Biomedical subjects
Publications and source records attributed to Thomas Gasser.
Analysis of the apolipoprotein E genotype in sibpairs with Parkinson's disease showed the E4 allele was over represented in those who shared the adjacent chromosome 19 markers. This suggests that apolipoprotein E4 is responsible for the linkage peak in this region and that it is a modest risk factor for Parkinson's disease.
Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.
Pantothenate kinase-associated neurodegeneration (PKAN) may serve as a model for Parkinson disease (PD) since many PKAN patients suffer from parkinsonism and both conditions lead to iron accumulation in the basal ganglia. We screened the gene coding for pantothenate kinase 2 (PANK2) for sequence variants in PD. We found no mutations in 67 PD patients with affected sibs or early-onset disease. Moreover, PANK2 polymorphisms were not associated with late-onset idiopathic PD in 339 patients. We conclude that PANK2 variants exert, if any, only a very small effect in the genetic risk of PD.
For a non-invasive identification of eloquent brain areas in neurosurgical procedures up to now only preoperative functional brain mapping techniques are available. These are based, e.g., on preoperative functional magnetic resonance imaging (fMRI) investigations in awake patients. The aim of this study was to investigate the feasibility to perform fMRI during neurosurgical procedures in anesthetized patients. For that purpose, a passive stimulation paradigm with peripheral nerve stimulation was applied. A 1.5-T MR scanner placed in a radiofrequency-shielded operating room with an adapted operating table was used for intraoperative fMRI. The fMRI data were analyzed during acquisition by an online statistical evaluation package installed on the MR scanner console. In addition, phase reversal of somatosensory evoked potentials was used for verification of intraoperative fMRI. In four anesthetized patients with lesions in the vicinity of the central region a total of 11 fMRI measurements were successfully acquired and analyzed online. Activation was found in the somatosensory cortex, which could be confirmed by intraoperative phase reversal for each measurement. Furthermore, statistical parametric mapping (SPM) was employed for an extensive offline data analysis. We did not observe any neurological deterioration or complications due to the stimulation technique. Intraoperative fMRI is technically feasible allowing a real-time identification of eloquent brain areas despite brain shift.
BACKGROUND: Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample. PATIENTS: The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls. RESULTS: The previously identified association with an ADH class IV allele remained significant (P<.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder. CONCLUSION: Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.
alpha-Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of alpha-synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the alpha-synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case-control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the alpha-synuclein gene. Several markers within the 3'-block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5'-block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age.
Direct genomic DNA sequencing fails to detect epsilon-sarcoglycan (SGCE) mutations in up to 30% of familial myoclonus-dystonia (M-D) cases. We identified novel large heterozygous deletions of SGCE exon 5 or exon 6 in two M-D pedigrees. Like nonsense mutations, exon rearrangements result in the generation of premature stop codons downstream of the deleted exon. SGCE exon dosage assays may identify additional families with SGCE mutation and thus reduce "genetic heterogeneity."
Multiple mutations in the gene for the leucine-rich repeat kinase (LRRK2) cause autosomal dominant late-onset parkinsonism (PARK8). The Gly2019Ser mutation appears to be common in different populations. To investigate whether this novel gene influences the non-Mendelian sporadic form of Parkinson's disease, we genotyped 121 single nucleotide polymorphisms comprehensively covering the entire LRRK2 gene region in a set of 340 Parkinson's disease patients and 680 matched control subjects from Germany. No association could be demonstrated. We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson's disease risk.
We report on a woman who had a severe sporadic nonprogressive dystonia-parkinsonism syndrome with rapid onset of symptoms at age 21. Secondary causes for dystonia were ruled out. No response to levodopa/carbidopa was seen. The patient fulfilled all diagnostic criteria of rapid-onset dystonia-parkinsonism, except for autosomal-dominant inheritance. Bilateral deep brain stimulation of the globus pallidus failed to alleviate her symptoms.
Data on the frequency of alpha-synuclein mutations in Parkinson's disease (PD) are limited. Screening the entire coding region in 1,921 PD patients with denaturing high performance liquid chromatography and subsequent sequencing we only detected silent mutations (g.2654A>G, g.10151G>A, and g.15986A>T) and the c.209G>A substitution corresponding to the p.A53T mutation. These results demonstrate that mutations in the alpha-synuclein gene are rare and suggest that other factors contribute to alpha-synuclein aggregation in the majority of PD patients.
To date, the etiology of multiple system atrophy (MSA) has proved impenetrable. We investigated the role of genetic variation in the UCHL-1 gene in MSA and looked for the presence of disease susceptibility alleles. We determined the linkage disequilibrium structure of the gene and employed a haplotype tagging strategy with power to represent 95% of the haplotype diversity. This approach was performed using a set of tagging single nucleotide polymorphisms (SNPs) that can infer the allelic state of all the common SNPs in UCHL-1 with a high coefficient of determination. This strategy enabled us to scan across the gene and maintain the power to detect signal(s) from any potential functional variant(s). In 257 Gilman-probable or -definite MSA subjects and 1,536 controls, we did not detect a case-control frequency difference for either the tagged haplotypes or for individual tagging SNPs. This search included the S18Y variant of UCHL-1, which has been reported to be protective in Parkinson's disease.
There is evidence from in vitro and animal experiments that oral creatine (Cr) supplementation might prevent or slow down neurodegeneration in Huntington's disease (HD). However, this neuroprotective effect could not be replicated in clinical trials, possibly owing to treatment periods being too short to impact on clinical endpoints. We used proton magnetic resonance spectroscopy ((1)H-MRS) as a surrogate marker to evaluate the effect of Cr supplementation on brain metabolite levels in HD.Twenty patients (age 46+/-7.3 years, mean duration of symptoms 4.0+/-2.1 years, number of CAG repeats 44.5+/-2.7) were included. The primary endpoint was metabolic alteration as measured by (1)H-MRS in the parieto-occipital cortex before (t1) and after 8-10 weeks (t2) of Cr administration. Secondary measures comprised the motor section of the Unified Huntington's Disease Rating Scale and the Mini Mental State Examination. (1)H-MRS showed a 15.6% decrease of unresolved glutamate (Glu)+glutamine (Gln; Glu+Gln=Glx; p<0.001) and a 7.8% decrease of Glu (p<0.027) after Cr treatment. N-acetylaspartate trended to fall (p=0.073) whereas total Cr, choline-containing compounds, glucose, and lactate remained unchanged. There was no effect on clinical rating scales. This cortical Glx and Glu decrease may be explained by Cr enhancing the energy-dependent conversion of Glu to Gln via the Glu-Gln cycle, a pathway known to be impaired in HD. Since Glu-mediated excitotoxicity is presumably pivotal in HD pathogenesis, these results indicate a therapeutic potential of Cr in HD. Thus, longterm clinical trials are warranted.
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OBJECTIVE: To describe the interdisciplinary surgical approach in spheno-orbital meningiomas and to evaluate the operative results regarding resectability and functional outcome. PATIENTS AND METHODS: A series of 16 patients underwent surgical resection of spheno-orbital meningiomas followed by bony reconstruction. Four patients presented with a recurrent meningioma and had undergone surgical resection previously. Radical tumour removal was attempted in all cases, although no aggressive effort was made to remove tumour tissue infiltrating the cavernous sinus or soft tissues deep in the orbit to avoid severe functional disturbances. All patients but one were female (mean age 53 years). Mean follow-up period was 68 months (range 4-155 months). RESULTS: The leading symptom was proptosis in 14 patients, accompanied in 7 cases by progressive visual impairment. Surgical resection was thought to have been complete in 11 patients (69%) and incomplete in 5 (31%). Residual tumour was deliberately left when there was infiltration of the cavernous sinus (n = 4), the pterygopalatine fossa (n = 2) and/or the deep intraorbital soft tissues (n = 1). Tumour recurrence was observed in 9 patients, among whom were 6 patients with an initially "completely" resected meningioma. Eight patients underwent re-operation. Complete resection was achieved in 3 of these latter patients with an isolated exclusively intraorbital tumour manifestation. CONCLUSION: By means of combined skull base approaches, spheno-orbital meningiomas are grossly resected totally with a long-term survival free of recurrence and an acceptable quality of life. In some cases, deliberate subtotal tumour resection is useful to avoid severe neurological damage with sufficient tumour control and a valuable progression-free survival.
Parkinson's disease (PD) is a genetically heterogeneous disease. Recently, significant linkage has been reported to a 39.5 cM region on the long arm of chromosome 2 (2q36-37; PARK11) in North American Parkinson families under an autosomal dominant model of inheritance. We have performed a replication study to confirm linkage to this region in a European population. Linkage analysis in 153 individuals from 45 European families with a strong family history of PD did not show any significant LOD score in this region. Therefore, PARK11 does not seem to play a major role for familial PD in the European population.
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PURPOSE OF REVIEW: Parkinson's disease is the second most common neurodegenerative disorder and affects 2% of the population over the age of 60 years. Due to the increasing proportion of elderly individuals in developed countries, Parkinson's disease and related neurodegenerative disorders represent a growing burden on the health care system. In the majority of cases, the cause of the disease is still unknown, and its elucidation remains one of the major challenges of the neurosciences. Recent findings in rare genetic forms of Parkinson's disease have allowed the development of novel animal models, providing a basis for a better understanding of the molecular pathogenesis of the disease, setting the stage for the development of novel treatment strategies. RECENT FINDINGS: Several novel genes for monogenic forms of Parkinson's disease, such as PINK-1 for an autosomal-recessive early-onset variant, and LRRK2 for a relatively common late-onset autosomal-dominant form have recently been discovered, and several novel animal models have been generated on the basis of genes that had been found earlier. SUMMARY: The combination of genetic, pathologic and molecular findings provide increasing evidence that the pathways identified through the cloning of different disease genes are interacting on different levels and share several major pathogenic mechanisms.
OBJECTIVE: The introduction of intraoperative 1.5-T magnetic resonance imaging may provide up-to-date functional information in the surgical environment. However, feasible passive paradigms that allow the examination of anesthetized patients will be a precondition for intraoperative functional magnetic resonance imaging (fMRI). The aim of this study is to evaluate the feasibility of a recently developed passive fMRI paradigm for functional neuroimaging in anesthetized patients. METHODS: We investigated four anesthetized patients with intracranial pathological conditions not related to the sensorimotor cortex. All patients had been anesthetized with standard total intravenous anesthesia for more than 24 hours before the fMRI scan. Anesthesia and monitoring were sustained during the scanning procedure. A simultaneous electrical stimulation of the median and tibial nerves was applied to elicit a cortical activation using a custom-designed magnetoelectrically shielded conductor. Statistical evaluation using Statistical Parametric Mapping software (Wellcome Department of Imaging Neuroscience, University College, London, England) and the Talairach Daemon Client (Version 1.1; Research Imaging Center, University of Texas Health Science Center, San Antonio, TX) followed. RESULTS: Three of four patients showed a good activation of the sensorimotor cortex under anesthesia. In one patient, no significant activation was observed, presumably as a result of increased body impedance because of severe edema. Standard dosages of the narcotics did not influence the cortical response; however, stimulation intensity had to be increased compared with awake patients. We did not detect relevant interferences with magnetic resonance imaging arising from the technical setup. CONCLUSION: The method presented proved to be a feasible paradigm for fMRI evaluation of the sensorimotor cortex in anesthetized patients and thus forms a relevant step toward real intraoperative functional neuroimaging.