Early Parkinson's Disease Group Research Articles

Sympathetic dysfunction as an early indicator of autonomic involvement in Parkinson's disease.

The specific characteristics of autonomic involvement in patients with early Parkinson's disease (PD) are unclear. This study aimed to evaluate the characteristics of autonomic dysfunction in drug-naïve patients with early-stage PD without orthostatic hypotension (OH) by analyzing Valsalva maneuver (VM) parameters. We retrospectively analyzed drug-naïve patients without orthostatic hypotension (n = 61) and controls (n = 20). The patients were subcategorized into early PD (n = 35) and mid-PD (n = 26) groups on the basis of the Hoehn and Yahr staging. VM parameters, including changes in systolic blood pressure at late phase 2 (∆SBPVM2), ∆HRVM3, Valsalva ratio (VR), pressure recovery time, adrenergic baroreflex sensitivity, and vagal baroreflex sensitivity, were assessed. In the early PD group, ∆SBPVM2, a marker of sympathetic function, was significantly lower compared with that in controls (risk ratio = 0.95, P = 0.027). Receiver operating characteristic (ROC) curve analysis showed an optimal cut-off value of -10mmHg for ∆SBPVM2 [P = 0.002, area under the curve (AUC): 0.737]. VR exhibited an inverse relationship with Unified Parkinson's Disease Rating Scale Part 3 scores in the multivariable regression analysis (VR: P = 0.038, β = -28.61), whereas age showed a positive relationship (age: P = 0.027, β = 0.35). The ∆BPVM2 parameter of the VM may help detect autonomic nervous system involvement in early-PD without OH. Our results suggest that sympathetic dysfunction is an early manifestation of autonomic dysfunction in patients with PD.

Different associated factors of subjective cognitive complaints in patients with early and advanced Parkinson's disease.

Subjective cognitive complaints (SCCs), defined as cognitive decline reported by subjects or their informants, are common in the early stage of Parkinson's disease (PD). Previous studies have shown a significant association between SCCs and non-motor features as well as objective cognitive decline in PD patients. However, the discrepancy in SCC prevalence and SCC-related factors between patients with early PD and those with advanced PD remains poorly understood. We recruited a total of 114 and 69 early PD patients and advanced PD patients, respectively. Univariate and multivariate logistic regression analyses were performed for early PD and advanced PD patients. The prevalence of SCCs in the early PD and advanced PD groups was 60.5 and 68.1%, respectively. In the early PD group, the presence of SCCs in early PD participants was significantly associated with a higher nonmotor symptoms questionnaire (NMSQ) score (OR = 1.05, 95% CI = 1.00-1.10, p = 0.040). SCCs in the advanced PD group were related to lower attention scores (OR = 0.24, 95% CI = 0.05-0.90, p = 0.043) and lower visuospatial/executive abilities scores (OR = 0.18, 95% CI = 0.04-0.86, p = 0.032). The prevalence and SCC-related factors are distinct in early PD and advanced PD. These findings suggest that SCCs in PD patients with different disease statuses appear to have different related factors that may depend on different disease severities.

Specific Distribution of Digital Gait Biomarkers in Parkinson's disease Using Body-Worn Sensors and Machine Learning.

Gait impairment leads to reduced social activities and low quality of life in people with Parkinson's disease (PD). PD is associated with unique gait signs and distributions of gait features. The assessment of gait characteristics is crucial in the diagnosis and treatment of PD. At present, the number and distribution of gait features associated with different PD stages are not clear. Here, we used whole-body multinode wearable devices combined with machine learning to build a classification model of early PD (EPD) and mild PD (MPD). Our model exhibited significantly improved accuracy for the EPD and MPD groups compared with the healthy control (HC) group (EPD vs. HC accuracy=0.88, kappa=0.75, AUC=0.88; MPD vs. HC accuracy=0.94, kappa=0.84, AUC =0.90). Furthermore, the distribution of gait features was distinguishable among the HC, EPD and MPD groups (EPD based on variability features (40%); MPD based on amplitude features (30%)). Here, we showed promising gait models for PD classification and provided reliable gait features for distinguishing different PD stages. Further multicentre clinical studies are needed to generalize the findings.

Cerebral cortical thinning in Parkinson's disease depends on the age of onset.

Patients with older-onset Parkinson's disease (PD) have more severe motor symptoms, faster progression, and a worse prognosis. The thinning of the cerebral cortex is one of the causes of these issues. Patients with older-onset PD manifest more extended neurodegeneration associated with α-synuclein deposition in the cerebral cortex; however, the cortical regions that undergo thinning are unclear. We aimed to identify cortical regions with different thinning depending on the age of onset in patients with PD. Sixty-two patients with PD were included in this study. Patients with PD onset at <63 years old were included in the early or middle-onset PD group, and those with PD onset at >63 years old were included in the late-onset PD (LOPD) group. Brain magnetic resonance imaging data of these patients were processed using FreeSurfer to measure their cortical thickness. The LOPD group displayed less cortical thickness in the superior frontal gyrus, middle frontal gyrus, precentral gyrus, postcentral gyrus, superior temporal gyrus, temporal pole, paracentral lobule, superior parietal lobule, precuneus, and occipital lobe than the early or middle-onset PD group. Compared with patients with early and middle-onset PD, elderly patients displayed extended cortical thinning with disease progression. Differences in the clinical manifestations of PD according to the age of onset were partly due to variations in the morphological changes in the brain.

Early approaches of YKL-40 as a biomarker and therapeutic target for Parkinson's disease.

Aim: To investigate whether the estimation of cerebrospinal fluid (CSF) and brain YKL-40 levels may be used as an efficient biomarker for Parkinson's disease (PD). Methods: Lipopolysaccharides (LPS) was injected into the right substantia nigra pars compacta (SNpc). Rats were divided into: control group, early LPS-induced PD group (14 days), and advanced LPS-induced PD group (28 days). YKL-40 and other related factors were detected in CSF and brain tissue. Results: Increased expression of YKL-40 was observed in brain tissue and CSF of PD-induced rats associated with triggered inflammatory cytokine release. Conclusion: The current study was limited to detecting YKL-40 and other inflammatory factors in brain and CSF. YKL-40 may be considered as an early biomarker and therapeutic target for PD.

Erythrocytic alpha-synuclein in early Parkinson's disease: A 3-year longitudinal study

BackgroundEarly diagnosis of Parkinson's disease (PD) could significantly improve outcomes for patients and future disease-modifying treatments. Several studies have revealed that α-synuclein levels in peripheral erythrocytes are associated with PD, but the diagnostic value in early PD is still unknown. MethodsThis study included both cross-sectional and longitudinal design. The subjects included 45 patients with early PD and 79 age-matched healthy controls. Participants were re-examined with repeated blood collection and clinical assessments after 3 years. The electrochemiluminescence assay was used to measure total and oligomeric α-synuclein levels respectively. The diagnostic value of erythrocytic α-synuclein for early PD was determined by receiver operator characteristic (ROC) curve. Correlations between RBC α-synuclein levels and changes over 3 years in clinical characteristic scores were further investigated with a linear regression. ResultsTotal and oligomeric α-synuclein levels in erythrocyte were significantly increased in early PD groups compared with control group (Total α-synuclein, p < 0.001; Oligomer, p < 0.001). Levels of total and oligomeric α-synuclein in erythrocytes were correlated with MDS-UPDRS III scores in early PD (Total α-synuclein, p = 0.008; Oligomer, p = 0.037). After adjusting for age, gender and dopaminergic medication, an association was found between higher erythrocytic oligomeric α-synuclein levels at baseline and greater increase in MDS-UPDRS III scores over 3 years (p = 0.007). ConclusionOur study suggests that total and oligomeric α-synuclein in erythrocyte were elevated even in the initial motor stage of PD. Higher erythrocytic oligomeric α-synuclein levels at baseline predicts a faster clinical decline over time in patients with early PD.

Proton Magnetic Resonance Spectroscopy for Diagnosis of Non-Motor Symptoms in Parkinson's Disease

BackgroundThe current diagnosis of Parkinson's disease (PD) is mainly based on the typical clinical manifestations. However, 60% dopaminergic neurons have died when the typical clinical manifestations occur. Predictive neurobiomarkers may help identify those PD patients having non-motor disorders or in different stage and achieving the aim of early diagnosis. Up to date, few if any neuroimaging techniques have been described useful for non-movement disorders diagnosis in PD patients. Here, we investigated the alteration of metabolites in PD patients in different stage of PD and non-motor symptoms including sleep, gastrointestinal and cognitive dysfunction, by using the 1H-MRS.MethodsA total of 48 subjects were included between 2017 and 2019: 37 PD (15 men, age 47–82 years) and 11 healthy people (8 men, age 49–74 years). All participants underwent MRI and multi-voxel 1H-MRS examination within 3 days in admission. Six kinds of metabolites, such as creatine (Cr), N-acetyl aspartate/creatine (NAA/Cr), N-acetyl aspartate/choline (NAA/Cho), choline/creatine (Cho/Cr), lipid/creatine (LL/Cr), and myo-Inositol/creatine ratio (mI/Cr) were tested among the PD group and the control groups. Statistical analyses and correlation analyses were performed by using SPSS. The p < 0.05 was considered statistically significant.ResultsCompared late PD group with a control group or early group, higher Cr ratio and lower NAA/Cr ratio were observed in the late PD group (p < 0.05). The mI/Cr in the late PD group was also lower than that in the early PD group (p < 0.05). Regarding the relationship between metabolites and NMS, Cho/Cr was higher in the sleep disorder group, whereas mI/Cr was lower in the gastrointestinal dysfunction group in comparison with the non-symptom groups. Moreover, Cr, Cho/Cr, mI/Cr, and LL/Cr were identified to have higher concentrations in the cognitive group in thalamus.ConclusionsProton magnetic resonance spectroscopy is an advanced tool to quantify the metabolic changes in PD. Three biomarkers (Cr, NAA/Cr, and mI/Cr) were detected in the late stage of PD, suggesting that these markers might be potential to imply the progression of PD. In addition, subgroups analysis showed that MRS of thalamus is a sensitive region for the detection of cognitive decline in PD, and the alteration of neurochemicals (involving Cr, Cho, mI, and LL) may be promising biomarkers to predict cognitive decline in PD.

24-hour ambulatory blood pressure alterations in patients with Parkinson's disease.

ObjectsAbnormal blood pressure (BP) regulation is a feature of autonomic dysfunction in Parkinson's disease (PD) patients. The present study was to analyze the BP alterations by 24‐h ambulatory BP monitoring in PD patients with different disease stages and subtypes.Methods32 consecutive patients PD patients and 43 control patients in our hospital from 2017 to 2020 were included. The circadian BP rhythm was divided into three types according to the 24‐h ambulatory BP monitoring. Dipping was defined as an average systolic BP (SBP) reduction during night‐time of 10%–19%. Reverse dipping was defined as an average increase in night‐time SBP values. The differences of the circadian BP rhythm and BP variability (BPV) were analyzed between PD group and the control group, the early PD group and the advanced PD group, as well as the tremor‐dominant group and the nontremor‐dominant group.ResultsThere was statistical difference in circadian BP rhythm between PD group and control group (p < .05). There were statistical differences in circadian BP rhythm between the early PD group and the advanced PD group (p < .05). The mean values of night‐time SBP and diastolic BP (DBP) in the advanced PD group were higher than those in the control group and the early PD group (p < .05). The DBP CV in the advanced PD group was higher than that in the control group and the early PD group (p < .05). There was no significant difference of circadian BP rhythm, mean BP, and BPV between the tremor‐dominant and the nontremor‐dominant PD group after matching the disease duration.ConclusionsReverse dipping was more common in PD patients in this study, especially in the advanced PD patients. 24‐h ambulatory BP monitoring is an important method to evaluate the BP alterations in PD patients. Clinicians should be alert to reverse dipping in PD patients and intervene to prevent serious clinical events.

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository.

Background:Genetic, biologic and clinical data suggest that Parkinson’s disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository.Objective:To present the QPN and to perform preliminary analysis of the QPN data.Methods:A total of 1,070 consecutively recruited PD patients were included in the analysis. Demographic and clinical data were analyzed, including comparisons between males and females, PD patients with and without RBD, and stratified analyses comparing early and late-onset PD and different age groups.Results:QPN patients exhibit a male:female ratio of 1.8:1, an average age-at-onset of 58.6 years, an age-at-diagnosis of 60.4 years, and average disease duration of 8.9 years. REM-sleep behavior disorder (RBD) was more common among men, and RBD was associated with other motor and non-motor symptoms including dyskinesia, fluctuations, postural hypotension and hallucinations. Older patients had significantly higher rates of constipation and cognitive impairment, and longer disease duration was associated with higher rates of dyskinesia, fluctuations, freezing of gait, falls, hallucinations and cognitive impairment. Since QPN’s creation, over 60 studies and 30 publications have included patients and data from the QPN.Conclusions:The QPN cohort displays typical PD demographics and clinical features. These data are open-access upon application (http://rpq-qpn.ca/en/), and will soon include genetic, imaging and bio-samples. We encourage clinicians and researchers to perform studies using these resources.

Quantitative metabolomics of saliva using proton NMR spectroscopy in patients with Parkinson's disease and healthy controls.

Parkinson's disease (PD) is a multisystem disorder of unknown etiology, highlights a broad array of symptoms and pathological features influencing organs throughout the body. The metabolic profile of saliva in patients with PD may be influenced by malabsorption in the gastroenteric tract, neurodegeneration, and mitochondrial dysfunction. In the present study, we apply a powerful NMR metabolomics approach for biomarker identification in PD using saliva, a non-invasive bio-fluid. Metabolic profiling of saliva were studied in patients with PD (n = 76) and healthy controls (HC, n = 37) were analyzed and differentiated PD from HC. A total of 40 metabolites including aromatic amino acids, short-chain fatty acids, branched chain amino acids, taurine, and N-acetylglutamate were identified. Spectral binned data and concentration of metabolites were estimated for analysis. Increased concentration of phenylalanine, tyrosine, histidine, glycine, acetoacetate, taurine, TMAO, GABA, N-acetylglutamate, acetoin, acetate, alanine, fucose, propionate, isoleucine, and valine were observed in PD as compared to HC. Further, subgroup analysis among early PD, advanced PD, and HC groups, revealed increased metabolite concentration in early PD group as compared to advanced PD and HC group. Analysis revealed potential biomarkers and their involvement in amino acid metabolism, energy metabolism, neurotransmitters metabolism, and microflora system. Patients with early PD exhibited higher metabolite concentration as compared to advanced PD group which might be associated with dopaminergic treatment. The results of our data indicate that patients with PD might be characterized by metabolic imbalances like gut microflora system, energy metabolites, and neurotransmitters which may contribute to the PD pathogenesis.

Factor structure of the Montreal Cognitive Assessment in Parkinson disease.

The Montreal Cognitive Assessment (MoCA) is a common tool for screening mild cognitive impairment (MCI) and dementia. Studies in multiple clinical groups provide evidence for various factor structures mapping to different cognitive domains. We tested the factor structure of the MoCA in a large cohort of early Parkinson disease (PD). Complete MoCA data were available from an observational cohort study for 1738 patients with recent-onset PD (64.6% male, mean age 67.6, SD 9.2). Confirmatory factor analysis (CFA) was applied to test previously defined two-factor, six-factor, and three-factor models in the full sample and in a subgroup with possible cognitive impairment (MoCA < 26). Secondary analysis used exploratory factor analysis (EFA; principal factors with oblique rotation). The mean MoCA score was 25.3 (SD 3.4, range 10-30). Fit statistics in the six-factor model (χ2 /df 17.77, root mean square error of approximation [RMSEA] 0.10, comparative fit index [CFI] 0.74, Tucker-Lewis index [TLI] 0.69, standardised root mean square residual [SRMR] 0.07) indicated poorer fit than did previous studies. Findings were similar in the two-factor and three-factor models. EFA suggested an alternative six-factor solution (short-term recall, visuospatial-executive, attention/working memory, verbal-executive, orientation, and expressive language), although CFA did not support the validity of the new model. The factor structure of the MoCA in early PD was not consistent with that of previous research. This may reflect higher cognitive performance and differing demographics in our sample. The results do not support a clear, clinically relevant factor structure in an early PD group, suggesting that the MoCA should be followed with detailed assessment to obtain domain-specific cognitive profiles.

Does the Clock Tick Slower or Faster in Parkinson's Disease? - Insights Gained From the Synchronized Tapping Task.

The rhythm of the internal clock is considered to be determined by the basal ganglia, with some studies suggesting slower internal clock in Parkinson’s disease (PD). However, patients may also show motor hastening when they walk (festination) or are engaged in repetitive tapping, indicating faster ticking of the internal clock. Is the internal clock slower or faster in PD? The purpose of this study was to answer this question, i.e., how fast and slow a rhythm they can synchronize with, especially with reference to the limit of sensorimotor synchronization or temporal integration, representing the threshold of slower pace they can entrain into their motor actions, which is known to lie between 2 and 3 s in normal subjects but not yet studied in PD. We employed a synchronized tapping task that required subjects to tap the key in synchrony with repetitive tones at fixed interstimulus intervals (ISI) between 200 and 4800 ms. Twenty normal subjects and sixteen PD patients were enrolled, who were classified into early and advanced PD groups by UPDRS-III (early: 15 or less, advanced: more than 15). The ISI at which the response changes from synchronizing with the tones to lagging behind them was considered to be the limit of temporal integration. Early PD patients responded ahead of the tones (negative asynchrony), which became more apparent with repeated tapping. This suggested “faster” ticking clock even in the presence of the pacing tones. In normal subjects, the limit of temporal integration was around 2–3 s: below this, subjects could synchronize with the tones, while above it they had difficulty in synchronization. In early PD patients, the limit of temporal integration was significantly longer than in normal subjects, pointing to their enhanced ability to synchronize also with slower paces of tones, but advanced PD patients had significantly shortened limits, suggesting that advanced patients lost this ability. In conclusion, the limit of temporal integration is initially longer but gets shorter as the disease progresses. It can be explained by the hastening of the internal clock at the earlier stages of PD, followed by the loss of temporal integration.

Association of serum carotenoid, retinol, and tocopherol concentrations with the progression of Parkinson's Disease.

BACKGROUND/OBJECTIVESA pivotal role of oxidative stress has been emphasized in the pathogenesis as well as in the disease progression of Parkinson's disease (PD). We aimed at investigating serum levels of antioxidant vitamins and elucidating whether they could be associated with the pathogenesis and progression of PD.MATERIALS/METHODSSerum levels of retinol, α- and γ-tocopherols, α- and β-carotenes, lutein, lycopene, zeaxanthin and β-cryptoxanthin were measured and compared between 104 patients with idiopathic PD and 52 healthy controls matched for age and gender. In order to examine the relationship between antioxidant vitamins and the disease progression, multiple group comparisons were performed among the early PD (Hoehn and Yahr stage I and II, N = 47), advanced PD (stage III and IV, N = 57) and control groups. Separate correlation analyses were performed between the measured antioxidant vitamins and clinical variables, such as Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) motor score.RESULTSCompared to controls, PD patients had lower levels of α- and β-carotenes and lycopene. α-carotene, β-carotene and lycopene levels were significantly reduced in advanced PD patients relative to early PD patients and were negatively correlated with Hoehn and Yahr stage and UPDRS motor score in PD patients. No significant differences were found in serum levels of retinol, α- and γ-tocopherols, and other carotenoids between PD patients and controls. No significant correlations were found between these vitamin levels and clinical variables in PD patients.CONCLUSIONSWe found that serum levels of some carotenoids, α-carotene, β-carotene and lycopene, were lower in PD patients, and that these carotenoids inversely correlated with clinical variables representing disease progression. Our findings suggest that decreases in serum α-carotene, β-carotene and lycopene may be associated with the pathogenesis as well as progression of PD.

131I-MIBG myocardial scintigraphy for differentiation of Parkinson's disease from multiple system atrophy or essential tremor in Chinese population

ObjectiveClinical distinction of Parkinson's disease (PD) from multiple system atrophy (MSA) or essential tremor (ET) is sometimes difficult. The purpose of this study was to assess changes in cardiac sympathetic nerve function in PD, MSA, and ET by 131I-MIBG myocardial scintigraphy MethodsPatients with PD (25), MSA (18), or ET (11) and 10 healthy controls (HC) were enrolled. 131I-MIBG myocardial scintigraphy was performed for each subject, and heart/mediastinum (H/M) ratios were calculated at two sample times (15min and 4h after the injection of 131I-MIBG), representing the 131I-MIBG myocardial uptake ratios. The washout ratio (WOR) of MIBG which indicates the activity tone of the presynaptic sympathetic nerves was calculated for each subject. ResultsThe H/M ratios at the two sample times (15min and 4h) were 1.65±0.36 and 1.50±0.43 in the PD group, 1.97±0.36 and 2.08±0.57 in the MSA group, 2.34±0.34 and 2.46±0.51 in the ET group, and 2.41±0.26 and 2.66±0.47 in the HC group. The H/M ratios at the two sample times were lower in the PD group than in the MSA, ET, or HC groups, with statistical significance (all P<0.05). The H/M ratios at the two sample times were significantly lower in the MSA group than in the HC group (all P<0.05). There was no significant difference in H/M ratios at either sample time between the ET and HC group (all P>0.05). The washout ratios (WORs) of MIBG were significantly increased in PD group compared with those in MSA, ET and HC groups. In subgroup analysis, The H/M ratios at the two sample times were decreased in early PD group compared with those in early MSA and early ET groups, with statistical significance (all P<0.05). ConclusionsCardiac sympathetic dysfunction can occur in both PD and MSA patients, especially in PD patients, whereas it remains normal in ET patients. 131I-MIBG myocardial scintigraphy can help distinguish patients with PD from those with MSA or ET with good sensitivity and specificity.

Study on changes of plasma levels of oxidative stress biomarkers and its relation with cognition function in patients with parkinson's disease

To study the changes of plasma levels of oxidative stress biomarkers in patients with parkinson's disease (PD), and to explore its association with cognition function. Seventy-two PD patients from June 2013 to May 2012 were enrolled. All of them were outpatients or inpatients at the First Affiliated Hospital of Nanjing Medical University. And forty-five age- and gender- matched healthy subjects were used as controls. The information including gender, age, illness duration, years of education and Hoehn & Yahr (H-Y) stage were recorded. Cognition function of all the patients with PD and the controls were measured by using Montreal Cognitive Assessment (MoCA) scale. Plasma levels of catalase (CAT), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), total glutathione (T-GSH) and malondialdehyde (MDA) were measured by ELISA . Then we compared and analyzed the results. Plasma levels of CAT, T-SOD and T-GSH in PD group were significantly lower than the control group [(159 ± 9) kU/L vs (170 ± 5) kU/L, P< 0.01; (97 ± 24) kU/L vs (124 ± 25) kU/L, P<0.01; (17 ± 10) µmol/L vs (60 ± 51) µmol/L, P< 0.01]. Plasma levels of CAT, T-GSH, GSH-Px and MDA were no differences between early PD group (H-Y stage I-II) and middle-late PD group (H-Y stage III or higher) of patients (P>0.05). Plasma levels of T-GSH in PD group with mild cognitive impairment (MCI) were obviously lower than PD group without MCI [(14 ± 7) µmol/L vs (19 ± 11) µmol/L, P< 0.05]. In PD patients, MoCA scores were positively correlated with years of education (β=0.634, P= 0.000) and plasma levels of T-GSH (β= 0.204, P= 0.014), and were negatively correlated with H-Y stage (β=-0.194, P=0.020). The damage of plasma antioxidant mechanism may be involved in the pathogenesis of patients with PD. Decrease in plasma levels of T-GSH may be associated with MCI in PD patients . Plasma levels of T-GSH may be a potential early predictive index in PD patients with cognitive dysfunction.

Magnetic resonance correlation of iron content with neuromelanin in the substantia nigra of early-stage Parkinson's disease.

Magnetic resonance (MR) studies have demonstrated a significant reduction of neuromelanin in the substantia nigra (SN) of Parkinson's disease (PD) patients with high accuracy for differential diagnosis compared to non-PD controls and essential tremor. However, studies state that not knowing how paramagnetic effects of iron influence neuromelanin signal is a limitation. In this study a neuromelanin-sensitive MR sequence was combined with T2* relaxometry iron quantification analysis to study the SN of early-stage PD patients to investigate the correlation between these parameters. The inclusion criteria were untreated de novo PD patients and a 2-5 year disease duration (early PD); in addition, age-matched controls were enrolled. These were studied at 3.0 T with a high-resolution T1-weighted MR sequence to visualize neuromelanin and a relaxometry sequence for iron quantification. The primary outcome was the correlation of the width of the neuromelanin high signal region and the T2* values in the lateral, central and medial segments of the SN. Very weak correlations of T2* values with neuromelanin width, positive for global and negative for the medial and lateral SN segments, were found in both PD groups and control subjects. The SN neuromelanin width was markedly reduced in the de novo and early PD groups compared with controls in all SN segments, but no significant difference in T2* values was found between the groups. The SN neuromelanin signal does not have a significant correlation with iron content in PD patients or controls. The neuromelanin MR signal reduction in PD does not seem to be significantly influenced by paramagnetic iron effects.

Another face of placebo: the lessebo effect in Parkinson disease: meta-analyses.

To study the impact of negative expectation related to receiving a placebo (the "lessebo effect") on efficacy outcome measures of symptomatic treatments in Parkinson disease (PD). We conducted meta-analyses of double-blind randomized controlled trials (RCTs) of dopamine agonists in PD and compared the pooled mean score change of the motor section of the Unified Parkinson's Disease Rating Scale (mUPDRS) across active treatment arms according to the presence of a placebo arm or the probability of placebo assignment (0%, <50%, and 50%) of the original RCT. A mixed-effects model was used. Heterogeneity was assessed by subgroup analyses and meta-regression modeling. A total of 28 study arms were extracted from active-controlled trials (3,277 patients) and 42 from placebo-controlled trials (4,554 patients). The overall difference between groups in the pooled mean score change in the mUPDRS was 1.6 units (95% confidence interval [CI] 0.2, 3.0; p = 0.023), in favor of the active-controlled group. In subgroup analyses, this difference was of higher magnitude in the early PD group without motor fluctuations (3.3 mUPDRS units, 95% CI 1.1, 5.4; p = 0.003) and for study duration ≤ 12 weeks (4.1 mUPDRS units, 95% CI 1.0, 7.2; p = 0.009). There was no between-group difference using probability of placebo assignment as criterion. This study shows that the use of a placebo can be associated with a clinically significant reduction in the magnitude of change of the mUPDRS after an active treatment in RCTs for PD. These new findings have potential implications in the development of new treatments and appraisal of current treatment options for PD and possibly for other neurologic disorders.

Effect of Dopamine Therapy on Nonverbal Affect Burst Recognition in Parkinson's Disease

BackgroundParkinson's disease (PD) provides a model for investigating the involvement of the basal ganglia and mesolimbic dopaminergic system in the recognition of emotions from voices (i.e., emotional prosody). Although previous studies of emotional prosody recognition in PD have reported evidence of impairment, none of them compared PD patients at different stages of the disease, or ON and OFF dopamine replacement therapy, making it difficult to determine whether their impairment was due to general cognitive deterioration or to a more specific dopaminergic deficit.MethodsWe explored the involvement of the dopaminergic pathways in the recognition of nonverbal affect bursts (onomatopoeias) in 15 newly diagnosed PD patients in the early stages of the disease, 15 PD patients in the advanced stages of the disease and 15 healthy controls. The early PD group was studied in two conditions: ON and OFF dopaminergic therapy.ResultsResults showed that the early PD patients performed more poorly in the ON condition than in the OFF one, for overall emotion recognition, as well as for the recognition of anger, disgust and fear. Additionally, for anger, the early PD ON patients performed more poorly than controls. For overall emotion recognition, both advanced PD patients and early PD ON patients performed more poorly than controls. Analysis of continuous ratings on target and nontarget visual analog scales confirmed these patterns of results, showing a systematic emotional bias in both the advanced PD and early PD ON (but not OFF) patients compared with controls.ConclusionsThese results i) confirm the involvement of the dopaminergic pathways and basal ganglia in emotional prosody recognition, and ii) suggest a possibly deleterious effect of dopatherapy on affective abilities in the early stages of PD.

The association between non-motor symptoms in Parkinson's disease and age at onset

ObjectiveAge at onset is likely to be related to a wide range of problems in Parkinson's disease (PD), including cardinal motor features, motor complications and non-motor symptoms (NMS). This study investigated the effect of the age at onset on NMS. MethodsTwo hundred and thirty patients were examined and classified into one of three groups based on age at onset: early onset PD (EOPD) group (<45 years), middle-age onset group (45–64 years) and old-age onset group (≥65 years). The trends relating to NMS were compared across the three groups. The EOPD and old-age onset groups were separately studied to determine their association to the appearance of non-motor features using logistic regression analysis. ResultsThere were upward trends in the occurrence of dribbling (P=0.009; all P values are stated for trend), impaired taste/smelling (P=0.016), constipation (P=0.006), urinary urgency (P=0.002), nocturia (P=0.018), hallucinations (P=0.016) and acting out during dreams (P=0.011) with the increase of age at onset. Older age at onset is an independent risk factor for dementia (OR=8.42, CI 3.16–22.44), dribbling (OR=4.14, CI 1.93–8.87), impaired taste/smelling (OR=2.23, CI 1.20–4.13), constipation (OR=3.42, CI 1.88–6.24), incomplete bowel emptying (OR=2.23, CI 1.19–4.20), urinary urgency (OR=2.58 CI 1.46–4.57), nocturia (OR=2.65, CI 1.49–4.71), hallucinations (OR=5.32, CI 1.78–15.97), dizziness (OR=3.03, CI 1.59–5.79), falling (OR=3.60, CI 1.67–7.77), insomnia (OR=2.29, CI 1.28–4.11), intense vivid dreaming (OR=2.10, CI 1.21–3.66) and acting out during dreams (OR=2.23, CI 1.24–4.01). ConclusionsPD patients with different ages at onset present clinically different symptoms in terms of NMS. Old-age onset PD is characterized by more olfactory and sensory symptoms, autonomic symptoms, sleep disorders, dementia and psychosis compared to EOPD.

Changes in spontaneous brain activity in early Parkinson's disease

Resting state brain activity can provide valuable insights into the pathophysiology of Parkinson's disease (PD). The purpose of the present study was (a) to investigate abnormal spontaneous neuronal activity in early PD patients using resting-state functional MRI (fMRI) with a regional homogeneity (ReHo) method and (b) to demonstrate the potential of using changes in abnormal spontaneous neuronal activity for monitoring the progression of PD during its early stages. Seventeen early PD patients were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr disability scale and the Mini-mental State Examination (MMSE) were compared with seventeen gender- and age-matched healthy controls. All subjects underwent MRI scans using a 1.5T General Electric Signa Excite II scanner. The MRI scan protocol included whole-brain volumetric imaging using a 3D inversion recovery prepared (IR-Prep) fast spoiled gradient-echo pulse sequence and 2D multi-slice (22 axial slices covering the whole brain) resting-state fMRI using an echo planar imaging (EPI) sequence. Images were analyzed in SPM5 together with a ReHo algorithm using the in-house software program REST. A corrected threshold of p<0.05 was determined by AlphaSim and used in statistical analysis. Compared with the healthy controls, the early PD group showed significantly increased ReHo in a number of brain regions, including the left cerebellum, left parietal lobe, right middle temporal lobe, right sub-thalamic nucleus areas, right superior frontal gyrus, middle frontal gyrus (MFG), right inferior parietal lobe (IPL), right precuneus lobe, left MFG and left IPL. Additionally, significantly reduced ReHo was also observed in the early PD patients in the following brain regions: the left putamen, left inferior frontal gyrus, right hippocampus, right anterior cingulum, and bilateral lingual gyrus. Moreover, in PD patients, ReHo in the left putamen was negatively correlated with the UPDRS scores (r=−0.69). These results indicate that the abnormal resting state spontaneous brain activity associated with patients with early PD can be revealed by Reho analysis.