Isabel Wurster

Enlarged hyperechogenic substantia nigra as a risk marker for Parkinson's disease

SN hyperechogenicity (SN+), determined by transcranial sonography, has been proposed as a risk factor for Parkinsons disease (PD). Recently, we reported a 17.4‐fold increased risk for PD in individuals with SN+ older than 50 years within 3 years.

Prodromal features for Parkinson's disease – baseline data from the TREND study

A number of non‐motor features are known to precede motor manifestations of Parkinsons disease (PD). They are supposed to already represent the prodromal neurodegenerative state in those who later develop PD and are thus called prodromal markers. In this study, three prodromal markers, depression, rapid eye movement behaviour disorder (RBD) and hyposmia, were selected and were related to other prodromal features in elderly individuals without PD.

Reduced but not oxidized cerebrospinal fluid glutathione levels are lowered in Lewy body diseases.

Reduced (GSHR) but not oxidized glutathione (GSSG) has been shown to be dramatically altered in the substantia nigra (SN) of Lewy body disease (LBD) patients post mortem; but up to now, there is no convincing evidence that these changes can be monitored in vivo. We investigated GSHR and GSSG in rapidly processed cerebrospinal fluid (CSF) and plasma samples of 80 LBD and 35 control subjects and detected reduced CSF GSHR levels in LBD subjects. The reduction was negatively associated with age but not with disease‐associated parameters. Plasma GSHR, CSF GSSG, and plasma GSSG levels did not significantly differ between the groups. Our findings confirm the results from neuropathologic studies, which demonstrated an alteration of the glutathione system in LBD. We hypothesize that alterations of the glutathione system occur in a very early stage of the disease or may even represent a risk marker for LBD.

The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinsons disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.

Serum and Cerebrospinal Fluid Uric Acid Levels in Lewy Body Disorders: Associations with Disease Occurrence and Amyloid-β Pathway

Recent studies have provided evidence that uric acid (UA), a natural antioxidant, may play a role in the development and progression of Parkinsons disease (PD) and of dementia. In this clinical study we were therefore interested in the role of UA in Lewy body disorders (LBD), which includes Parkinsons disease (PD) and a common form of neurodegenerative dementias, dementia with Lewy bodies (DLB). Ninety-five LBD patients (55 non-demented PD patients, PDND; 20 PD patients with dementia, PDD; and 20 DLB patients) and 76 controls underwent clinical and biochemical analyses including, from a subcohort, cerebrospinal fluid (CSF) analyses, and analysis of three single nucleotide polymorphisms (SNPs) known to be associated with altered serum UA levels. We confirmed previous findings of lowered serum UA levels in LBD patients compared to controls. In CSF, UA levels were significantly higher in PDND patients (median 0.7 mg/dl) compared only to demented LBD patients (0.4 mg/dl; p = 0.03), but not to controls (0.5 mg/dl; p = 0.12). CSF UA levels correlated positively with CSF Aβ42 levels. This correlation was highest in controls (ρ = 0.67), intermediate in PDND (ρ = 0.49), but not observable in demented LBD patients (ρ = 0.10). These findings suggest an involvement of serum UA in LBD occurrence, and an involvement of CSF UA in cognitive decline in LBD, possibly through the Aβ pathway. SNP rs1165205 (SLC17A3) was weakly associated with altered CSF UA levels. Taken together, our results provide first evidence for disease-relevant but potentially distinct roles of UA in the blood and CSF compartment, respectively, in LBD.

Diffusion Imaging of Nigral Alterations in Early Parkinson's Disease With Dopaminergic Deficits

This study reports the baseline characteristics of diffusion tensor imaging data in Parkinsons disease (PD) patients and healthy control subjects from the Parkinsons Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits.

Mild Parkinsonian Signs in the Elderly – Is There an Association with PD? Crossectional Findings in 992 Individuals

Background Mild parkinsonian signs (MPS) are common in the elderly population, and have been associated with vascular diseases, mild cognitive impairment and dementia; however their relation to Parkinsons disease (PD) is unclear. Hypothesizing that individuals with MPS may reflect a pre-stage of PD, i.e. a stage in which the nigrostriatal system is already affected although to a milder degree than at the time of PD diagnosis, aim of this study was to evaluate the similarities between MPS and PD. Methods The TREND study is a prospective cross-sectional cohort study in individuals >50 years with biennial assessments designed to identify markers for an earlier diagnosis of Parkinsons and Alzheimers disease. For this substudy 992 individuals were included for analyses (892 controls, 73 MPS individuals, 27 PD patients). Parameters defining risk of PD (sex, age, positive family history), prodromal markers (hyposmia, REM sleep behavior disorder, depression and autonomic failure) as well as quantitative fine motor, axial motor and cognitive parameters were compared between the three cohorts. Results As expected, PD patients differed from controls with regard to 12 of 15 of the assessed parameters. MPS individuals differed significantly from controls in 12 of the PD-associated parameters, but differed from PD only in 5 parameters. Conclusion This study shows that individuals with MPS share many prodromal and clinical markers of PD with PD patients, implying that either a common dynamic process or similar constitutional factors occur in MPS individuals and PD patients.

Differentiation between idiopathic and atypical parkinsonian syndromes using three-dimensional magnetic resonance spectroscopic imaging

Objectives Degeneration of dopaminergic neurons in the substantia nigra (SN) pars compacta is the primary cause of idiopathic Parkinsons disease (iPD). In early stages of disease in particular, presentation of symptoms is non-specific leading to difficulties in differentiating between iPD and atypical parkinsonian syndromes (aPS). The aim of this study was to evaluate the feasibility of three-dimensional magnetic resonance spectroscopic imaging (MRSI) of the SN region for differentiation between iPD and aPS. Methods 20 patients with iPD, 10 with aPS and 22 controls were examined on a 3 T MR scanner using three-dimensional MRSI with a voxel size of 0.252 ml and an echo time of 30 ms. Excitation volume was positioned in such a way that in each hemisphere 1 voxel defines the rostral and 1 voxel the caudal SN region. Using a fully automatic spectra evaluation, the metabolite ratios of N-acetyl aspartate/creatine (NAA/Cr) were calculated. Results In all cases spectra with good quality were obtained. Differences in rostral to caudal NAA/Cr ratios were significant between controls and iPD patients, as well as between iPD and aPS patients (p<0.001 for both). For controls, rostral NAA/Cr was greater than caudal, whereas in iPD patients this ratio was reversed. aPS patients showed similar ratios as controls. Conclusions Typical reversed rostral to caudal NAA/Cr ratios in iPD patients suggests that they could be linked to specific pathology of neuronal loss in the SN pars compacta. Therefore, the results suggest that MRSI may support the differential diagnosis of patients with clinically unclassifiable parkinsonian syndromes who do not yet fulfil the established clinical criteria.

Genome-wide association study in essential tremor identifies three new loci.

Essential tremor has a high heritability, but its molecular genetic determinants remain unknown. Müller et al. conduct a genome-wide association study in more than 2800 patients with essential tremor and more than 6800 controls of European descent, and identify three new loci associated with the disease.

Transcranial Sonography in Essential Tremor

Essential tremor (ET) is the most common adult movement disorder. Especially in early stages the clinical differentiation between essential and Parkinsonian tremor may be a diagnostic challenge. Recent studies have consistently found hyperechogenic alterations in the area of the substantia nigra (SN) in patients with Parkinsons disease (PD) using transcranial sonography (TCS). The present chapter summarizes five studies, which have been performed to investigate SN echogenicity in patients with ET compared with PD patients and healthy control subjects and also includes our own experience. All of the studies published so far have shown that hyperechogenicity of the SN is a typical finding in about 90% of patients with PD, but not in patients with ET. In ET patients, the prevalence of hyperechogenicity is in the range of healthy control subjects or slightly above, which may indicate an increased risk for PD in the subgroup of ET patients with hyperechogenicity, consistent with the increased risk for PD that has been established in ET patient cohorts. As TCS is a noninvasive and inexpensive method, it seems to be a valuable instrument in the differentiation between ET and PD. Future follow-up studies on ET patients with SN hyperechogenicity will reveal whether those with increased echosignal are indeed the ones who may develop PD later in life.