic deposits which are specific for CADASIL and therefore diagnostic. Before sending (blood or biopsy) samples, please contact us for further details (sample processing etc.). The respective forms can be downloaded from this website (Diagnostik).

Background on CADASIL

NOTCH3 encodes a cell surface receptor, which has a role in arterial development and is expressed on vascular smooth muscle cells. The Notch3 receptor is a hetero-dimer composed of a large extracellular fragment and a smaller transmembrane intracellular fragment. Mutations are greatly stereotyped in that most if not all mutations change the number of cysteine residues within one of the extracellular epidermal-growth-factor-like repeat domains. There have been single reports on mutations not involving cysteine residues but the role of these sequence variants remains controversial. The mutational spectrum is broad. About 95% of the patients have missense mutations which cluster in exons 3 to 6. Preliminary evidence suggests that some mutations are associated with a slightly more aggressive phenotype. In general, however, the genotype seems to have no major influence on the phenotype. The mechanisms by which NOTCH3 mutations become pathogenic are still poorly understood. Most mutations do not seem to interfere with Notch3 receptor signalling. However, studies in patients and transgenic mice have shown that the mutant Notch3 receptor accumulates in arteries and precapillaries. Electron microscopy shows granular osmiophilic deposits within the vascular basal lamina, which are specific for CADASIL, present throughout the arterial system and can therefore be used for diagnostic purposes. An important observation has been that the clinical course and MRI findings may vary from relatively benign to very severe. Recent evidence suggests that variations in disease severity are due to a modifying influence of genetic factors distinct from the causative NOTCH3 mutation.

Team Members

Recent Publications

Opherk C, Duering M, Peters N, Karpinska A, Rosner S, Schneider E, Bader B, Giese A, Dichgans M. CADASIL mutations enhance spontaneous multimerization of NOTCH3. Hum Mol Genet. 2009 Aug 1;18(15):2761-7

Dichgans M. Cognition in CADASIL. Stroke. 2009 Mar;40(3 Suppl):S45-7. Epub 2008 Dec 8.

Peters N, Freilinger T, Opherk C, Pfefferkorn T, Dichgans M. Enhanced L-arginine-induced vasoreactivity suggests endothelial dysfunction in CADASIL. J Neurol. 2008 Aug;255(8):1203-8

References (1998-2008)

Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731-9. Pubmed

Dichgans M, Ludwig H, Muller-Hocker J, Messerschmidt A, Gasser T. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000;8:280-5. Pubmed

Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M. Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study.Stroke. 2001;32:17-21. Pubmed

Dichgans M, Herzog J, Gasser T. NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. Neurology. 2001;57:1714-7. Pubmed

Dichgans M, Holtmannspotter M, Herzog J, Peters N, Bergmann M, Yousry TA. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study. Stroke 2002;33:67-71. Pubmed

Tatsch K, Koch W, Linke R, Poepperl G, Peters N, Holtmannspoetter M, Dichgans M. Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL: an 18F-FDG PET study. J Nucl Med. 2003;44:862-9. Pubmed

Dichgans M. Monogenic causes of stroke. Int Psychogeriatr. 2003;15 Suppl 1:15-22. Pubmed

Peters N, Dichgans M. CADASIL: familiäre Schlaganfälle und subkortikale vaskuläre Demenz. (CADASIL: a monogenic condition causing stroke and subcortical ischemic vascular dementia). Nervenheilkunde 2004;23:86-89.

Peters N, Herzog J, Opherk C, Dichgans M. A two-year clinical follow-up study in 80 CADASIL subjects: Progression patterns and implications for clinical trials. Stroke 2004;35:1603-08. Pubmed

Peters N, Opherk C, Zacherle S, Capell A, Gempel P, Dichgans M. CADASIL associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. Exp Cell Res. 2004;299:454-64. Pubmed

Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain 2004;127:2533-9. Pubmed

Peters N, Bergmann T, Castro M, Opherk C, Herzog J, Dichgans M. Spectrum of mutations in CADASIL. Arch of Neurology 2005; 62:1091-4. Pubmed

Peters N, Opherk C, Danek A, Ballard C, Herzog J, Dichgans M. The pattern of cognitive performance in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Am J of Psych. 2005;162:2078-85. Pubmed

Ragoschke-Schumm A, Axer H, Fitzek C, Dichgans M, Peters N, Meuller-Hocker J, Witte OW, Isenmann S. Intracerebral hemorrhage in CADASIL. J Neurol Neurosurg Psychiatry 2005;76:1606-7. Pubmed

Holtmannspötter M, Peters N, Opherk C, Martin D, Herzog J, Brückmann H, Gschwendtner A, Dichgans M. Diffusion MR Histograms as a Surrogate Marker and Predictor of Disease Progression in CADASIL: a Two-Year Follow-up Study. Stroke 2005;36:2559-65 Pubmed

Peters N, Holtmannspötter M, Opherk C, Gschwendtner A, Herzog J, Sämann P, Dichgans M. Brain Volume Changes in CADASIL: a serial MRI Study in Pure Subcortical Ischemic Vascular Disease. Neurology 2006;66:1517-22. Pubmed

Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black S, Powers WJ, DeCarli C, Merino JG, Kalaria RN, Vinters HV, Holtzmann DM, Rosenberg GA, Dichgans M, Marler JR, LeBlanc G. NINDS-CSN Vascular Cognitive Impairment Harmonization Criteria. Stroke;37(9):2220-41 Pubmed

Opherk C, Peters N, Holtmannspötter M, Gschwendtner A, Müller-Myhsok B, Dichgans M. Heritability of MRI lesion volume in CADASIL: evidence for genetic modifiers. Stroke 2006;37(11):2684-2689 Pubmed

Visnavathan A, Guichard JP, Gschwendtner A, Buffon F, Cumurcuic R, Boutron C, Vicaut E, Holtmannspoetter M, Pachai C. Bousser MG, Dichgans M, Chabriat H. Blood Pressure and HemoglobinA1c are Associated with Microhemorrhage in CADASIL: A Two-Center Cohort Study Brain 2006;129:2375-2383 Pubmed

Jouvent E, Viswanathan A, Mangin JF, O'Sullivan M, Guichard JP, Gschwendtner A, Cumurciuc R, Buffon F, Pachai C, Bousser MG, Dichgans M, Chabriat HC. Brain Atrophy is Related to Lacunar Lesions and Tissue Microstructural Changes in CADASIL. Stroke. 2007 Jun;38(6):1786-90

Viswanathan A, Gschwendtner A, Guichard JP, Buffon F, Cumurciuc R, O'Sullivan M, Holtmannspötter M, Pachai C, Bousser MG, Dichgans M, Chabriat H. Lacunar lesions are independently associated with disability and cognitive impairment in CADASIL. Neurology. 2007 Jul 10;69(2):172-9.

Collaborators

H. Chabriat, Paris, Frankreich
H. Markus, London, Großbritannien
C. Haass/A. Capell, Adolf-Butenandt-Institut (SFB596), München
S. Greenberg, Boston, USA
W. Wurst, Max-Planck-Institut für Psychiatrie (SFB 596), München
P. Breuer, Max-Planck-Institut für Biochemie, Martinsried