Andrzej Friedman

Swallowing disorders in Parkinson's disease

The aim of this study was to assess the reflex and oral, pharyngeal, esophageal phase of swallowing in patients with Parkinsons disease (PD). Eighteen patients with PD and 22 healthy control subjects were investigated using electromyography (EMG) and esophageal scintigraphy. This study demonstrated delayed triggering of the swallowing reflex (443+/-84 ms in patients with PD vs. 230+/-96 ms in controls, p<0.05) and prolongation of laryngeal movement (980+/-140 vs. 649+/-145 ms, p<0.05). We found prolongation of the esophageal phase of swallowing (14.46+/-5.30 vs. 7.45+/-1.64 s, p<0.001) in PD patients. The dysphagia limit i.e. the maximum amount of water swallowed at once was smaller in PD patients than in controls (6.23+/-3.67 vs. >20 ml). Dysphagia was observed in all patients studied although only 13 of them complained about it. In the remaining five cases swallowing impairment was subclinical and it consisted of decreased dysphagia limit and prolongation of the esophageal phase. Dysphagia at the subclinical level may be one of the early symptoms of PD.

Spontaneous remissions in spasmodic torticollis

We reviewed the frequency of spontaneous remissions in spasmodic torticollis (ST). One hundred sixteen patients with idiopathic ST (72 F, 44 M) were examined. The age at onset ranged from 9 to 69 (mean, 38.1 ± 1.3). Twenty-one patients (18%) were Jewish. Eleven patients (9%) had a history of familial dystonia. Remissions longer than 1 year unrelated to treatment were observed in 14 patients (12%) (9 F, 5 M). They occurred in the first year of ST in 13 patients (93%) and in the eighth year in 1. Duration of remissions ranged from 1 to 20 years (mean, 6.5 ± 1.6). Two patients had three remissions, and another had two. The mean age at the onset of ST in patients with remission was 26.4 ± 3.3 (SEM) and ranged from 9 to 49. The age at the onset in the patients without remissions was 39.7 ± 1.4, ranging from 10 to 69 (p < 0.01). In the remission group, 3 patients were Jewish (21%); in the non-remission group, 18 (18%) were Jewish. There was a familial history in 1 case with remission (7%) and in 10 cases (10%) without remission. Spontaneous remissions in the course of ST seem to be more frequent in patients with early onset, and they occur usually during the first year.

Ferritin as an important player in neurodegeneration.

Oxidative stress is considered one of the pathways leading to neuronal death in neurodegenerative disease. Many published studies aimed to assess the possible role of iron in this process but no consensus has been reached. On the other hand little is known about the role played by the main iron storage protein - ferritin. In this review we discuss the data obtained using several methods - Mössbauer spectroscopy, electron microscopy and ELISA - from human brain tissue both in controls and in four neurodegenerative disorders - Parkinsons (PD) and Alzheimers disease, progressive supranuclear palsy and neuroferritinopathy. Iron may only cause oxidative stress injury when it is available as labile iron for Fenton reaction. This may be related to the decreased ability of ferritin to retain iron within the iron core of ferritin. This happens in PD and in neuroferritinopathy. In PD there is a decrease in the concentration of L ferritin, while in neuroferritinopathy there is a genetically induced mutation in L ferritin causing its loss of function. We discuss the importance of the ratio H/L ferritin and its changes in neurodegeneration.

Iron and reactive oxygen species activity in parkinsonian substantia nigra

OBJECTIVES We sought to determine concentrations of total and labile iron in substantia nigra from patients with Parkinson disease and from controls to assess if oxidative stress is triggered by an increased concentration of iron. METHODS Total iron concentration in the whole substantia nigra was evaluated in 17 parkinsonian and 29 control samples. Concentrations of labile iron and copper were assessed in 6 parkinsonian and 8 control samples. The total iron concentration, the Fe(2+)/Fe(3+) ratio, and iron-binding compounds were determined by Mössbauer spectroscopy. Labile iron and copper were measured by electrothermal atomic absorption spectrometry. Activity of reactive oxygen species was evaluated by visible light fluorescence. RESULTS The labile iron concentration was significantly higher and corresponded to significantly higher reactive oxygen species activity in parkinsonian vs control samples. No significant difference was found in the total concentrations of copper or iron in the whole substantia nigra between parkinsonian and control samples. Mössbauer spectroscopy detected no Fe(2+) in any samples. CONCLUSIONS The substantia nigra of parkinsonian patients contained more labile iron compared with that of controls. This labile iron generated higher reactive oxygen species activity. The oxidative stress damage in parkinsonian substantia nigra may be related to an excess of labile iron and not of the total iron in the diseased tissue.

Quantitative assessment of parkinsonian sialorrhea and results of treatment with botulinum toxin

Aim: To assess quantitatively sialorrhea in Parkinsons disease (PD) and the efficacy of botulinum toxin (BOTOX) in its treatment.Material: 11 patients with a clinical diagnosis of idiopathic PD and drooling were assessed at least two points on the UPDRS Part II and 14 control subjects.Methods: Salivation was measured by weighing dental rolls before, and 2min after, insertion at six points of highest secretion of saliva in the mouth (buccal vestibule, and sublingual area). PD patients were assessed before and 1 week after injections of five units of BOTOX into each parotid salivary gland and the results were compared to the salivation production of controls.Results: Average secretion of saliva in PD patients was significantly higher than in controls-0.39+/-0.4g/2min. (range: 0.02-1.82) vs 0.19+/-0.16g/2min. (range: 0.02-0.98) (P=0.03). After treatment, the average secretion of saliva in PD patients decreased to 0.25+/-0.26g/2min. (range: 0.004-0.99) and did not differ significantly from controls. Nine patients improved also according to UPDRS. No side effects were observed in any of the patients injected.Conclusion: Botulinum toxin may be an effective and safe treatment of parkinsonian sialorrhea.

Parkinsonism and dystonia caused by the illicit use of ephedrone--a longitudinal study.

A neurological syndrome characterized by levodopa unresponsive bradykinesia, retropulsion with falls backwards, dysarthria, gait disturbance, dystonia, and emotional lability was identified in 13 male opiate addicts following the prolonged intravenous use of ephedrone (methcathinone), a central nervous stimulant prepared from pseudoephedrine, potassium permanganate, and vinegar. The natural history, response to treatment, and clinical features has been studied, and MR and dopamine transporter SPECT brain imaging were carried out. Pubic hair was sampled for manganese. The clinical and radiological picture closely resembled previous reports of chronic manganese poisoning and increased mean manganese level in pubic hair observed for at least 1 year after cessation of ephedrone. Odor identification was intact. Cognitive assessment showed a mild executive dysfunction and a mild depression. DaTSCANs were all normal. The neurological syndrome bears some similarities to PSP but differs from Parkinsons disease. Delayed neurological progression despite discontinuation of ephedrone occurred in one‐third of cases. Ephedrone poisoning should be considered as a possible cause of secondary Parkinsonism in young adults, particularly from Eastern Europe.

Quality of life in Polish patients with long-lasting Parkinson's disease.

The objective of this study was to evaluate possible relationships between quality of life (QoL) of Polish patients with long‐lasting Parkinsons disease and various demographic and clinical factors. The study comprised 141 patients of Movement Disorders outpatient clinics in Warsaw and Gdansk with at least 5 years of the disease duration. Mean age of patients was 68.09 ± 8.51 years, mean duration of disease was 11.87 ± 5.14 years. To assess the quality of life, the Parkinsons Disease Questionnaire (PDQ‐39) was used. Additional questions concerned duration of disease, initial and current treatment and expenses associated with therapy. Self‐perceived symptoms of depression were in our study the most important factor determining QoL. Duration of the disease and expenses related to the treatment also have a significant impact on the QoL. Patients age and presence of dyskinesia seem to be irrelevant to the quality of life.

Iron as a cause of Parkinson disease - a myth or a well established hypothesis?

Iron is considered to be a possible trigger of oxidative stress leading to neurodegeneration. This mechanism of neuronal death is proposed as a cause of Parkinson disease. Although most of researchers agree with this, controversies remain regarding the amounts of iron needed for this process. According to non destructive methods of assessment of the concentration of the total iron in substantia nigra, there is no difference between PD and control. However there is no need for an increase of the total iron in parkinsonian SN to trigger the oxidative stress but only of the non-ferritin bound labile iron. Our recent studies suggest an increase of this iron in PD SN. This finding corresponds well to a decrease of L-ferritin concentration in parkinsonian SN and also to a difference of the size of iron core of ferritin between PD and control SN. The significance of these finding will be discussed.

Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

See Gandhi and Plun-Favreau (doi:10.1093/aww320) for a scientific commentary on this article. It has been postulated that heterozygous mutations in recessive Parkinson’s genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson’s disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson’s disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson’s disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.

Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease.

OBJECTIVE Mutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinsons disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin. METHODS Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function. RESULTS We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants. CONCLUSIONS Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.