Reduced plasma taurine level in Parkinson's disease: association with motor severity and levodopa treatment

Purpose: This study aimed to evaluate the level of taurine in plasma, and its association with the severity of motor and non-motor symptoms (NMS) and chronic levodopa treatment in Parkinson's disease (PD). Patients and methods: Plasma taurine level was measured in treated PD (tPD), untreated PD (ntPD) and control groups. Motor symptoms and NMS were assessed using the Unified Parkinson's Disease Rating Scale, the short form of the McGill Pain Questionnaire, the Hamilton Depression Scale, the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms and the Pittsburgh Sleep Quality Index. Longtime exposure to levodopa was indicated by its approximate cumulative dosage. Results: The plasma taurine levels of PD patients were decreased when compared with controls and negatively associated with motor severity but not NMS. Moreover, tPD patients exhibited lower levels of plasma taurine than ntPD patients. Interestingly, plasma taurine levels negatively correlated with cumulative levodopa dosage in tPD. After controlling for potential confounders, the association between taurine and levodopa remained significant. Conclusion: Our study supports that taurine may play important roles in the pathophysiology of PD and the disturbances caused by chronic levodopa administration.     

Changes in endolysosomal enzyme activities in cerebrospinal fluid of patients with Parkinson's disease

Parkinson's disease (PD) is characterized neuropathologically by the cytoplasmic accumulation of misfolded α‐synuclein in specific brain regions. The endolysosomal pathway appears to be involved in α‐synuclein degradation and, thus, may be relevant to PD pathogenesis. This assumption is further strengthened by the association between PD and mutations in the gene encoding for the lysosomal hydrolase glucocerebrosidase. The objective of the present study was to determine whether endolysosomal enzyme activities in cerebrospinal fluid (CSF) differ between PD patients and healthy controls. Activity levels of 6 lysosomal enzymes (β‐hexosaminidase, α‐fucosidase, β‐mannosidase, β‐galactosidase, β‐glucocerebrosidase, and cathepsin D) and 1 endosomal enzyme (cathepsin E) were measured in CSF from 58 patients with PD (Hoehn and Yahr stages 1–3) and 52 age‐matched healthy controls. Enzyme activity levels were normalized against total protein levels. Normalized cathepsin E and β‐galactosidase activity levels were significantly higher in PD patients compared with controls, whereas normalized α‐fucosidase activity was reduced. Other endolysosomal enzyme activity levels, including β‐glucocerebrosidase activity, did not differ significantly between PD patients and controls. A combination of normalized α‐fucosidase and β‐galactosidase discriminated best between PD patients and controls with sensitivity and specificity values of 63%. In conclusion, the activity of a number of endolysosomal enzymes is changed in CSF from PD patients compared with healthy controls, supporting the alleged role of the endolysosomal pathway in PD pathogenesis. The usefulness of CSF endolysosomal enzyme activity levels as PD biomarkers, either alone or in combination with other markers, remains to be established in future studies. © 2013 Movement Disorder Society     

Hyperhomocysteinemia in levodopa‐treated patients with Parkinson's disease dementia

Dementia is a frequent non‐motor feature of Parkinson's disease (PD). Elevated plasma homocysteine (Hcy) levels have been associated with both cognitive impairment and dementia. Increased Hcy levels have been observed in levodopa‐treated patients with PD. The objective of our study was to evaluate the association between plasma Hcy levels and dementia in PD. We performed a multicenter cross‐sectional study on patients with PD with (PDD) and without (PDnD) dementia and age‐ and sex‐matched healthy controls. We compared Hcy levels in patients with PDD and PDnD and healthy controls, and we performed logistic regression analysis to search for an association between the presence of dementia and increased Hcy levels in PD. Patients with PD (121), PDD (42), and PDnD (79), and age‐ and sex‐matched controls (154) were enrolled. Hcy levels were higher in patients with PD compared to controls (17.5 μmol/L ± 10.2 vs. 11 ± 4.1; P < 0.00001). Among patients with PD, Hcy levels were higher in the PDD group compared to the PDnD group (20.7 μmol/L ± 12.1 vs. 15.8 ± 8.5; P = 0.002). In a multivariate logistic regression model, higher Hcy levels [Odds ratios comparing the top (>18.9 μmol/L) with the bottom tertile (<12.4 μmol/L): 3.68; 95% CI: 1.14–11.83] were significantly associated with dementia. These data support the association between elevated Hcylevels and the presence of dementia in PD. © 2009 Movement Disorder Society     

Alimentary,my dear Watson? The challenges of enteric α‐synuclein as a Parkinson's disease biomarker

An accurate early diagnostic test for Parkinson's disease (PD) is a critical unmet need. Recently, independent groups using different histological techniques have reported that the presence of alpha‐synuclein (α‐syn) in colonic biopsy tissue is able to distinguish living patients with PD from those without the disease. In addition, a further study has suggested that the presence of α‐syn in colonic biopsy tissue may be evident in early or even prodromal PD. However, several questions remain regarding the translation of these findings into using the assessment of α‐syn deposition in the enteric nervous system as a diagnostic biomarker for prodromal PD. Here we address critical issues related to the location and quantification of enteric α‐syn, detection of α‐syn with currently available histological techniques, timing of detection of α‐syn deposition, and, most crucially, whether enteric α‐syn can distinguish those with PD from both healthy individuals and individuals with other related diseases. We conclude that, although enteric α‐syn is a very exciting prospect, further studies will be vital to determine whether enteric α‐syn deposition has the potential to be the biomarker for prodromal PD that the field so desperately seeks. © 2013 International Parkinson and Movement Disorder Society     

Elevated homocysteine levels in levodopa‐treated idiopathic Parkinson's disease: a meta‐analysis

To assess the association between the elevation of plasma homocysteine (Hcy) level and long‐term levodopa (L‐dopa) therapy in idiopathic Parkinson's disease (PD). We performed a systematic literature review to recruit original studies published up to May 14, 2012. Studies enrolled should be controlled, with specific information of long‐term L‐dopa application and plasma Hcy in patients with PD. Effects were summarized using standardized mean differences (SMDs) or weighted mean differences (WMDs). Our search enrolled 22 eligible studies. Plasma Hcy levels were significantly higher in L‐dopa‐treated patients than those in healthy controls [SMD 0.97; 95% confidence interval (CI) 0.80–1.14, P < 0.001], L‐dopa‐naïve patients with PD (SMD 0.99; 95% CI 0.54–1.44, P < 0.001), and untreated patients (SMD 0.52; 95% CI 0.18–0.86, P < 0.01). However, its levels in untreated patients with PD were not significantly higher than in healthy controls (SMD 0.24; 95% CI ?0.03 to 0.51, P > 0.05). Patients with PD treated with L‐dopa plus catechol‐O‐methyltransferase inhibitor (COMT‐I) showed lower plasma Hcy concentrations compared with L‐dopa‐treated patients (WMD 4.62; 95% CI 2.89–6.35, P < 0.001). L‐dopa treatment is associated with the increase in plasma Hcy level in patients with PD. COMT‐I may attenuate L‐dopa‐induced elevation of Hcy level.     

Cerebrospinal fluid Tau/α‐synuclein ratio in Parkinson's disease and degenerative dementias

Although alpha‐synuclein is the main constituent of Lewy bodies, cerebrospinal fluid determination on its own does not seem fundamental for the diagnosis of synucleinopathies. We evaluated whether the combination of classical biomarkers, Aβ_1–42, total tau, phosphorylated tau, and α‐synuclein can improve discrimination of Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, and frontotemporal dementia. Aβ_1–42, total tau, phosphorylated tau, and α‐synuclein were measured in a series of patients with Parkinson's disease (n = 38), dementia with Lewy bodies (n = 32), Alzheimer's disease (n = 48), frontotemporal dementia (n = 31), and age‐matched control patients with other neurological diseases (n = 32). Mean α‐synuclein levels in cerebrospinal fluid were significantly lower in the pathological groups than in cognitively healthy subjects. An inverse correlation of α‐synuclein with total tau (r = ?0.196, P < .01) was observed. In the group of patients with Parkinson's disease, Aβ_1–42, total tau, and phosphorylated tau values were similar to controls, whereas total tau/α‐synuclein and phosphorylated tau/α‐synuclein ratios showed the lowest values. Cerebrospinal fluid α‐synuclein alone did not provide relevant information for Parkinson's disease diagnosis, showing low specificity (area under the curve, 0.662; sensitivity, 94%; specificity, 25%). Instead, a better performance was obtained with the total tau/α‐syn ratio (area under the curve, 0.765; sensitivity, 89%; specificity, 61%). Combined determination of α‐synuclein and classical biomarkers in cerebrospinal fluid shows differential patterns in neurodegenerative disorders. In particular, total tau/α‐synuclein and phosphorylated tau/α‐synuclein ratios can contribute to the discrimination of Parkinson's disease. © 2011 Movement Disorder Society     

Regional cortical grey matter loss in Parkinson's disease without dementia is independent from visual hallucinations

In our previous functional magnetic resonance imaging study, Parkinson's disease (PD) patients with visual hallucinations (VH) showed reduced activations in ventral/lateral visual association cortices preceding image recognition, compared with both PD patients without VH and healthy controls. The primary aim of the current study was to investigate whether functional deficits are associated with grey matter volume changes. In addition, possible grey matter differences between all PD patients and healthy controls were assessed. By using 3‐Tesla magnetic resonance imaging (MRI) and voxel‐based morphometry (VBM), we found no differences between PD patients with (n = 11) and without VH (n = 13). However, grey matter decreases of the bilateral prefrontal and parietal cortex, left anterior superior temporal, and left middle occipital gyrus were found in the total group of PD patients, compared with controls (n = 14). This indicates that previously demonstrated functional deficits in PD patients with VH are not associated with grey matter loss. The strong left parietal reduction in both nondemented patient groups was hemisphere specific and independent of the side of PD symptoms. © 2010Movement Disorder Society.     

Decreased olfactory bulb volume in idiopathic Parkinson's disease detected by 3.0‐Tesla magnetic resonance imaging

A number of neuropathological studies have demonstrated that the olfactory system is among the first brain regions affected in Parkinson's disease (PD). These findings correlate with pathophysiological and pathological data that show a loss in olfactory bulb (OB) volume in patients with PD. However, to date, MRI has not been a reliable method for the in vivo detection of this volumetric loss in PD. Using a 3.0‐Tesla MRI constructive interference in the steady‐state sequence, OB volume was evaluated in patients with PD (n = 16) and healthy control subjects (n = 16). A significant loss of OB volume was observed in patients with PD, compared to the healthy control group (91.2 ± 15.72 versus 131.4 ± 24.56 mm³, respectively). Specifically, decreased height of the left OB appears to be a reliable parameter that is adaptable to clinical practice and significantly correlates with OB volume loss in patients with idiopathic PD. Measuring both the volume and height of the OB by MRI may be a valuable method for the clinical investigation of PD. © 2012 Movement Disorder Society     

Tau/α‐synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study

Background : No CSF or plasma biomarker has been validated for diagnosis or progression of PD. Objectives : To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. Methods : CSF levels of α‐synuclein, amyloid‐ß1‐42, total tau, and threonine‐181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin‐1ß, interleukin‐2, interleukin, interferon‐γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. Results : CSF levels of α‐synuclein, amyloid‐ß1‐42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α‐synuclein, phosphorylated tau/α‐synuclein, total tau/amyloid‐ß1‐42+α‐synuclein, and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α‐synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut‐off value of ≤ 0.71). Phosphorylated tau/α‐synuclein and phosphorylated tau/amyloid‐ß1‐42+α‐synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin‐6 levels were positively correlated with UPDRS‐I, ‐II, and ‐III scores. Conclusions : The CSF phosphorylated tau/α‐synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin‐6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society     

Cysteine elevation in levodopa‐treated patients with Parkinson's disease

Homocysteine, cysteine, and cysteinyl‐glycine are all metabolically interrelated. Levodopa/decarboxylase inhibitor (LD/DCI) administration increases total homocysteine (tHcy) plasma levels. Objectives were to investigate associations between LD/DCI intake, concentrations of tHcy, cysteine, and cysteinyl‐glycine in PD patients and healthy controls. Cysteine levels were significant lower in controls and PD patients with tHcy below the treshold of 15 [μmol/L] when compared with PD patients with tHcy above 15. Cysteinyl‐glycine did not significantly differ between the three cohorts. Significant associations appeared between tHcys and cysteine in PD patients. tHcy and cysteine concentrations correlated to LD/DCI intake and severity of PD. The cysteine increase may be due to the significant higher dosing of daily LD/DCI and the significant higher morning LD/DCI dose 1 hour before blood sampling in PD patients with tHcy above 15 when compared with the remaining PD patients and the controls. The correlation outcomes support the view that LD/DCI intake may also increase cysteine. © 2009 Movement Disorder Society     

Cerebrospinal fluid lysosomal enzymes and alpha‐synuclein in Parkinson's disease

To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β‐glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α‐synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β‐glucocerebrosidase, β‐mannosidase, β‐hexosaminidase, and β‐galactosidase were measured with established enzymatic assays, while α‐synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β‐glucocerebrosidase‐encoding gene (GBA1). In the PD group, β‐glucocerebrosidase activity was reduced (P < 0.05) and patients at earlier stages showed lower enzymatic activity (P < 0.05); conversely, β‐hexosaminidase activity was significantly increased (P < 0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total α‐synuclein were significantly reduced (P < 0.05) in PD, in contrast to increased levels of α‐synuclein oligomers, with a higher oligomeric/total α‐synuclein ratio in PD patients when compared with controls (P < 0.001). A combination of β‐glucocerebrosidase activity, oligomeric/total α‐synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve = 0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD. © 2014 International Parkinson and Movement Disorder Society     

Serum homocysteine and physical exercise in patients with Parkinson's disease

Background: Hyperhomocysteinemia is a major risk factor for cerebral and peripheral vascular diseases, as well as cortical and hippocampal injury, including an increased risk of dementia and cognitive impairment. Elevated serum homocysteine (Hcy) concentrations are common in patients with Parkinson's disease (PD) who have been treated with levodopa; however, physical exercises can help reduce Hcy concentrations. The aim of the present study was to compare serum Hcy levels in patients with PD who partook in regular physical exercises, sedentary PD patients, and healthy controls. Methods: Sixty individuals were enrolled in the present study across three groups: (i) 17 patients who did not partake of any type of exercise; (ii) 24 PD patients who exercised regularly; and (iii) 19 healthy individuals who did not exercise regularly. All participants were evaluated by Hoehn and Yahr scale, the Unified Parkinson’s Disease Rating Scale (UPDRS) and Schwab and England scale (measure daily functionality). The serum levels of Hcy were analyzed by blood samples collected of each participant. An analysis of variance and a Tukey’s post hoc test were applied to compare and to verify differences between groups. Pearson’s correlation and stepwise multiple regression analyses were used to consider the association between several variables. Results: Mean plasma Hcy concentrations in individuals who exercised regularly were similar to those in the healthy controls and significantly lower than those in the group that did not exercise at all (P= 0.000). In addition, patients who did not exercise were receiving significantly higher doses of levodopa than those patients who exercised regularly (P= 0.001). A positive relationship between levodopa dose and Hcy concentrations (R²= 0.27; P= 0.03) was observed in patients who did not exercise, but not in those patients who exercised regularly (R²= 0.023; P= 0.15). Conclusions: The results of the present study suggest that, even with regular levodopa therapy, Hcy concentrations in PD patients who exercise regularly are significantly lower than in patients who do not exercise and are similar Hcy concentrations in healthy controls.     

Increases of pentraxin 3 plasma levels in patients with Parkinson's disease

Pentraxin 3 is a prototypic long pentraxin. Pentraxin 3 is a soluble recognition receptor that is involved in innate immunity and the inflammatory response. Its expression is induced by proinflammatory signals. The aim of this study was to compare the plasma levels of pentraxin 3 in healthy subjects and patients with neurodegenerative disorders such as mild cognitive impairment, Alzheimer's disease, and Parkinson's disease (PD). Thirty-nine patients with mild cognitive impairment, 75 patients with Alzheimer's disease, 66 patients with PD, and 41 healthy elderly controls were recruited for this study. We performed an extensive battery of neuropsychological tests, including a Mini-Mental Status Examination, clinical dementia rating, and the Unified Parkinson's Disease Rating Scale. A variety of clinical information was collected from the administered semistructured questionnaire. Plasma pentraxin 3 levels were measured using a specific enzyme-linked immunosorbent assay. Plasma pentraxin 3 levels were significantly higher in the PD patients than in the patients with mild cognitive impairment and Alzheimer's disease and in the control subjects. Plasma pentraxin 3 levels in the PD patients were correlated with activities of daily living (r = 0.368; P = .003) and motor function (r = 0.358; P = .004). Plasma pentraxin 3 levels could be a new biochemical marker for PD, and they may be associated with the severity of motor dysfunction and other clinical symptoms in PD patients.     

Distinct metabolomic signature in cerebrospinal fluid in early parkinson's disease

Objective: The purpose of this study was to profile cerebrospinal fluid (CSF) from early‐stage PD patients for disease‐related metabolic changes and to determine a robust biomarker signature for early‐stage PD diagnosis. Methods: By applying a non‐targeted and mass spectrometry‐driven approach, we investigated the CSF metabolome of 44 early‐stage sporadic PD patients yet without treatment (DeNoPa cohort). We compared all detected metabolite levels with those measured in CSF of 43 age‐ and gender‐matched healthy controls. After this analysis, we validated the results in an independent PD study cohort (Tübingen cohort). Results: We identified that dehydroascorbic acid levels were significantly lower and fructose, mannose, and threonic acid levels were significantly higher (P < .05) in PD patients when compared with healthy controls. These changes reflect pathological oxidative stress responses, as well as protein glycation/glycosylation reactions in PD. Using a machine learning approach based on logistic regression, we successfully predicted the origin (PD patients vs healthy controls) in a second (n = 18) as well as in a third and completely independent validation set (n = 36). The biomarker signature is composed of the three markers—mannose, threonic acid, and fructose—and allows for sample classification with a sensitivity of 0.790 and a specificity of 0.800. Conclusion: We identified PD‐specific metabolic changes in CSF that were associated with antioxidative stress response, glycation, and inflammation. Our results disentangle the complexity of the CSF metabolome to unravel metabolome changes related to early‐stage PD. The detected biomarkers help understanding PD pathogenesis and can be applied as biomarkers to increase clinical diagnosis accuracy and patient care in early‐stage PD. © 2017 International Parkinson and Movement Disorder Society     

Idiopathic Parkinson's disease patient‐derived induced pluripotent stem cells function as midbrain dopaminergic neurons in rodent brains

Patient‐specific induced pluripotent stem cells (iPSCs) are a promising source for cell transplantation therapy. In Parkinson's disease (PD) patients, however, their vulnerability and the transmission of pathological α‐Synuclein are possible drawbacks that may prevent PD‐specific iPSCs (PDiPSCs) from being used in clinical settings. In this study, we generated iPSCs from idiopathic PD patients and found that there was no significant vulnerability between dopaminergic (DA) neurons generated from healthy individuals and idiopathic PD patients. PDiPSC‐derived DA neurons survived and functioned in the brains of PD model rats. In addition, in the brains of α‐Synuclein transgenic mice, PDiPSC‐derived DA neurons did not cause pathological α‐Synuclein accumulation in the host brain or in the grafts. These results suggested that iPSCs derived from idiopathic PD patients are feasible as donor cells for autologous transplantation to treat PD. © 2017 Wiley Periodicals, Inc.     

A population‐based study on combined markers for early Parkinson's disease

The prerequisite for an earlier diagnosis of Parkinson's disease (PD) are markers that are both sensitive and specific for clinically definite PD and its prediagnosic phases. Promising candidates include enlarged hyperechogenicity of the substantia nigra (SN+) on transcranial sonography (TCS) and hyposmia. However, despite good sensitivity and specificity, both markers have yet failed to yield reliable predictions. We pursue the possibility of combined use in an ongoing population‐based cohort. Subjects were recruited from 10,000 inhabitants of Luebeck/Germany aged 50 to 79 years and additional PD patients from our outpatient clinic. After neurological examination, 715 subjects were grouped into clinically definite PD (n = 106), possible prediagnostic PD (ppPD; n = 73), and a control group subdivided into healthy individuals (n = 283) and controls with diseases other than PD (n = 253). Subjects underwent TCS and smell testing. Sensitivity and specificity of SN+ and hyposmia were good for PD; however, positive predictive values (PPV) of both SN+ (5.2%) and olfaction (2.5%) were low. At least one positive/both positive markers were present in 33%/1% of healthy controls, 33%/2% of diseased controls, 62%/7% of ppPD, and 94%/51% of PD. When combining SN+ and hyposmia, PPV increased to 17.6%, with a sensitivity of 51% and a specificity of 98%. Both SN+ and hyposmia offer good enrichment towards PD and ppPD, are stable against other diseases, and the combination of markers highly increases specificity. However, if the combination of SN+ and hyposmia were used as criterion for PD diagnosis, almost half of clinically definite PD and more than 90% of ppPD would have been missed. © 2014 International Parkinson and Movement Disorder Society     

Cortical thinning associated with mild cognitive impairment in Parkinson's disease

The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual‐visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n = 43) and PD patients with MCI (n = 47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains. © 2014 International Parkinson and Movement Disorder Society     

Depression and quality of life in monogenic compared to idiopathic,early‐onset Parkinson's disease

Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19). For comparison purposes, we included patients with idiopathic PD (IPD; n = 128; early onset, n = 38; late onset, n = 90), healthy controls (n = 127), and data on depressive symptoms of 144 patients with major depression (treated controls). Depression affected 31% of early‐onset PD cases, 21% of late‐onset cases, and 44% of manifesting carriers of mutations in PD genes, but was rare in the nonmanifesting carriers (7%) and healthy controls (5%). Subjects with Parkinson‐associated depression reported fewer feelings of guilt or self‐doubt than treated controls, but the occurrence of suicidal ideation was associated with severity of depression only. Social phobia (P = 0.018) and agoraphobia (P = 0.059) were more common in manifesting carriers than in any other group. QoL was decreased in the Parkinson groups, particularly in the early‐onset cases (P < 0.001), and QoL correlated with depression in all analyses. In our study, monogenic and IPD cases were comparable in QoL and depression characteristics. The QoL and, possibly, overall prognosis of all PD patients can be improved by appropriate attention and treatment for depression, sleep impairments, and anxiety, even if the treatment of the motor problems cannot be further optimized. © 2012 Movement Disorder Society     

THIS ARTICLE HAS BEEN RETRACTED: Pathological biochemistry of α‐synucleinopathy

Lewy bodies (LBs) are hallmark lesions in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We raised a monoclonal antibody LB509 against purified LBs from the brains of patients with DLB that strongly immuolabled LBs, and found that α‐synuclein is one of the major components of LBs. Thus, the deposition of α‐synuclein, an abundant presynaptic brain protein, as fibrillary aggregates in affected neurons or glial cells, was highlighted as a hallmark lesion of a subset of neurodegenerative disorders, including PD, DLB and multiple system atrophy collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in and multiplication of α‐synuclein gene in some pedigrees of familial PD has strongly implicated α‐synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific post‐translational modifications that characterize and underlie the aggregation of α‐synuclein in synucleinopathy brains by mass spectrometry and using a specific antibody, and found that serine 129 of α‐synuclein deposited in synucleinopathy lesions is selectively and extensively phosphorylated. Furthermore we generated transgenic C. elegans overexpressing α‐synuclein in neurons, and found that overexpression of familial PD‐linked mutant form of α‐synuclein impairs functions of dopamine neurons. These findings collectively underscore the importance of deposition of α‐synuclein as well as its phosphorylation in the pathogenesis of α‐synucleinopathies.