APOE and AGT in the Finnish p.Arg133Cys CADASIL population.

BACKGROUND: CADASIL is an inherited systemic small vessel disease, the affected status of brain vessels leading to subcortical vascular dementia. The defective gene is NOTCH3 in which over 230 different pathogenic mutations have been identified. The clinical course of CADASIL is highly variable even within families. Previous studies have shown that additional genetic factors modify the phenotype. AIMS AND METHODS: Altogether, 134 Finnish CADASIL patients with p.Arg133Cys mutation were analysed for possible associations between the apolipoprotein E (APOE) genotype, angiotensinogen (AGT) p.Met268Thr polymorphism or neutral p.Ala202Ala NOTCH3 polymorphism and earlier first-ever stroke or migraine. RESULTS: We found no association between the APOE genotypes, AGT polymorphism, NOTCH3 polymorphism and earlier first-ever stroke or migraine. CONCLUSIONS: The APOE, AGT and NOTCH3 polymorphism did not modify the onset of strokes or migraine in our CADASIL sample, which is one of the largest mutationally homogenous CADASIL populations published to date. International collaboration, pooled analyses and genomewide approaches are warranted to identify the genetic factors that modify the highly variable CADASIL phenotype.

Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.

Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Wålinder described hereditary multi-infarct dementia (MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.

Comparison of medetomidine and dexmedetomidine as premedicants in dogs undergoing propofol-isoflurane anesthesia.

OBJECTIVE: To compare 3 dose levels of medetomidine and dexmedetomidine for use as premedicants in dogs undergoing propofol-isoflurane anesthesia. ANIMALS: 6 healthy Beagles. PROCEDURE: Dogs received medetomidine or dexmedetomidine intravenously at the following dose levels: 0.4 microg of medetomidine or 0.2 microg of dexmedetomidine/kg of body weight (M0.4/D0.2), 4.0 microg of medetomidine or 2.0 microg of dexmedetomidine/kg (M4/D2), and 40 microg of medetomidine or 20 microg of dexmedetomidine/kg (M40/D20). Sedation and analgesia were scored before induction. Anesthesia was induced with propofol and maintained with isoflurane. End-tidal isoflurane concentration, heart rate, and arterial blood pressures and gases were measured. RESULTS: Degrees of sedation and analgesia were significantly affected by dose level but not drug. Combined mean end-tidal isoflurane concentration for all dose levels was higher in dogs that received medetomidine, compared with dexmedetomidine. Recovery time was significantly prolonged in dogs treated at the M40/D20 dose level, compared with the other dose levels. After induction, blood pressure decreased below reference range and heart rate increased in dogs treated at the M0.4/D0.2 dose level, whereas blood pressure was preserved in dogs treated at the M40/D20 dose level. However, dogs in these latter groups developed profound bradycardia and mild metabolic acidosis during anesthesia. Treatment at the M4/D2 dose level resulted in more stable cardiovascular effects, compared with the other dose levels. In addition, PaCO2 was similar among dose levels. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine is at least as safe and effective as medetomidine for use as a premedicant in dogs undergoing propofol-isoflurane anesthesia.