Glioma proliferation as assessed by 3'-fluoro-3'-deoxy-L-thymidine positron emission tomography in patients with newly diagnosed high-grade glioma.

PURPOSE: The aim of this study was to investigate the relationship between the in vivo derived kinetic parameters of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and the proliferation rate measured in vitro by Ki-67 staining in patients with newly diagnosed high-grade gliomas. EXPERIMENTAL DESIGN: Thirteen patients with newly diagnosed high-grade gliomas were investigated with (18)F-FLT and methyl-(11)C- l-methionine ((11)C-MET) positron emission tomography (PET) and T1-, Gd-T1-, and T2-weighted magnetic resonance imaging on consecutive days. Tracer kinetic parameters of (18)F-FLT as well as the standardized uptake value and the tumor-to-background (T/B) ratio of (18)F-FLT and (11)C-MET were determined. Data of kinetic modeling, standardized uptake value, and T/B values derived from (18)F-FLT-PET were compared with T/B values derived from (11)C-MET-PET and to the in vitro proliferation marker Ki-67. RESULTS: A significant correlation was observed between the metabolic rate constant Ki and the proliferation index as measured by Ki-67 immunostaining [Ki, r=0.79 (P=0.004)]. Also, the phosphorylation rate constant k3 correlated with Ki-67 [k3, r=0.76 (P=0.006)], whereas the rate constant for transport through the blood brain barrier K1 showed a weaker correlation with Ki-67 [K1, r=0.62 (P=0.044)]. No significant correlation between (11)C-MET and (18)F-FLT uptake ratios and Ki-67 was observed. CONCLUSIONS: This study shows that kinetic analysis of (18)F-FLT tracer uptake is essential for the in vivo assessment of tumor proliferation in high-grade gliomas, whereas uptake ratios of (11)C-MET and (18)F-FLT failed to correlate with the in vitro determined proliferation marker. Thus, kinetic analysis of (18)F-FLT might provide an accurate method for the assessment of early response to glioma treatment in the future.

Pathological consequences of VCP mutations on human striated muscle.

Mutations in the valosin-containing protein (VCP, p97) gene on chromosome 9p13-p12 cause a late-onset form of autosomal dominant inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD). We report on the pathological consequences of three heterozygous VCP (R93C, R155H, R155C) mutations on human striated muscle. IBMPFD skeletal muscle pathology is characterized by degenerative changes and filamentous VCP- and ubiquitin-positive cytoplasmic and nuclear protein aggregates. Furthermore, this is the first report demonstrating that mutant VCP leads to a novel form of dilatative cardiomyopathy with inclusion bodies. In contrast to post-mitotic striated muscle cells and neurons of IBMPFD patients, evidence of protein aggregate pathology was not detected in primary IBMPFD myoblasts or in transient and stable transfected cells using wild-type-VCP and R93C-, R155H-, R155C-VCP mutants. Glutathione S-transferase pull-down experiments showed that all three VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3. Structural analysis demonstrated that R93 and R155 are both surface-accessible residues located in the centre of cavities that may enable ligand-binding. Mutations at R93 and R155 are predicted to induce changes in the tertiary structure of the VCP protein. The search for putative ligands to the R93 and R155 cavities resulted in the identification of cyclic sugar compounds with high binding scores. The latter findings provide a novel link to VCP carbohydrate interactions in the complex pathology of IBMPFD.

No evidence for association between NOTCH4 and schizophrenia in a large family-based and case-control association analysis.

OBJECTIVES: An analysis of 80 British parent-offspring trios by Wei and Hemmings in 2000 revealed thre1e out of five markers within the NOTCH4 locus to be strongly associated with schizophrenia. In our present study, we have examined NOTCH4 markers in large samples of German and Palestinian-Arab origin. METHODS: Our study population comprised a German case-control sample (n=512 schizophrenia patients and n=232 controls) and two independent parent-offspring trio samples of German (n=159 trios) and Palestinian-Arab (n=208 trios) descent. We examined a total of ten single nucleotide polymorphisms within the NOTCH4 locus and the adjacent loci, spanning a region of approximately 100 kb. RESULTS: Neither single marker nor haplotype analyses showed association with schizophrenia. In addition, analyses of the German case-control and trio samples revealed no significant association between NOTCH4 polymorphisms and early-onset schizophrenia. CONCLUSIONS: Our results suggest that NOTCH4 is unlikely to play a major role in the genetic predisposition to schizophrenia in the German or the Palestinian-Arab population.

Distinct neuromuscular phenotypes in myotonic dystrophy types 1 and 2 : a whole body highfield MRI study.

Myotonic Dystrophy Type 1 (DM1) and 2 (DM2) present with distinct though overlapping clinical phenotypes. Comparative imaging data on skeletal muscle involvement are not at present available. We used the novel technique of whole body 3.0 Tesla (T) Magnetic Resonance Imaging (MRI) to further characterize musculoskeletal features in DM2 and compared the results with DM1.MRI findings of 15 DM1 and 14 DM2 patients were evaluated with respect to patterns of skeletal muscle affection and clinical data using the Muscular Impairment Rating Scale (MIRS) and Medical Research Council scale (MRC). All DM1 patients had pathological MRI compared with only 5 DM2 patients. In contrast to DM2, DM1 patients showed a characteristic distribution of muscle involvement with frequent and early degeneration of the medial heads of gastrocnemius muscles, and a perifemoral semilunar pattern of quadriceps muscle affection sparing the rectus femoris. The most frequently affected muscles in DM1 were the medial heads of gastrocnemius, soleus, and vastus medialis muscles. In DM2, however, the erector spinae and gluteus maximus muscles were most vulnerable to degeneration. MRI data were in line with the clinical grading in 12 DM1 and 3 DM2 patients. In 3 DM1 and 5 DM2 patients, MRI detected subclinical muscle involvement. 9 DM2 patients with mild to moderate proximal muscle weakness and/or myalgias had normal MRI. Pathological MRI changes in DM2 emerged with increasing age and were restricted to women. Whole body 3.0T MRI is a sensitive imaging technique that demonstrated a characteristic skeletal muscle affection in DM1. In contrast, MRI was no reliable indicator for skeletal muscle involvement in mildly affected DM2 patients since myalgia and mild paresis were usually not reflected by MRI signal alterations.

Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs.

Mutations in the fukutin-related protein (FKRP) have recently been demonstrated to cause limb girdle muscular dystrophy type 2I (LGMD2I), one of the most common forms of the autosomal recessive LGMDs in Europe. We performed a systematic clinical and muscle MRI assessment in 6 LGMD2I patients and compared these findings with those of 14 patients with genetically confirmed diagnosis of other forms of autosomal recessive LGMDs or dystrophinopathies. All LGMD2I patients had a characteristic clinical phenotype with predominant weakness of hip flexion and adduction, knee flexion and ankle dorsiflexion. These findings were also mirrored on MRI of the lower extremities which demonstrated marked signal changes in the adductor muscles, the posterior thigh and posterior calf muscles. This characteristic clinical and MRI phenotype was also seen in LGMD2A. However, in LGMD2A there was a selective involvement of the medial gastrocnemius and soleus muscle in the lower legs which was not seen in LGMD2I. The pattern in LGMD2A and LGMD2I were clearly different from the one seen in alpha-sarcoglycanopathy and dystrophinopathy type Becker which showed marked signal abnormalities in the anterior thigh muscles. Our results indicate that muscular MRI is a powerful tool for differentiating LGMD2I from other forms of autosomal recessive LGMDs and dystrophinopathies.

Association between a polymorphism in the pseudoautosomal X-linked gene SYBL1 and bipolar affective disorder.

In the past decade, several chromosomal regions have been analyzed for linkage with bipolar affective disorder (BPAD). There have been conflicting results regarding the involvement of X-chromosomal regions in harboring susceptibility genes for BPAD. Recently, a new candidate gene (SYBL1) for BPAD has been described on Xq28. SYBL1, which maps to the Xq pseudoautosomal region (PAR), encodes a member of the synaptobrevin family of proteins involved in synaptic vesicle docking, exocytosis, and membrane transport. A subsequent case-control association study, including 110 US-American patients with BPAD and 119 unrelated controls, investigated a potential etiological role of a novel polymorphism (G-->C transversion) in a regulatory region of the SYBL1 gene. In this analysis, the C allele showed a statistical trend to be more frequent in males with BPAD than in respective controls (P=0.06). This finding prompted us to verify whether a similar effect was also present in a larger German sample of 164 unrelated patients with BPAD (148 patients with BP I disorder, 16 patients with BP II disorder) and 267 controls. We observed a significantly increased frequency of genotypes homozygous for the C allele in females with BPAD in comparison with controls (P=0.017). Thus, our data strengthen the role of the SYBL1 gene as a candidate gene for BPAD.