Thomas Foki

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.

To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.

Improvement of Clinical Language Localization with an Overt Semantic and Syntactic Language Functional MR Imaging Paradigm

BACKGROUND AND PURPOSE: Functional MR imaging (fMRI) is a promising but, in some aspects, still debated noninvasive tool for functional language mapping. We developed a clinical fMRI overt language design at the sentential level to optimize sensitivity for language-related areas of the brain. To evaluate applicability and sensitivity, we investigated a consecutive series of presurgical patients with epilepsy with minimal morphologic brain abnormalities. MATERIALS AND METHODS: Thirty right-handed patients with temporal lobe epilepsy (TLE) and a control group of 23 right-handed healthy subjects participated in the study. The language design included semantic and syntactic error-detection tasks and was constructed to represent the most relevant aspects of everyday language demands. It was applied during block-designed fMRI runs. We performed image preprocessing and statistical analysis with SPM5 at a group level, applying widely used statistical criteria. The study was approved by the local ethics committee, and all participants gave written informed consent. RESULTS: Given the strict statistical criteria, the sensitivity for inferior frontal and posterior temporal activations (comprising Broca and Wernicke regions) was improved relative to previous findings in the literature. For both language areas, we found 100% sensitivity in healthy subjects (Brodmann areas, BA22 and BA44) and 97% sensitivity in patients (when including BA47). Lateralization results demonstrated the capability to detect atypical language lateralizations in patients, which were more frequent in than those in healthy subjects. CONCLUSIONS: We developed a clinical language fMRI design that integrates various relevant aspects of everyday language demands and provides robust localization of core language areas.

Contrast-to-noise ratio (CNR) as a quality parameter in fMRI

To evaluate the impact of data quality on the localization of brain activation in functional magnetic resonance imaging (fMRI) and to explore whether the temporal contrast‐to‐noise‐ratio (CNR) provides a quantitative parameter to estimate fMRI quality.

PARK11 gene (GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenic for Parkinson's disease

The GIGYF2 (Grb10-Interacting GYF Protein-2) gene has recently been proposed to be the responsible gene for the PARK11 locus. Ten different putative pathogenic variants were identified in cohorts of Parkinsons disease (PD) patients from Italy and France. Among these variants Asn56Ser and Asn457Thr were found repeatedly. In the present study we screened 669 PD patients (predominantly of central European origin) and 1051 control individuals for the presence of these two variants. Asn56Ser was found in one patient with a positive family history of the disease and in one control individual. The affected sister of the patient did not carry this variant. Asn457Thr was found in one patient, who was exceptional for his Egyptian origin and in three control individuals. This variant was not found in 50 control individuals from Egypt. We conclude that neither of these two variants plays a major role in the pathogenesis of PD in our study population.

How much are clinical fMRI reports influenced by standard postprocessing methods? An investigation of normalization and region of interest effects in the medial temporal lobe

Recent evidence has indicated that standard postprocessing methods such as template‐based region of interest (ROI) definition and normalization of individual brains to a standard template may influence final outcome of functional magnetic resonance imaging investigations. Here, we provide the first comprehensive investigation into whether ROI definition and normalization may also change the clinical interpretation of patient data. A series of medial temporal lobe epilepsy patients were investigated with a clinical memory paradigm and individually delineated as well as template‐based ROIs. Different metrics for activation quantification were applied. Results show that the application of template‐based ROIs can significantly change the clinical interpretation of individual patient data. This relates to sensitivity for brain activation and hemispheric dominance. We conclude that individual ROIs should be defined on nontransformed functional data and that use of more than one metric for activation quantification is beneficial. Hum Brain Mapp, 2010.

Does clinical memory fMRI provide a comprehensive map of medial temporal lobe structures

Successful clinical application of fMRI tasks requires reliable knowledge about the brain structures mapped by the task. With memory fMRI, diverging evidence exists concerning the location of major signal sources as well as hippocampal contributions. To clarify these issues, we investigated a frequently applied memory test (home town walking) in 33 patients with unilateral medial temporal lobe pathology, comparing healthy and diseased hemispheres. We focused on a detailed investigation of individual fMRI maps on non-transformed high-resolution functional images. Results show a clear dominance of activations around the collateral sulcus, corresponding to parahippocampal and entorhinal cortex activities. Hippocampus activity was absent in the vast majority of patients. The diseased hemispheres showed lower activation than the healthy hemispheres. We conclude that (1) the investigated memory test may be successfully applied for evaluation of the parahippocampal cortex, (2) the hippocampus is not reliably mapped by the task, and (3) the methods described for investigation of individual high-resolution functional images allow generation of application profiles for clinical fMRI tasks.

FMRI correlates of apraxia in Parkinson's disease patients OFF medication

Impairment of hand dexterity in Parkinsons disease (PD) is usually attributed to bradykinesia. Recently, behavioral studies illustrated that decreased dexterity might also be due to limb-kinetic apraxia (LkA), as demonstrated by impaired performance in a coin rotation task. Here, we provide a first investigation on whether functional magnetic resonance imaging (fMRI) may reveal specific brain activation patterns for PD patients with impaired performance in a coin rotation task. We compared coin rotation as an apraxia task to simple finger tapping as a bradykinesia task in ten PD patients OFF medication and matched healthy controls. In addition to a tendency for general overactivation, PD patients showed a perirolandic dissociation with precentral overactivation and postcentral underactivation. This finding significantly separated PD patients from healthy controls.

Limb-kinetic apraxia affects activities of daily living in Parkinson's disease: a multi-center study

Impaired dexterity (fine hand movements) is often present in Parkinsons disease (PD), even at early to moderate disease stages. It has a detrimental impact on activities of daily living (ADL) such as buttoning, contributing to reduced quality of life. Limb‐kinetic apraxia, a loss of the ability to make precise, independent but coordinated finger and hand movements, may contribute to impaired dexterity even more than bradykinesia per se. However, the impact of limb‐kinetic apraxia on ADL remains controversial. Our aim was to identify the strongest predictor of buttoning and unbuttoning in PD. It was hypothesized that coin rotation (a surrogate of limb‐kinetic apraxia) represents the most important determinant.

Finger dexterity deficits in Parkinson's disease and somatosensory cortical dysfunction

INTRODUCTION The patho-physiological basis for finger dexterity deficits in Parkinsons disease (PD) is controversial. Previously, bradykinesia was regarded as the major mechanism. However, recent research suggested limb-kinetic apraxia as an important component of impaired fine motor skills in PD. In contrast to bradykinesia, limb-kinetic apraxia only marginally responds to dopaminergic treatment. Here we investigate the novel hypothesis that the dexterity deficits are related to an intrinsic dysfunction of primary somatosensory cortex (S1), which is not reversible by dopaminergic medication. METHODS Applying a standard and approved dexterity task (coin rotation), brain activation networks were investigated using functional magnetic resonance imaging in PD patients both ON and OFF medication and matched healthy controls. RESULTS PD patients both ON and OFF medication showed impaired S1 activation relative to controls (p < 0.05; region of interest based analysis). The impaired S1 activation remained unchanged by dopaminergic medication. Despite the considerable clinical deficit, no other brain area showed impaired activation. In contrast, structures of the basal ganglia--motor cortex loop responded to dopaminergic medication. Behaviorally, dexterity performance both ON and OFF was significantly (p < 0.05) reduced relative to controls. CONCLUSIONS Our results provide first evidence that dexterity deficits in PD are related to an S1 dysfunction which is insensitive to dopaminergic treatment.

Variability of Clinical Functional MR Imaging Results: A Multicenter Study

PURPOSE To investigate intersite variability of clinical functional magnetic resonance (MR) imaging, including influence of task standardization on variability and use of various parameters to inform the clinician whether the reliability of a given functional localization is high or low. MATERIALS AND METHODS Local ethics committees approved the study; all participants gave written informed consent. Eight women and seven men (mean age, 40 years) were prospectively investigated at three experienced functional MR sites with 1.5- (two sites) or 3-T (one site) MR. Nonstandardized motor and highly standardized somatosensory versions of a frequently requested clinical task (localization of the primary sensorimotor cortex) were used. Perirolandic functional MR variability was assessed (peak activation variability, center of mass [COM] variability, intraclass correlation values, overlap ratio [OR], activation size ratio). Data quality measures for functional MR images included percentage signal change (PSC), contrast-to-noise ratio (CNR), and head motion parameters. Data were analyzed with analysis of variance and a correlation analysis. RESULTS Localization of perirolandic functional MR activity differed by 8 mm (peak activity) and 6 mm (COM activity) among sites. Peak activation varied up to 16.5 mm (COM range, 0.4-16.5 mm) and 45.5 mm (peak activity range, 1.8-45.5 mm). Signal strength (PSC, CNR) was significantly lower for the somatosensory task (mean PSC, 1.0% ± 0.5 [standard deviation]; mean CNR, 1.2 ± 0.4) than for the motor task (mean PSC, 2.4% ± 0.8; mean CNR, 2.9 ± 0.9) (P < .001, both). Intersite variability was larger with low signal strength (negative correlations between signal strength and peak activation variability) even if the task was highly standardized (mean OR, 22.0% ± 18.9 [somatosensory task] and 50.1% ± 18.8 [motor task]). CONCLUSION Clinical practice and clinical functional MR biomarker studies should consider that the center of task-specific brain activation may vary up to 16.5 mm, with the investigating site, and should maximize functional MR signal strength and evaluate reliability of local results with PSC and CNR.