Jörg Spiegel

Striatal FP-CIT uptake differs in the subtypes of early Parkinson's disease.

Summary.In idiopathic Parkinson’s disease (PD), a tremor-dominant type (TDT), an akinetic-rigid type (ART), and a mixed type (MT) are distinguished. We compared cerebral [I-123]FP-CIT SPECT in the PD subtypes (67 patients Hoehn and Yahr stage 1:26 with ART, 19 with MT, 22 with TDT). We measured the ratios putamen/occipital lobe binding and caudate nucleus/occipital lobe binding. Parkinsonian motor symptoms were quantified by UPDRS motor scale. In both putamen and caudate nucleus contralateral to the clinically affected body side TDT patients showed a significantly higher FP-CIT uptake than ART or MT patients (ANOVA; p<0.01). Contralateral putamen and caudate nucleus FP-CIT uptake correlated significantly with severity of rigidity (p<0.01) and hypokinesia (p<0.01) but not with severity of resting or postural tremor (p>0.05). The missing correlation between striatal FP-CIT uptake and tremor suggests, that further systems besides the nigrostriatal dopaminergic system may contribute to generation of parkinsonian tremor.

Enlarged Substantia Nigra Hyperechogenicity and Risk for Parkinson Disease: A 37-Month 3-Center Study of 1847 Older Persons

OBJECTIVE To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. DESIGN Longitudinal 3-center observational study with 37 months of prospective follow-up. SETTING Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. PARTICIPANTS Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. MAIN OUTCOME MEASURE Incidence of new-onset PD in relation to baseline transcranial sonography status. RESULTS There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants. CONCLUSIONS In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

FP-CIT and MIBG scintigraphy in early Parkinson's disease

Methods provided by nuclear medicine may be helpful in diagnosis of Parkinsons disease (PD). For that purpose, the sensitivity of iodine‐123 metaiodobenzylguanidine ([123I]MIBG) scintigraphy and [123I]FP‐CIT single photon emission computed tomography (SPECT) was studied in patients with PD onset (Hoehn and Yahr Stage 1). Cerebral [123I]FP‐CIT and cardiac [123I]MIBG scintigraphy were carried out in 18 patients with idiopathic Parkinsons disease, according to Hoehn and Yahr Stage 1. For quantification purposes, we calculated the striatum/posterior lobe binding of FP‐CIT and the heart‐to‐mediastinum (H/M) count ratio regarding MIBG scintigraphy. In 15 of 18 patients, we observed markedly reduced or asymmetric striatal FP‐CIT tracer accumulation. FP‐CIT binding of the affected striatum was significantly lower as compared with that of the unaffected side. Striatal FP‐CIT binding correlated significantly with the motor part of the Unified Parkinsons disease rating scale (UPDRS) but not with age, disease duration, or gender. MIBG scintigraphy delivered significant pathological results in 13 of 18 patients. There was no significant correlation between the H/M ratio relating to MIBG scintigraphy and the motor part of UPDRS, age, disease duration, or gender; however, binding of striatal FP‐CIT correlated significantly with cardiac MIBG accumulation. According to the clinical criteria, it might be difficult to prove the diagnosis of PD in patients with slight symptoms and in these cases, FP‐CIT SPECT and MIBG scintigraphy may contribute to the early diagnosis of PD. In addition, the functional loss of nigrostriatal and cardiac sympathetic neurons seems to be coupled closely.

Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls

BACKGROUND Patients with Parkinsons disease (PD) frequently have gastrointestinal symptoms (e.g. constipation) and exhibit the PD-typical pathohistology in the enteric nervous system (ENS). Both, clinical symptoms and pathohistological changes in the ENS occur at early stages and can precede the motor manifestations of PD. Two recent studies reported an association between changes in gut microbiota composition and PD. We hypothesized that alterations in gut microbiota might be accompanied by altered concentrations of short chain fatty acids (SCFA), one main metabolic product of gut bacteria. METHODS We quantitatively analyzed SCFA concentrations (using gas chromatography) and microbiota composition (using quantitative PCR) in fecal samples of 34 PD patients and 34 age-matched controls. RESULTS Fecal SCFA concentrations were significantly reduced in PD patients compared to controls. The bacterial phylum Bacteroidetes and the bacterial family Prevotellaceae were reduced, Enterobacteriaceae were more abundant in fecal samples from PD patients compared to matched controls. CONCLUSIONS Our study confirms the recently reported association between PD and the abundance of certain gut microbiota and shows a reduction in fecal SCFA concentrations (one main metabolic product of certain gut bacteria). The reduction in SCFA might, theoretically, induce alterations in the ENS and contribute to gastrointestinal dysmotility in PD. Prospective longitudinal studies in subjects at risk for PD are required to further elucidate the causal role of gut microbiota and microbial products in the development of PD and PD-associated dysmotility.

Myocardial sympathetic degeneration correlates with clinical phenotype of Parkinson's disease

In idiopathic Parkinsons disease (PD), different clinical subtypes are distinguished due to predominant motor symptoms: a tremor‐dominant type (TDT), an akinetic rigid type (ART), and a mixed type (MT). We compared myocardial sympathetic innervation, measured by MIBG scintigraphy, in different subtypes of PD at early and advanced stages of PD. We applied MIBG scintigraphy in 102 patients with PD. About 57 patients were at Hoehn and Yahr (H&Y) stage 1, 22 at H&Y stage 2, and 23 at H&Y stages 3 and 4. For quantification of myocardial MIBG uptake, the heart‐to‐mediastinum (H/M) count‐ratio was calculated. At all H&Y stages, myocardial MIBG uptake was significantly higher in TDT patients than in ART or MT patients (P < 0.05; ANOVA). Furthermore, at each H&Y stage, myocardial MIBG uptake correlated significantly with severity of hypokinesia (P < 0.05; Spearmans correlation) and rigidity (P < 0.05), but not with severity of resting or postural tremor. The significant correlation between myocardial sympathetic degeneration and severity of hypokinesia and rigidity suggests that myocardial sympathetic degeneration and hypokinetic‐rigid symptoms develop in a closely coupled manner in early as well as advanced PD. No such correlation can be found between myocardial sympathetic degeneration and parkinsonian tremor.

Functional relevance of ceruloplasmin mutations in Parkinson’s disease

Increased iron levels of the substantia nigra and the discovery of ceruloplasmin mutations in patients with Parkinsons disease (PD) imply impaired iron metabolism in this neurodegenerative disorder. Ceruloplasmin has ferroxidase activity oxidizing iron(II) to iron(III). In the present study, we analyzed the amount of ceruloplasmin, iron, ferritin, and transferrin and the ceruloplasmin ferroxidase activity in serum of patients with the diagnosis of PD carrying the ceruloplasmin mutations I63T, D544E, and R793H. The impact of these missense mutations on the biosynthesis of holo‐ceruloplasmin was investigated in cell culture experiments. Functional relevance was found for the ceruloplasmin mutations I63T and D544E. In vivo, the I63T mutation resulted in half the normal ceruloplasmin concentration and markedly reduced ferroxidase activity in serum from a heteroallelic PD patient. In cell culture, the I63T glycosylphosphatidylinositol (GPI)‐linked ceruloplasmin isoform was retained in the endoplasmatic reticulum of human embryonic kidney cells. Furthermore, the D544E polymorphism resulted in significantly reduced serum ceruloplasmin levels and ferroxidase activity in heteroallelic patients and in expression of mainly apo‐ceruloplasmin in cell culture. Our studies indicate that altered activity of ceruloplasmin may present a vulnerability factor for iron induced oxidative stress in PD.

Screening for mutations of the ferritin light and heavy genes in Parkinson's disease patients with hyperechogenicity of the substantia nigra.

Recently, an insertional mutation in the ferritin-L gene was reported in some patients with familial basal ganglia degeneration, which, however, could not be detected in another Parkinsons disease (PD) population. We investigated 186 PD patients, in whom an increased amount of iron of the substantia nigra (SN) was priorly identified by transcranial ultrasound, for mutations of the whole coding region of ferritin-L and ferritin-H by denaturing high-pressure liquid chromatography and subsequent sequencing. In the ferritin-L gene two silent mutations were detected. In the ferritin-H gene the sequence variation 161A-->G was found in one patient but none of the 186 controls. Although functional analysis will show, whether this sequence variation might be causative for single cases of PD, the results indicate that mutations in the ferritin genes are not a common cause for PD with increased levels of iron of the SN.

Screening for mutations of the IRP2 gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra.

Summary.IRP2 plays an important role in brain iron metabolism. We recently identified an increased amount of iron in patients with Parkinson’s disease (PD) and hyperchogenicity of the substantia nigra (SN). Therefore, the IRP2 gene was screened for mutations in 176 PD patients with increased echogenicity of the SN. We identified one non-synonymous polymorphism (I888V) in exon 21 and a −88C > T polymorphism in the promoter region of IRP2 at similar frequencies in patients and controls without increased SN iron levels. In one patient a −74C > T variation was found which was not present in the control group. Our data indicate that mutations in the IRP2 gene are not a common cause of PD associated with SN iron accumulation.

Long‐term course of substantia nigra hyperechogenicity in Parkinson's disease

A hyperechogenicity of the (SN+) in transcranial sonography corroborates the diagnosis of idiopathic Parkinsons disease (iPD). Although it is thought to represent a biomarker of the disease that is independent of disease severity and progression, differing results have been reported describing a positive correlation of the size and advancing clinical stage. In 50 parkinsonian patients, transcranial ultrasound and clinical examination was performed twice with a mean time interval of 6.4 years. SN+ did not change in size significantly between the first and second examination, whereas clinical parkinsonian symptoms—as determined by the motor part of the UPDRS—significantly worsened (P < 0.001). We found a highly significant intraindividual correlation in SN+ sizes between both examinations (P < 0.001). The size of SN+ did not correlate with the UPDRS part III at the time of first or second ultrasound examination. Progression of motor symptoms between the first and second investigation did not correlate with the size of SN+ at baseline. Furthermore, even in the subgroup of patients with an interval of ≥8 years between examinations, there was no significant change in SN+ size. SN+ represents a largely stable biomarker in iPD and does not reflect disease progression. The size of SN+ does not predict the further course of the disease.

Principal Component Analysis of gait in Parkinson's disease: Relevance of gait velocity

Principal Component Analysis (PCA) is a method to estimate the relation between data points. We used PCA to analyse movements of the upper and lower extremities during treadmill walking in healthy subjects and two groups of Parkinsonian patients. Healthy subjects (n=35) showed a typical pattern with high values of PC1 and low values in a descending order of PC2-PC4. Increase of speed resulted in a significant increase of PC1 and a significant decrease of the following PCs. In more severely affected patients (n=19, UPDRS>20), PC1 was significantly decreased and PC2-PC4 were significantly increased compared to healthy subjects. Speed could be increased only within a small range without corresponding changes of the PCs. In less severely affected patients (n=17), significant differences of the PCs were only found with fast pace. Separate analysis of arms and legs revealed that these changes are only due to altered movements of the arm. Analysis of the pattern of PCs in response to changes of gait velocities reveal alterations even in less severely affected Parkinsonian patients. The changes of the PCs with higher gait velocities in healthy subjects are suggestive of an increase of intersegmental coordination. This is impaired even in less severely affected Parkinsonian patients.