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Biomedical subjects

Gregor K Wenning

Publications and source records attributed to Gregor K Wenning.

At least 19 recordsLinked to original sources
PubMed2006

Cortical atrophy in the cerebellar variant of multiple system atrophy: a voxel-based morphometry study.

This study aimed to determine in vivo the atrophy patterns in clinically established cerebellar variant of multiple-system atrophy (MSA-C) using voxel-based morphometry (VBM). Thirteen patients with MSA-C (12 probable, 1 possible) and 13 healthy controls matched for age and sex were included. High-resolution MR images were acquired with a 1.5 T scanner. Images were normalized onto a study-specific template, segmented into the tissue compartments, modulated with the Jacobian determinants, and finally smoothed with a Gaussian kernel filter of 10 mm. The general linear model was used to assess statistical differences in gray and white matter. Infratentorial atrophy was observed in the cerebellar hemispheres, vermis, mesencephalon, and pons of MSA-C patients. Supratentorial volume loss was found in orbitofrontal and mid-frontal regions as well as in temporomesial and insular areas of both hemispheres. A negative correlation was observed between a cerebellar ataxia score and the volume of cerebellar hemispheres, peduncles, and pons. To compare this atrophy pattern to that of spinocerebellar ataxia (SCA2), which was previously reported by our group, a conjunction analysis was assessed. We observed a volume loss shared by both disorders comprising the cerebellum, vermis, pons, mesencephalon, orbitofrontal, mid-frontal, and temporomesial cortex of both hemispheres as well as the left insular cortex.

Adult↗
PubMed2006

Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG).

The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinson's disease staging, Schwab England Activities of Daily Living (SE ADL), and a three-point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA-parkinsonian, 58%; MSA-cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P<0.0001) and UMSARS I scores by 35.6% (P<0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

Adult↗
PubMed2005

The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease.

An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.

Age of Onset↗
PubMed2005

Voxel-wise analysis of diffusion weighted imaging reveals disruption of the olfactory tract in Parkinson's disease.

Diffusion weighted imaging (DWI) and the trace of diffusion tensor [Trace (D)], a marker of water molecule diffusivity, provide information on structural integrity of nervous tissues. To investigate structural lesions within the brain's neuronal architecture in early stages of Parkinson's disease, 12 patients with disease duration of 3.5 +/- 1.5 years were studied with DWI. Data were compared with 12 age-matched healthy control subjects. To objectively localize focal changes of structural neuronal integrity without having to make an a priori hypothesis as to its location statistical parametric mapping (SPM) was applied to our DWI study. SPM localized significant increases of diffusivity in the region of both olfactory tracts in patients (P < 0.001). Trace (D) cut-off values for the voxel cluster of the olfactory tracts have been calculated from the subjects entered into SPM and applied to a total of 17 different individuals (9 patients with Parkinson's disease, disease duration 3.1 +/- 1.3 years and 8 age-matched healthy subjects). Out of 17 subjects, 16 subjects, i.e. 94%, were correctly discriminated with a sensitivity of 100% and a specificity of 88%. All patients with Parkinson's disease were correctly classified and only one normal subject was classified as having the disease, underlining the high potential of this method to separate patients with the illness from healthy subjects. Increased diffusivity in the olfactory tract is in line with the well-established clinical finding of hyposmia in Parkinson's disease. Whether DWI can be used as a marker to identify individuals at risk to develop this disease remains to be shown.

Case-Control Studies↗
PubMed2005

Evidence for dopaminergic re-innervation by embryonic allografts in an optimized rat model of the Parkinsonian variant of multiple system atrophy.

Embryonic transplantation has been considered as an alternative treatment strategy for drug resistant parkinsonian symptoms in multiple system atrophy. So far our group has created a number of animal models of striatonigral degeneration, the core pathology underlying progressive Parkinsonism associated with multiple system atrophy, as testbed for neurorestaurative and neuroprotective approaches. Using embryonic allografts of either nigral, striatal, or combined nigro-striatal tissue we were able to consistently show graft survival in a denervated and lesioned striatum as well as improvement of rotational behaviour. However, due to severe lesions of the striatum and the chosen time window of 3-6 weeks between lesion and grafting, severe gliosis led to demarcation of the graft and prevented re-innervation of the remaining adult striatum. The aim of the present study was to modify our "double toxin-double lesion" rat model by reducing the dose of quinolinic acid injected into the striatum from 150 to 75 nmol and shortening the interval between lesion and grafting to 1-2 weeks. Injection of 75 nmol quinolinic acid still led to a significant reduction of DARPP-32 positive neurons and volume in the striatum. Analysis of embryonic mesencephalic grafts revealed survival of dopaminergic neurons and outgrowth of fibres re-innervating the adult striatum. Rotation behaviour was improved in the graft group. Considering embryonic transplantation a possible future antiparkinson therapeutic intervention in multiple system atrophy patients our data stress the necessity of optimal patient selection, i.e. early stage disease with limited striatal dysfunction.

Amphetamine↗
PubMed2005

Voxel-wise analysis of [123I]beta-CIT SPECT differentiates the Parkinson variant of multiple system atrophy from idiopathic Parkinson's disease.

To investigate the cerebral dopamine transporter status in the early stages of the parkinson-variant of multiple system atrophy (MSA-P), 15 patients with MSA-P and a disease duration up to 3 years were studied with [123I]beta-CIT single photon emission computed tomography (SPECT). Data were compared with 13 age-matched healthy control subjects and 15 patients with idiopathic Parkinson's disease (IPD), matched for age and disease duration. Parametric SPECT images of the specific-to-nondisplaceable equilibrium partition coefficient (V3''), which is proportional to the receptor density (Bmax) have been generated. To objectively localize focal changes in dopaminergic function throughout the entire brain volume without having to make an a priori hypothesis as to their location, statistical parametric mapping (SPM) was applied to our [123I]beta-CIT SPECT study. Both MSA-P and IPD patients showed significant decreases in striatal [123I]beta-CIT SPECT uptake. However, in MSA-P patients an additional reduction in midbrain [123I]beta-CIT signal was localized with SPM compared with control subjects (MSA-P, V3'': 0.89 +/- 0.37 versus controls V3'': 1.81 +/- 0.38; P < 0.001) and patients with IPD (V3'': 1.84 +/- 0.26; P < 0.001). Stepwise linear discriminant analysis of mean [123I]beta-CIT uptake in the putamen, caudate and midbrain identified the caudate and midbrain as indices to classify correctly 95.2% of subjects as either normal, patients with MSA-P or IPD. Voxel-wise analysis of [123I]beta-CIT SPECT revealed more widespread decline of monoaminergic transporter availability in MSA-P compared with IPD, matching the underlying pathological features. We suggest that the quantification of midbrain DAT signal should be included in the routine clinical analysis of [123I]beta-CIT SPECT in patients with uncertain parkinsonism.

Aged↗
PubMed2005

The role of alpha-synuclein in the pathogenesis of multiple system atrophy.

The discovery of glial cytoplasmic inclusions (GCIs) in 1989 helped to define multiple system atrophy (MSA) as a clinicopathological entity, and drew attention to the prominent role played by these inclusions in the pathogenesis of the disorder. Subsequently, GCIs were shown to be highly positive for alpha-synuclein, a neuronal protein that is normally absent in oligodendroglia except during embryonic development. The source of oligodendroglial alpha-synuclein aggregation in MSA is unknown. Since genetic overexpression has been excluded, active uptake from dying neurons remains a possibility. The similar topography of oligodendroglial and neuronal pathology in MSA suggests a fundamental disturbance of the functional unit between oligodendroglia, axon, and neuron. Transgenic MSA mouse models are now available to determine these aspects of cellular disturbance experimentally.

Animals↗
PubMed2005

Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome.

In patients with Parkinson's disease, hyperechogenicity of the substantia nigra using transcranial ultrasound has been related to increased tissue concentrations of iron. Recently, deficient iron transport mechanisms in substantia nigra neurons have been described in postmortem tissue of patients with restless legs syndrome (RLS). This study was performed to study substantia nigra echogenicity in RLS patients compared with normal control subjects and Parkinson's disease patients. RLS patients had significantly reduced midbrain areas of hyperechogenicity compared with control subjects, and even more markedly reduced hyperechogenicity compared with Parkinson's disease patients. These findings lend further support to nigral iron deficiency as a pathogenetic factor in RLS.

Aged↗
PubMed2005

How to diagnose dementia with Lewy bodies: state of the art.

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people that has only been recognized in the past decade and that remains widely underdiagnosed. At postmortem examination, affected patients show numerous alpha-synuclein-positive Lewy bodies (LB) in many parts of the cerebral cortex, particularly neocortical and limbic areas in addition to the nigral LB degeneration characteristic of Parkinson's disease (PD). Clinical presentation, unlike PD, is with progressive cognitive decline with particular deficits of visuospatial ability as well as frontal executive function accompanied by usually only mildly to moderately severe parkinsonism, which is often akineto-rigid without the classical parkinsonian rest-tremor. Further accompanying features include spontaneous recurrent visual hallucinations and conspicuous fluctuations in alertness and cognitive performance. The two main differential diagnoses are Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). To improve the differential diagnosis of DLB, consensus criteria have been developed that establish possible and probable levels of clinical diagnostic accuracy. Generally, their sensitivity is variable and low but their specificity is high. Current consensus is to restrict a diagnosis of DLB only to patients with parkinsonism who develop dementia within 12 months of the onset of motor symptoms. Using operationalized criteria, DLB can be diagnosed clinically with an accuracy similar to that achieved for AD or PD. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. We review the present state of the best practice in the clinical diagnosis of DLB. Future modifications of diagnostic criteria would ideally include the full range of clinical presentations that can be associated with LB disease.

Accidental Falls↗
PubMed2005

Grading of neuropathology in multiple system atrophy: proposal for a novel scale.

Multiple system atrophy (MSA), a sporadic progressive synucleinopathy of advanced age, is separated into two clinic opathological subtypes: MSA-P (striatonigral degeneration [SND]) with predominant parkinsonian features and MSA-C (olivopontocerebellar atrophy [OPCA]) with predominant cerebellar ataxia. We propose a novel morphological grading system for both subtypes to compare lesion intensities and their possible clinical validity. Forty-two autopsy cases of MSA were separated into four grades (SND 0-III and OPCA 0-III) based on semiquantitative assessment of neuronal loss, astrogliosis, and presence of alpha-synuclein-positive glial cytoplasmic inclusions (GCI) in striatum, globus pallidus, substantia nigra, pontine basis, cerebellum, and inferior olives. Whereas a recent grading system restricted to SND reflected disease progression and dopa-responsiveness, there was considerable variation in the morphological combination between SND and OPCA, with only around half the cases with OPCA II (moderate) and III (severe) showing comparable grades of both types, whereas OPCA 0 and I (no or little degeneration) was combined with all grades of SND. Twenty-two cases showing OPCA 0 + SND II (n = 3), OPCA I + SND I-II (n = 11), and OPCA I + SND III (n = 8) were classified as pure or predominant SND, consistent with MSA-P. Twenty cases showing OPCA II + SND II/III (n = 7) and OPCA III + SND III (n = 13) were classified as predominant OPCA, consistent with MSA-C. In MSA-P, the mean age of onset was higher than it was in MSA-C (55.1 vs. 50.5 years), but the mean duration of illness was shorter in MSA-P (5.3 vs. 6.7 years). Presenting symptoms in MSA-P were mainly parkinsonism, whereas in MSA-C they were mainly gait disorders (14 vs. 1; P < 0.001). Among clinical key symptoms, parkinsonism was more frequent than were cerebellar signs in MSA-P; in MSA-C it was the reverse (P < 0.01), whereas other symptoms (autonomic/urinary failure) showed no differences. Parkinsonism was infrequent in MSA-C even when OPCA was associated with SND, suggesting a masking effect by cerebellar system involvement. High terminal Hoehn and Yahr stages were more frequent in MSA-P (P < 0.01), some with good-to-moderate initial levodopa (L-dopa) response. Although the proposed morphological grading of both MSA-P and -C correlates well with initial symptoms and clinical key features of both types, further prospective studies are required to validate the clinical utility of the proposed MSA grading scales for future intervention studies.

Cerebellar Ataxia↗
PubMed2005

In vitro models of multiple system atrophy.

alpha-Synuclein represents the major constituent of oligodendroglial cytoplasmic inclusions, the hallmark lesion of multiple system atrophy (MSA), a progressive disorder that is associated with selective degenerative cell loss in basal ganglia, cerebellum, brainstem, and spinal cord. The role of abnormal alpha-synuclein aggregation in oligodendroglial cells is still obscure, in particular, whether alpha-synuclein might impair oligodendroglial and, secondarily, neuronal integrity of those cells in the diseased brain. In an attempt to answer some of these questions, we have developed an "in vitro model of MSA" by expressing the wild-type or C-terminally truncated form of alpha-synuclein in glial cell cultures. With this simplified system, we have demonstrated that alpha-synuclein significantly affects the survival of glia and its vulnerability to environmental stress, which might represent a major step in the pathogenesis of MSA.

Basal Ganglia↗
PubMed2005

Therapeutic strategies in multiple system atrophy.

This review provides an update on therapeutic principles and their implications for practical management in multiple system atrophy (MSA), a sporadic neurodegenerative disorder characterized clinically by various combinations of dysautonomia, Parkinsonism, or cerebellar ataxia, often associated with other warning features (red flags), and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in selected multiple regions of the brain and spinal cord. Because of the small number of randomized controlled trials, the management of MSA is largely based on empirical or open-label evidence. Parkinsonism often shows a poor or unsustained response to chronic levodopa therapy, although more patients than previously recognized may experience an initial moderate-to-good dopaminergic response. There is no effective drug treatment for cerebellar ataxia. However, features of dysautonomia such as orthostatic hypotension, urinary retention or incontinence, constipation, and impotence, may often be relieved if recognized by the treating physician. Because no drug treatment consistently benefits patients with this disease in the long-term, palliative therapies are all the more important. Novel symptomatic and neuroprotective therapies are urgently required.

Adrenergic alpha-Antagonists↗
PubMed2005

Homocysteine and serum markers of immune activation in primary dystonia.

The cause of primary dystonia remains unknown. Several reports point to immune system disturbances in primary dystonia and a recent study demonstrated hyperhomocysteinemia in cervical dystonia. Homocysteine (HCY) is an amino acid and elevated HCY concentrations were shown to be associated with immune system activation and increased neopterin serum concentrations. We examined HCY serum concentrations together with serum markers of immune activation in patients with different types of primary dystonia. Eighty-three patients with different types of primary dystonia were included and investigated at least 3 months following botulinum toxin treatment. Thirty-six healthy volunteers with similar age and sex distribution served as controls. Total serum HCY, kynurenine, and tryptophan concentrations were determined by high-performance liquid chromatography; neopterin, folate, and vitamin B12 concentrations were measured by immunoassays. Routine blood analysis, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood count (WBC), was performed. Patients with primary dystonia had significantly higher HCY concentrations compared to controls. Among the dystonia subtypes, no significant difference of HCY serum concentrations was observed. CRP and ESR were within the normal range in >90% of the patients and all had normal WBC. Neopterin, kynurenine, and tryptophan serum concentrations were similar in patients and controls and not correlated with HCY serum concentrations. The results provide evidence against enhanced cellular immune activation in patients with primary dystonia. However, hyperhomocysteinemia was present in all dystonia subtypes and unrelated to immune activation in this study. HCY is a neuronal excitotoxic amino acid and hyperhomocysteinemia is considered an independent vascular risk factor. Further studies are required to define the background of hyperhomocysteinemia in primary dystonia.

Adult↗
PubMed2005

Progression of parkinsonism in multiple system atrophy.

BACKGROUND: Progression of parkinsonian motor impairment is usually rapid and relentless in multiple system atrophy (MSA). However, it may also be subject to considerable variation. Prospective natural history studies using validated rating scales are required to accurately determine the progression of parkinsonism in MSA. OBJECTIVE: To assess the progression of parkinsonism in patients with the Parkinson variant of MSA. METHODS: Parkinsonian motor impairment was assessed on regular therapy at two time points (mean follow-up 11.8 months, SD 1.4) using the Hoehn and Yahr scale (H&Y), the Schwab and England ADL scale (SES) and the motor examination section of the UPDRS (UPDRS-III) in 38 patients with clinically probable MSA-P. RESULTS: We examined 38 patients with probable MSA-P (mean age 63.2 years, SD 7.4; mean disease duration 4.1 years, SD 3.0). The mean difference of UPDRS-III between baseline and follow-up was 10.8 (95% CI 8.6-12.9), consistent with an average annual 28.3 % increase of UPDRS-III baseline scores. Several variables were associated with faster progression of parkinsonism including low baseline global motor disability as assessed by H&Y and SES, low baseline UPDRS-III score, and short disease duration. UPDRS-III progression was unrelated to gender, age at symptom onset, and age at baseline visit. CONCLUSION: This is the first observational study on UPDRS rates of decline in MSA. The observed 28.6% annual increase of UPDRS-III scores illustrates the rapid progression of motor impairment in MSA. Furthermore, motor progression appeared to be accelerated during the early disease stages. Our data allow sample size calculations that may be helpful for the planning of future therapeutic trials.

Age of Onset↗
PubMed2005

The Lewis family revisited: no evidence for autosomal dominant multiple system atrophy.

In 1964, Lewis reported a familial ataxia-dysautonomia syndrome reminiscent of Shy-Drager syndrome subsequently known as multiple system atrophy (MSA). Here we review this report and propose that the Lewis family may represent an unusual form of autosomal dominant cerebellar ataxia type I, which might be categorized either as SCA3 (Machado-Joseph disease) or a new SCA subtype. There remains no conclusive evidence to support the notion of hereditary MSA.

Adult↗
PubMed2005

Animal models of multiple system atrophy.

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder presenting with autonomic failure and motor impairment, primarily comprising L-dopa-resistant parkinsonism but occasionally involving cerebellar ataxia. These features result from progressive multisystem neuronal loss that is associated with oligodendroglial alpha-synuclein inclusions. The growing number of animal models for MSA reflects the search for a preclinical test-bed for elucidating MSA pathogenesis and for developing novel therapeutic interventions. Here, the currently available MSA animal models will be reviewed and leads for future research will be identified.

Animals↗
PubMed2005

Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism unresponsive to dopaminergic therapy, cerebellar ataxia, and dysautonomia. Neuropathology shows a characteristic neuronal multisystem degeneration that is associated with widespread oligodendroglial alpha-synuclein (alpha-SYN) inclusions. Presently no animal model completely replicates the specific neuropathology of MSA. Here we investigated the behavioral and pathological features resulting from oligodendroglial alpha-SYN overexpression in transgenic mice exposed to mitochondrial inhibition by 3-nitropropionic acid. In transgenic mice 3-nitropropionic acid induced or augmented motor deficits that were associated with MSA-like pathology including striatonigral degeneration and olivopontocerebellar atrophy. Widespread astrogliosis and microglial activation were also observed in the presence of alpha-SYN in oligodendrocytes. Our results indicate that combined mitochondrial inhibition and overexpression of oligodendroglial alpha-SYN generates a novel model of MSA that may be useful for evaluating both pathogenesis and treatment strategies.

Animals↗