CADASIL Patients Research Articles

The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients.

Mutations in Notch3 cause CADASIL (cerebral autosomal dominant adult onset arteriopathy), which leads to stroke and dementia in humans. CADASIL arteriopathy is characterized by major alterations of vascular smooth muscle cells and the presence of specific granular osmiophilic deposits. Patients carry highly stereotyped mutations that lead to an odd number of cysteine residues within EGF-like repeats of the Notch3 receptor extracellular domain. Such mutations may alter the processing or the trafficking of this receptor, or may favor its oligomerization. In this study, we examined the Notch3 expression pattern in normal tissues and investigated the consequences of mutations on Notch3 expression in transfected cells and CADASIL brains. In normal tissues, Notch3 expression is restricted to vascular smooth muscle cells. Notch3 undergoes a proteolytic cleavage leading to a 210-kDa extracellular fragment and a 97-kDa intracellular fragment. In CADASIL brains, we found evidence of a dramatic and selective accumulation of the 210-kDa Notch3 cleavage product. Notch3 accumulates at the cytoplasmic membrane of vascular smooth muscle cells, in close vicinity to but not within the granular osmiophilic material. These results strongly suggest that CADASIL mutations specifically impair the clearance of the Notch3 ectodomain, but not the cytosolic domain, from the cell surface.

Evidence for cortical coding of saccade velocity in memory-guided saccades in patients with CADASIL

Saccadic eye movements were elicited in ten patients with CADASIL (an autosomal dominant cerebral angiopathy) and ten age-matched controls under six different conditions: 1) the gap paradigm, which tests visually guided, reflexive saccades; 2) the overlap paradigm; 3 and 4) the anti-gap and anti-overlap paradigms, which are thought to test especially the function of the frontal cortex; 5) the memory paradigm, which tests internally guided, intentional saccades; and 6) the sequential memory-guided saccades. Eye movements were recorded by means of DC electro-oculography, and the saccade latency, gain, duration, and peak eye velocity were estimated. The amplitude-to-duration as well as the amplitude-to-peak velocity ratios were calculated for both groups and conditions 1 and 5. There were no significant differences in the gains of the primary saccades in the gap, overlap, and memory paradigms. In general, the CADASIL patients showed a tendency toward longer saccade latencies and a larger number of unwanted saccades in the antitask saccade and memory saccade paradigms (suppression errors). Our main finding was that the patients had a highly significant reduction in peak velocity and a corresponding prolongation of the duration of the memory-guided saccades compared to the controls. In contrast, the duration and the peak velocity of the visually guided saccades did not differ between controls and patients. Thus, we observed a specific change in the dynamic properties of memory-guided saccades in CADASIL patients. The observed pattern of saccade abnormalities in the CADASIL patients does not allow localization to a specific cortical side; however, it might reflect the presence of a mostly frontal type of lesion. This finding contradicts the view that information passed from the cortex to the brainstem codes only the saccade vector and not saccade dynamics.

Thalamic microstructural alterations secondary to white-matter damage in CADASIL: evidence from diffusion tensor imaging study

P18 Background and Purpose: Variable microstructural changes have been reported within the white-matter in CADASIL. Lacunar infarcts are frequently observed in the subcortical grey matter. However, whether microstructural tissular alterations are also present within the non-infarcted putamen (NIP) or thalamus (NIT), remains unknown. Methods: We used diffusion tensor imaging, a MRI method highly sensitive to the cerebral microstructure, in 20 CADASIL patients and 12 age-matched controls. Both Trace(D) and anisotropy (volume-ratio index) of diffusion were measured within the NIP and NIT. In addition, diffusion parameters and the load of small infarcts were calculated within the white-matter of the centrum semi-ovale. A one way ANOVA was performed to compare the diffusion parameters between patients and controls. Thereafter, correlations between the significant results in our patients and the diffusion parameters in the white-matter or the MMSE scores were tested. Results: A significant increase in Trace(D) and decrease in anisotropy were observed in both the NIP and NIT in our patients. Conversely to the results in the NIP, only significant in the presence of associated putaminal infarcts, the diffusion changes in the NIT were significant both in the presence and absence of associated thalamic infarcts. The asymmetry indices of Trace(D) in the NIT and in the white-matter were strongly correlated. The diffusion increase in the NIT was also positively correlated both to Trace(D) and to the load of small deep infarcts within the centrum semi-ovale. Elsewhere, the diffusion increase in the NIT, but not in the NIP, was negatively correlated to the MMSE score in our patients. Conclusions: These results suggest that microstructural alterations are present in both the NIP and NIT in CADASIL. In the NIT, microstructural alterations appear secondary to remote lesions of thalamo-cortical pathways. Diffusion measured in the NIT mirror both the degree of white-matter tissular damage and the clinical severity in CADASIL. This study highlights the importance of secondary neurodegeneration in a typical model of “pure vascular dementia”.

Cognitive Alterations in Non-Demented CADASIL Patients

CADASIL is an inherited small-artery disease of the brain due to mutations of the Notch3 gene on chromosome 19. It is characterized by strokes, migraine with aura, and severe mood disturbances during mid adulthood and leads progressively to subcortical dementia. The precise onset of the cognitive decline in CADASIL remains unknown. We report here the cognitive evaluation of 8 non-demented symptomatic patients with CADASIL from 35 to 66 years of age. Altered performances were found in all subjects with the Wisconsin Card-Sorting Test (WCST), in 5/8 with the Trail-Making Test, and in 3/8 with copying of Rey’s figure. Altered performances with codes and similarities of the WAIS-R, the Wechsler Memory Scale, Raven’s Progressive Matrices, and the category and letter fluency task were observed less frequently (n ≤2). The score obtained with the WCST was not significantly correlated with the severity of the white-matter or basal ganglia signal abnormalities at MRI examination. Our data show that: (1) symptomatic CADASIL patients, although non-demented, can present with a subtle cognitive impairment; (2) tasks involving the frontal lobes are found most frequently altered, and (3) this subtle cognitive deficit can develop in the absence of major vascular events and does not appear to be correlated with the severity of brain lesions as seen at MRI examination.

CADASIL: skin biopsy allows diagnosis in early stages.

Our aim was to investigate the diagnostic impact of skin biopsies in CADASIL patients. Eight consenting CADASIL patients belonging to a German-Caucasian kindred were assessed clinically, genetically, by MRI and skin biopsy. Skin biopsy results were compared to 5 patients suffering from sporadic leucoencephalopathies (control group). Six CADASIL patients presented with symptoms ranging from migraine to severe tetraparesis with dementia. Two clinically unaffected patients had abnormal MRIs. On MRI 7 patients showed various degrees of leucoencephalopathy. One 22-year-old woman with migraine had a normal MRI. Granular, electron dense, osmiophilic material (GEM) was found in skin biopsies of all 8 patients including the 22-year-old woman with migraine and a normal MRI. As shown by genetic linkage analysis she was carrying the disease haplotype. GEM was not found in the control group. Our findings substantiate the impact of skin biopsies in defining the carrier status in CADASIL families.

A Human Homolog of Bacterial Acetolactate Synthase Genes Maps within the CADASIL Critical Region

CADASIL, a recently identified autosomal dominant condition characterized by the recurrence of subcortical infarcts leading to dementia, was previously mapped to chromosome 19p13.1 within a 2-cM interval, D19S226–D19S199. No recombination event was observed with D19S841, a highly polymorphic microsatellite marker isolated from a cosmid mapped to this region. We recently identified within this cosmid a conserved sequence that we used to screen a fetal brain cDNA library and isolated an ubiquitous and abundantly transcribed gene. We did not detect any mutation of this gene in CADASIL patients, suggesting that it is not implicated in this disorder. Interestingly, this gene encodes a putative protein homologous to several thiamine pyrophosphate-binding proteins previously identified in bacteria, yeast, and plants. The proteins with the highest degree of similarity were the acetolactate synthase enzymes which, in prokaryotes, are involved in the branched chain amino acid biosynthetic pathway, raising fascinating questions on the yet unknown function of this gene in mammals.