Cortical Lewy bodies and Aß burden are associated with prevalence and timing of dementia in Lewy body diseases.

AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aß plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aß plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aß plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Counselling dilemmas associated with the molecular characterisation of two Angelman syndrome families.

We report the molecular characterisation of two families with Angelman syndrome referred for prenatal diagnosis, in which atypical molecular findings resulted in counselling dilemmas. The first is a familial case of Angelman syndrome in which the two affected children have mutations which affect the imprinting mechanism, as shown by the presence of paternal DNA methylation patterns at D15S63 and SNRPN and biparental inheritance of 15q11-q13 markers. DNA prepared from a 21 week fetal blood sample detected a fetus with normal maternal and paternal DNA methylation patterns at D15S63, but inheritance of the same maternal chromosome 15q11-q13 as the two affected sibs. This is probably a result of germline mosaicism in the mother. The second is a case of Angelman syndrome with an atypical deletion of 15q11-q13, which involves both unusual proximal and distal breakpoints. The deletion was characterised in order to assess the risk of Angelman syndrome in a second pregnancy in the mother of this child.

Minimal definition of the imprinting center and fixation of chromosome 15q11-q13 epigenotype by imprinting mutations.

Patients with disorders involving imprinted genes such as Angelman syndrome (AS) and Prader-Willi syndrome (PWS) can have a mutation in the imprinting mechanism. Previously, we identified an imprinting center (IC) within chromosome 15q11-ql3 and proposed that IC mutations block resetting of the imprint, fixing on that chromosome the parental imprint (epigenotype) on which the mutation arose. We now describe four new microdeletions of the IC, the smallest (6 kb) of which currently defines the minimal region sufficient to confer an AS imprinting mutation. The AS deletions all overlap this minimal region, centromeric to the PWS microdeletions, which include the first exon of the SNRPN gene. None of five genes or transcripts in the 1.0 Mb vicinity of the IC (ZNF127, SNRPN, PAR-5, IPW, and PAR-1), each normally expressed only from the paternal allele, was expressed in cells from PWS imprinting mutation patients. In contrast, AS imprinting mutation patients show biparental expression of SNRPN and IPW but must lack expression of the putative AS gene 250-1000 kb distal of the IC. These data strongly support a model in which the paternal chromosome of these PWS patients carries an ancestral maternal epigenotype, and the maternal chromosome of these AS patients carries an ancestral paternal epigenotype. The IC therefore functions to reset the maternal and paternal imprints throughout a 2-Mb imprinted domain within human chromosome 15q11-q13 during gametogenesis.

Angelman syndrome associated with a maternal 15q11-13 deletion of less than 200 kb.

Angelman syndrome (AS) is a neurogenetic disorder arising from a lack of genetic contribution from the maternal chromosome 15q11-13. To date, the AS critical region has been defined by an inherited deletion of approximately 1.5Mb, spanning the 3-21 (D15S10), LS6-1 (D15S113) and GABRB3 loci. We have identified an individual with the typical features of AS who has a deletion of the maternal chromosome which encompasses LS6-1, but does not extend to either flanking marker. This deletion, initially detected by (CA)n repeat analysis, was further characterised by fluorescence in situ hybridisation (FISH) using cosmids derived from a 260 kb LS6-1 yeast artificial chromosome (YAC). Neither end cosmid from this YAC clone falls within the deletion, suggesting that the minimal AS region is less than 200 kb. We also studied three loci within 15q11-13 which detect parent-of-origin specific DNA methylation imprints, and found that both normal maternal and paternal patterns were present in this patient.

Human endoscopic ultrasonography.

Conventional transcutaneous ultrasound examinations are often compromised by intervening pulmonary or bowel gas and have limited resolution. Ultrasonic probes of frequencies greater than 5 MHz, which enhance resolution, cannot be used successfully on the skin surface, because they do not penetrate deeply enough to view intraabdominal organs in most adults. To overcome these problems, we tested an ultrasonic endoscope which had a 10-MHz, 64-element linear assay, generated real-time images at resolutions of less than 1 mm, and was an integral part of a 35-mm-long and 13-mm-wide endoscopic rigid tip. Thirty-two studies were performed in 15 healthy subjects, 4 patients with pancreatic cancer and 6 patients with chronic pancreatitis, and 1 patient each with a gastric ulcer and a suspected pancreatic abscess. We demonstrated that this procedure is safe, provides high resolution real-time ultrasound visualization of the heart, aorta, spleen, pancreas, liver, gallbladder, kidneys, and gastrointestinal mucosa and can detect moderate-sized pancreatic tumors and hepatic metastases less than 1 cm in diameter. Because endoscopic visualization of gastrointestinal mucosa and ultrasound examination of extraluminal organs can be obtained during a single procedure, rapid differentiation among mucosal and intramural disease of the hollow gut and disease of extraluminal organs should be possible with this diagnostic technique.

Natural history of experimental intracerebral hemorrhage: sonography, computed tomography and neuropathology.

The evolution of intracerebral hemorrhage was investigated in a canine model by high resolution sonography, computed tomography (CT), and neuropathologic examination. In 12 dogs, a parietal lobe hematoma was introduced by craniotomy. The sonographic appearance of acute hemorrhage was characteristic and consisted of a sharply circumscribed, homogeneous, highly echogenic lesion, the size and shape of which correlated closely to the area of increased density seen on the CT scan. This changed within 3-4 days to an echogenic rim surrounding a hypoechoic center. Histologically, this change corresponded to a loss of integrity of individual red blood cells. This occurred earliest in the hemorrhage center causing a hypoechoic center, while intact red blood cells at the periphery accounted for the echogenic rim. Shortly after the red blood cells lost their biconcave shape they began to lose their hemoglobin causing the hemorrhage to become isodense with surrounding brain on the CT scan. Faint contrast enhancement by CT was noted at this early stage and was related primarily to a mononuclear perivascular infiltrate at the edge of the hemorrhage. A collagen capsule formed around the hemorrhage over a 2 week period. This capsule slowly replaced intact red cells as the cause of the now shrinking echogenic rim. This capsule was also responsible for the increasing ring contrast enhancement around the resolving hemorrhage. The sequence of image changes seen on both CT and sonography in this experimental model closely resembled the findings seen in intracerebral hemorrhage in patients.