Untreated Parkinson's Disease Research Articles

Impaired finger dexterity and nigrostriatal dopamine loss in Parkinson's disease.

Impaired finger dexterity occurs in Parkinson's disease (PD) and has been considered a limb-kinetic apraxia associated with primary sensory cortical dysfunction. To study the role of nigrostriatal dopamine loss and elementary parkinsonian motor deficits in impaired finger dexterity of PD. Thirty-two right-handed untreated PD patients and 30 right-handed healthy controls were included. All patients underwent [18F] FP-CIT positron emission tomography studies. We examined the associations among unilateral coin rotation (CR) score, Unified Parkinson's Disease Rating Scale (UPDRS) subscores for bradykinesia and rigidity of the corresponding arm, and contralateral regional striatal dopamine transporter (DAT) uptake. We also measured the effect of oral levodopa dose on CR scores and UPDRS subscores. PD patients performed worse than controls on the CR task. Unilateral arm UPDRS bradykinesia scores were associated with DAT uptake in the contralateral putamen. The left CR score was associated with left arm bradykinesia and rigidity scores and DAT uptake in the right posterior putamen, whereas no such associations were found for the right CR score. There was a significant effect of handedness on the association of putamen DAT uptake with CR scores, but not with UPDRS subscores. An oral levodopa challenge improved CR scores and UPDRS subscores on both sides. Impaired finger dexterity in PD is related to elementary parkinsonian motor deficits and nigrostriatal dopamine loss. Impaired dominant hand dexterity associated with nigrostriatal dopamine loss seems to be compensated to some extent by the dominant cerebral cortex specialized for controlling precise finger movements.

Smartphone Allows Capture of Speech Abnormalities Associated With High Risk of Developing Parkinson's Disease.

Although smartphone technology provides new opportunities for the recording of speech samples in everyday life, its ability to capture prodromal speech impairment in persons with a high risk of developing Parkinson's disease (PD) has never been investigated. Speech data were acquired through a smartphone as well as a professional microphone with a linear frequency response from 50 participants with a rapid eye movement sleep behavior disorder that are at a high risk of developing PD and related neurodegenerative disorders. Additionally, recordings of 30 newly diagnosed, untreated PD patients and 30 healthy participants were evaluated. Acoustic assessment of 11 speech dimensions representing the key aspects of hypokinetic dysarthria in the early stages of PD was performed. Smartphone allowed the detection of speech abnormalities in participants with a high risk of developing PD. Acoustic measurements related to fundamental frequency variability, duration of pause intervals, and rate of speech timing extracted from spontaneous speech were sufficiently sensitive to significantly separate groups (area under curve of 0.85 between PD and controls) and showed very strong correlation and reliability between the professional microphone and the smartphone. Speech-based biomarkers collected through smartphones may have the potential to revolutionize the diagnostic process in neurodegenerative diseases and improve stratification for future neuroprotective therapy in PD.

Inflammation and fatigue in early, untreated Parkinson's Disease.

Parkinson's disease (PD)-related fatigue is a significant clinical problem, and the pathological processes that cause fatigue remain unknown. The aim of the present study was to explore the possible association of peripheral inflammation markers and fatigue in PD. We included 47 drug naïve, newly diagnosed PD patients with low (≤3.0) or high (>5.5) fatigue levels as evaluated by the Fatigue Severity Scale (FSS). Strict diagnostic criteria were applied for inclusion. Patients with possible confounding causes for fatigue were excluded. Serum concentrations of a panel of inflammatory markers (IL-8, TNF-α, MCP1, MIP-1β, IL-6, IL-6R, p-selectin, E-selectin-1, ICAM, VCAM-1, CCL5, IL1-Ra, and TNFR1) were measured using ELISA technology in PD patients with and without fatigue to assess the potential relationships of fatigue in newly diagnosed, treatment-naïve patients. Fatigued PD patients had significantly higher levels of the IL-1 receptor antagonist (IL1-Ra) (1790 pg/mL (SD1007) vs 1262 pg/mL (SD379)) and of the adhesion molecule VCAM 1 (1071 ng/mL (SD276) vs 895 ng/mL (SD229)) than non-fatigued patients. A binary logistic regression model, including high or low FSS score as the dependent variable and UPDRS motor score, MADRS, MMSE, ESS, and IL1-Ra/VCAM-1 as independent variables, showed a significant effect both for IL1-Ra and VCAM-1. Higher serum levels of the inflammatory molecules IL1-Ra and VCAM-1 were associated with higher fatigue levels in patients with newly diagnosed, drug-naïve PD. These findings highlight an altered immune response as a potential contributor to PD-related fatigue, from the earliest clinical stages of the disease.

Vitamin B12 and Homocysteine Levels Predict Different Outcomes in Early Parkinson's Disease

In moderately advanced Parkinson's disease (PD), low serum vitamin B12 levels are common and are associated with neuropathy and cognitive impairment. However, little is known about B12 in early PD. To determine the prevalence of low vitamin B12 status in early PD and whether it is associated with clinical progression. We measured vitamin B12 and other B12 status determinants (methylmalonic acid, homocysteine, and holotranscobalamin) in 680 baseline and 456 follow-up serum samples collected from DATATOP participants with early, untreated PD. Borderline low B12 status was defined as serum B12 <184 pmol/L (250 pg/mL), and elevated homocysteine was defined as >15 µmol/L. Outcomes included the UPDRS, ambulatory capacity score (sum of UPDRS items 13-15, 29&30), and MMSE, calculated as annualized rates of change. At baseline, 13% had borderline low B12 levels, 7% had elevated homocysteine, whereas 2% had both. Elevated homocysteine at baseline was associated with worse scores on the baseline MMSE. Analysis of study outcomes showed that compared with the other tertiles, participants in the low B12 tertile (<234 pmol/L; 317 pg/mL) developed greater morbidity as assessed by greater annualized worsening of the ambulatory capacity score. Elevated homocysteine was associated with greater annualized decline in MMSE (-1.96 vs. 0.06; P = 0001). Blood count indices were not associated with B12 or homocysteine status. In this study of early PD, low B12 status was common. Low B12 at baseline predicted greater worsening of mobility whereas elevated homocysteine predicted greater cognitive decline. Given that low B12 and elevated homocysteine can improve with vitamin supplementation, future studies should test whether prevention or early correction of these nutritionally modifiable conditions slows development of disability. © 2018 International Parkinson and Movement Disorder Society.

Relation of overactive bladder with motor symptoms and dopamine transporter imaging in drug-naïve Parkinson's disease

ObjectivesThe aim of the present study was to determine the relation of urinary dysfunction with motor symptoms and nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We therefore examined the relation of overactive bladder (OAB) symptoms with motor symptoms and striatal dopamine transporter (DAT) binding measured by [123-Iodine]-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenylnortropane) dopamine transporter single-photon emission computed tomography (123I-FP-CIT SPECT). Patients and methodsThirty-one untreated PD patients (12 men and 19 women with a mean age of 71.2 ± 6.7 years) were included in this study. Patients were evaluated with overactive bladder symptom score (OABSS) and divided into an OAB group and Non-OAB group. They underwent clinical assessments and 123I-FP-CIT SPECT imaging. Motor symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS). ResultsThe results showed that UPDRS motor score (p = 0.01) and akinetic-rigid score (p = 0.002) were higher and that striatal DAT availability (p = 0.01) was lower in the OAB group than in the Non-OAB group. However, tremor score, age, and duration of PD showed no significant differences between the OAB group and Non-OAB group. ConclusionsUrinary dysfunction in untreated PD is related with increase in motor symptoms (especially bradykinesia and axial symptoms) and reduction of striatal DAT availability.

Cortical atrophy patterns in early Parkinson's disease patients using hierarchical cluster analysis

IntroductionCortical brain atrophy detectable with MRI in non-demented advanced Parkinson's disease (PD) is well characterized, but its presence in early disease stages is still under debate. We aimed to investigate cortical atrophy patterns in a large sample of early untreated PD patients using a hypothesis-free data-driven approach. MethodsSeventy-seven de novo PD patients and 50 controls from the Parkinson's Progression Marker Initiative database with T1-weighted images in a 3-tesla Siemens scanner were included in this study. Mean cortical thickness was extracted from 360 cortical areas defined by the Human Connectome Project Multi-Modal Parcellation version 1.0, and a hierarchical cluster analysis was performed using Ward's linkage method. A general linear model with cortical thickness data was then used to compare clustering groups using FreeSurfer software. ResultsWe identified two patterns of cortical atrophy. Compared with controls, patients grouped in pattern 1 (n = 33) were characterized by cortical thinning in bilateral orbitofrontal, anterior cingulate, and lateral and medial anterior temporal gyri. Patients in pattern 2 (n = 44) showed cortical thinning in bilateral occipital gyrus, cuneus, superior parietal gyrus, and left postcentral gyrus, and they showed neuropsychological impairment in memory and other cognitive domains. ConclusionsEven in the early stages of PD, there is evidence of cortical brain atrophy. Neuroimaging clustering analysis is able to detect two subgroups of cortical thinning, one with mainly anterior atrophy, and the other with posterior predominance and worse cognitive performance.

Levodopa-induced dyskinesia in Parkinson's disease: still no proof? A meta-analysis.

We investigated whether there is a linear relationship between levodopa (LD) dose and treatment duration, and the development of levodopa-induced dyskinesia (LID) among patients with early untreated Parkinson's disease (PD). We performed a meta-analysis of randomized-controlled trials (RCTs) comparing LD monotherapy to any other antiparkinsonian treatment in early PD patients. Meta-regressions were conducted including as covariates the effects of LD dose, treatment duration, and age. We further proceeded in subgroup analyses based on the type of medications in the non-LD monotherapy (control) group and on whether patients in the control group received additional levodopa or not. Thirteen eligible RCTs were included, which revealed a significantly higher risk for dyskinesia in patients initially treated with LD monotherapy compared to any other treatment (OR=2.82). None of the subsequent meta-regressions revealed any significant relationship with dose, treatment duration or age. Patients treated on LD monotherapy or MAOΙ plus LD were at a greater risk to develop LID than patients who received DA only or DA plus supplemental LD. The increased heterogeneity compromised the robustness of the results. The alleged correlation between LID and LD dose and treatment duration cannot be verified based on the data available so far. Well-designed, large-scale, long-term, RCTs on drug-naïve PD patients could allow the better comprehension of the pattern of the association between LID and LD treatment parameters.

Altered mGluR5 binding potential and glutamine concentration in the 6-OHDA rat model of acute Parkinson's disease and levodopa-induced dyskinesia

Several lines of evidence point to alterations in glutamatergic signaling in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), involving the metabotropic glutamate receptor type 5 (mGluR5). Using small-animal positron emission tomography (PET) with [18F]FPEB and proton magnetic resonance spectroscopy, we investigated cerebral changes in the mGluR5 and glutamate/glutamine availability in vivo in PD rats and following onset of LIDs. In parallel, behavioral tests were performed. Comparing PD to control rats, mGluR5 binding potential was decreased in a cluster comprising the bilateral caudate-putamen (CP), ipsilateral motor cortex and somatosensory cortex, and the contralateral somatosensory cortex and parietal association cortex, with the most pronounced reduction in the ipsilateral CP. mGluR5 binding potentials were not significantly altered upon levodopa (L-DOPA) treatment. However, following L-DOPA, an increase in relative mGluR5 uptake was present in the contralateral motor cortex and somatosensory cortex. Glutamate and glutamine concentrations did not differ between control and untreated PD rats or between hemispheres. Though, glutamine levels were higher in the contralateral CP of saline- and L-DOPA-treated rats as compared to the ipsilateral side. Relative mGluR5 uptake in the CP of levodopa-treated rats was also found positively correlated with abnormal involuntary movement scores. Conclusively, mGluR5 availability and glutamine concentrations in the CP are involved in PD, whereas mGluR5 availability in cortical regions may be involved in LID pathology.

Neuropsychiatric symptoms in untreated Parkinson's disease.

Neuropsychiatric and cognitive symptoms are common in Parkinson’s disease (PD) and may precede and exceed motor symptoms as major factors impacting disease course and quality of life. Neuropsychiatric symptoms (NPS) in PD are various and are attributed to pathologic changes within multiple brain regions, to psychological stress, and to adverse effects of dopamine replacement therapy. Sleep disorders and mood symptoms such as apathy, depression, and anxiety may antedate the development of motor symptoms by years, while other NPS such as impulse control disorders, psychosis, and cognitive impairment are more common in later stages of the disease. Few studies report on NPS in the early, untreated phase of PD. We reviewed the current literature on NPS in PD with a focus on the early, drug-naive stages of PD. Among these early disease stages, premotor and early motor phases were separately addressed in our review, highlighting the underlying pathophysiological mechanisms as well as epidemiological characteristics, clinical features, risk factors, and available techniques of clinical assessment.

Electrode Position and Current Amplitude Modulate Impulsivity after Subthalamic Stimulation in Parkinsons Disease-A Computational Study.

Background: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) is highly effective in alleviating motor symptoms of Parkinson's disease (PD) which are not optimally controlled by dopamine replacement therapy. Clinical studies and reports suggest that STN-DBS may result in increased impulsivity and de novo impulse control disorders (ICD).Objective/Hypothesis: We aimed to compare performance on a decision making task, the Iowa Gambling Task (IGT), in healthy conditions (HC), untreated and medically-treated PD conditions with and without STN stimulation. We hypothesized that the position of electrode and stimulation current modulate impulsivity after STN-DBS.Methods: We built a computational spiking network model of basal ganglia (BG) and compared the model's STN output with STN activity in PD. Reinforcement learning methodology was applied to simulate IGT performance under various conditions of dopaminergic and STN stimulation where IGT total and bin scores were compared among various conditions.Results: The computational model reproduced neural activity observed in normal and PD conditions. Untreated and medically-treated PD conditions had lower total IGT scores (higher impulsivity) compared to HC (P < 0.0001). The electrode position that happens to selectively stimulate the part of the STN corresponding to an advantageous panel on IGT resulted in de-selection of that panel and worsening of performance (P < 0.0001). Supratherapeutic stimulation amplitudes also worsened IGT performance (P < 0.001).Conclusion(s): In our computational model, STN stimulation led to impulsive decision making in IGT in PD condition. Electrode position and stimulation current influenced impulsivity which may explain the variable effects of STN-DBS reported in patients.

CSF Biomarkers and Its Associations with 18F-AV133 Cerebral VMAT2 Binding in Parkinson's Disease-A Preliminary Report.

ObjectiveCerebrospinal fluid (CSF) biomarkers, such as α-synuclein (α-syn), amyloid beta peptide 1–42 (Aβ1–42), phosphorylated tau (181P) (p-tau), and total tau (t-tau), have long been associated with the development of Parkinson disease (PD) and other neurodegenerative diseases. In this investigation, we reported the assessment of CSF biomarkers and their correlations with vesicular monoamine transporter 2 (VMAT2) bindings measured with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-AV133) that is being developed as a biomarker for PD. We test the hypothesis that monoaminergic degeneration was correlated with CSF biomarker levels in untreated PD patients.MethodsThe available online data from the Parkinson’s Progression Markers Initiative study (PPMI) project were collected and analyzed, which include demographic information, clinical evaluations, CSF biomarkers (α-syn, Aβ1–42, p-tau, and t-tau), 18F-AV133 brain PET, and T1 weighted MRIs. Region of interest (ROI) and voxel-wise Pearson correlation between standardized uptake value ratio (SUVR) and CSF biomarkers were calculated.ResultsOur major findings are: 1) Compared with controls, CSF α-syn and tau levels decreased significantly in PD; 2) α-syn was closely correlated with Aβ1–42 and tau in PD, especially in early-onset patients; and 3) hypothesis-driven ROI analysis found a significant negative correlation between CSF Aβ1–42 levels and VMAT2 densities in post cingulate, left caudate, left anterior putamen, and left ventral striatum in PDs. CSF t-tau and p-tau levels were significantly negatively related to VMAT2 SUVRs in substantia nigra and left ventral striatum, respectively. Voxel-wise analysis showed that left caudate, parahippocampal gyrus, insula and temporal lobe were negatively correlated with Aβ1–42. In addition, superior frontal gyrus and transverse temporal gyrus were negatively correlated with CSF p-tau levels.ConclusionThese results suggest that monoaminergic degeneration in PD is correlated with CSF biomarkers associated with cognitive impairment in neurodegenerative diseases including Alzheimer’s disease. The association between loss of dopamine synaptic function and pathologic protein accumulations in PD indicates an important role of CSF biomarkers in PD development.

Aging modifies the effect of GCH1 RS11158026 on DAT uptake and Parkinson's disease clinical severity

Novel single nucleotide polymorphisms within Parkinson's disease (PD) can predict disease risk, but their influence on clinical, cognitive, and neurobiological indices remains unexplored. We investigated differences between functional polymorphisms at RS11158026 coding for guanosine triphosphate cyclohydrolase-1 (GCH1), an essential enzyme for dopamine production in nigrostriatal cells. Among newly diagnosed, untreated PD subjects and age-matched controls from the Parkinson's Progression Markers Initiative, T allele carriers showed higher PD risk (odds ratio = 1.23, p = 0.048), earlier age of onset by 5 years (p = 0.003), and lower striatal dopamine reuptake transporter uptake (p = 0.003). Carriers also had increased cerebrospinal fluid α-synuclein (p = 0.016), worse motor function (p = 0.041), anxiety (p = 0.038), and executive function (p < 0.001). Strikingly, these effects were only in younger T carriers (<50 years), where aging quells the effects of these genetic factors. This suggests GCH1 variants affect early PD risk through altered dopamine uptake, and aging alters how genetic factors contribute to disease development. Future studies should investigate how aging modifies genotypes' contributions on PD risk and sequelae.

Cardiovascular dysfunction in untreated Parkinson's disease: A multi-modality assessment

BackgroundThe clinical presentation of Parkinson's disease (PD) includes a wide spectrum of non-motor features, including cardiovascular autonomic failure. ObjectiveTo evaluate cardiovascular autonomic status and cardiac functional capacity in drug-naïve PD patients. Methods18 newly-diagnosed PD patients underwent laboratory cardiovascular autonomic function tests using power spectral analysis of the R-R interval, blood pressure (BP) short-term variability and non-invasive baroreflex sensitivity (BRS). A two-dimensional (2D) transthoracic echocardiogram, spirometry and cardiopulmonary exercise test (CPET) were also performed. Thirteen patients underwent myocardial scintigraphy with [123I] metaiodobenzylguanidine (MIBG). ResultsAt rest, total power spectral analysis of heart rate variability was lower in PD patients than in controls. BRS decreased during sympathetic activation in both patients and controls. While echocardiography and spirometry were normal, a mild degree of exercise intolerance was observed at the CPET in PD patients (mean V'O2max: 83% of predicted; mean Wmax: 80% of predicted). The heart-to-mediastinum (H/M) ratio of MIBG uptake was pathologically impaired in 9 patients, one of whom displayed a definite cardiovascular dysautonomic pattern. ConclusionsOur results confirm that subclinical to overt cardiovascular autonomic failure may occur from the early stages of PD. The less efficient adaptive response to physical stimuli during the CPET and postural changes observed in untreated PD patients possibly reflect cardiac sympathetic denervation, although the involvement of PD-related motor impairment in physical deconditioning cannot be excluded.

Probing the Role of Medication, DBS Electrode Position, and Antidromic Activation on Impulsivity Using a Computational Model of Basal Ganglia.

Everyday, we encounter situations where available choices are nearly equally rewarding (high conflict) calling for some tough decision making. Experimental recordings showed that the activity of Sub Thalamic Nucleus (STN) increases during such situations providing the extra time needed to make the right decision, teasing apart the most rewarding choice from the runner up closely trailing behind. This prolonged deliberation necessary for decision making under high conflict was absent in Parkinson's disease (PD) patients who underwent Deep Brain Stimulation (DBS) surgery of STN. In an attempt to understand the underlying cause of such adverse response, we built a 2D spiking network model (50 × 50 lattice) of Basal ganglia incorporating the key nuclei. Using the model we studied the Probabilistic learning task (PLT) in untreated, treated (L-Dopa and Dopamine Agonist) and STN-DBS PD conditions. Based on the experimental observation that dopaminergic activity is analogous to temporal difference (TD) and induces cortico-striatal plasticity, we introduced learning in the cortico-striatal weights. The results show that healthy and untreated conditions of PD model were able to more or less equally select (avoid) the rewarding (punitive) choice, a behavior that was absent in treated PD condition. The time taken to select a choice in high conflict trials was high in normal condition, which is in agreement with experimental results. The treated PD (Dopamine Agonist) patients made impulsive decisions (small reaction time) which in turn led to poor performance. The underlying cause of the observed impulsivity in DBS patients was studied in the model by (1) varying the electrode position within STN, (2) causing antidromic activation of GPe neurons. The effect of electrode position on reaction time was analyzed by studying the activity of STN neurons where, a decrease in STN neural activity was observed for certain electrode positions. We also observed that a higher antidromic activation of GPe neurons does not impact the learning ability but decreases reaction time as reported in DBS patients. These results suggest a probable role of electrode and antidromic activation in modulating the STN activity and eventually affecting the patient's performance on PLT.

Predictors of time to initiation of symptomatic therapy in early Parkinson's disease.

ObjectiveTo determine clinical and biological variables that predict time to initiation of symptomatic therapy in de novo Parkinson's disease patients.MethodsParkinson's Progression Markers Initiative is a longitudinal case–control study of de novo, untreated Parkinson's disease participants at enrolment. Participants contribute a wide range of motor and non‐motor measures, including biofluids and imaging biomarkers. The machine learning method of random survival forests was used to examine the ability of baseline variables to predict time to initiation of symptomatic therapy since study enrollment (baseline).ResultsThere were 423 PD participants enrolled in PPMI and 33 initial baseline variables. Cross‐validation results showed that the three‐predictor subset of disease duration (time from diagnosis to enrollment), the modified Schwab and England activities of daily living scale, and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) total score modestly predicted time to initiation of symptomatic therapy (C = 0.70, pseudo‐R 2 = 0.13). Prediction using the three variables was similar to using the entire set of 33. None of the biological variables increased accuracy of the prediction. A prognostic index for time to initiation of symptomatic therapy was created using the linear and nonlinear effects of the three top variables based on a post hoc Cox model.InterpretationOur findings using a novel machine learning method support previously reported clinical variables that predict time to initiation of symptomatic therapy. However, the inclusion of biological variables did not increase prediction accuracy. Our prognostic index constructed, based on the group‐level survival curve can provide an indication of the risk of initiation of ST for PD patients based on functions of the three top predictors.

The single intake of levodopa modulates implicit learning in drug naïve, de novo patients with idiopathic Parkinson's disease.

Although dopamine is known to aggravate implicit learning, the exact impact on behaviour when feedback is unavailable remains unclear. Previous studies revealed that non-rewarded learning habits are affected in long-term dopaminergic treated patients with Parkinson's disease (PD). We studied the influence of a onetime levodopa intake on implicit learning in de novo, untreated PD patients. De novo PD patients (n=22) before and after the single intake of levodopa and control subjects (n=23) took part in a Go/NoGo paradigm. One stimulus was defined as target, which was first consistently preceded by one of three non-target stimuli (conditioning). This coupling was dissolved thereafter (deconditioning). In the 'Go version' subjects were asked to respond to the target by pressing a key, whereas in the 'NoGo version' response had to be inhibited. PD patients and controls (n=14/n=19) with an initial learning effect due to the target were included for further statistical analysis. Within the subgroup incorrect responses upon NoGo stimuli increased during the deconditioning phase. In contrast, the same patients failed to show any change after receiving 200mg of levodopa. During the Go version, no change of the overall error rate between conditioning and deconditioning was detectable over all groups. Learning behaviour in untreated PD patients and healthy controls was indistinguishable. In contrast, the same patients varied in their implicit learning after one-time intake of levodopa, when actions had to be inhibited. Hence, the single intake of levodopa appears to modulate implicit learning behaviour in de novo PD patients.

How stable are Parkinson's disease subtypes in de novo patients: Analysis of the PPMI cohort?

ObjectiveTo determine the frequency and stability over time of the subgroup characterization of the tremor dominant (TD) versus postural instability gait disorder dominant (PIGD) Parkinson's disease (PD) in de novo patients. BackgroundThere is a substantial body of literature on the clinical sub classification of PD into TD versus PIGD subtype. However, there are limited data on the stability of this classification especially in early disease. MethodsParkinson's Progression Markers Initiative (PPMI) is a longitudinal case control study of de novo, untreated PD participants at enrollment. Participants undergo a number of assessments including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). TD versus PIGD subtype was defined based on the previously published formula. We report one-year analysis data. Results320 of 423 PD recruited subjects had data on subtype classification at year 1 and were included in the analysis. 228 (71%) were classified as TD, 56 (18%) as PIGD and 36 (11%) as indeterminate at baseline. At 12 months, 39% PIGD and 18% TD shifted subtypes: 29% PIGD shifted to TD and 11% to Indeterminate; 10% TD shifted to PIGD and 8% to Indeterminate. The classification was not affected by the dopaminergic treatment (p = 0.59). ConclusionsTD versus PIGD subtype classification has substantial variability over first year in PD de novo cohort specifically for PIGD subtype. Dopaminergic therapy does not impact the change of the PD subtype. This instability has to be taken into consideration specifically when establishing correlations with the biomarkers and for long term prognostication.

Urinary dysfunction and motor symptoms in untreated Parkinson's disease

Objectives: The aim of the present study was to determine the associations of motor symptoms in untreated Parkinson's disease (PD) with urinary dysfunction. We therefore examined the association between the overactive bladder symptom score (OABSS) and Unified Parkinson's Disease Rating Scale (UPDRS). Patients and methods: Thirty-one untreated PD patients without dementia (12 men and 19 women with a mean age of 72.0±6.7years) were included in this study. Their urinary tract dysfunctions were rated using the OABSS. The motor symptoms of all patients were also assessed using UPDRS. Results: OABSS had significant correlations with UPDRS motor score (Spearman's rho=0.39, p=0.03) and akinetic-rigid score (Spearman's rho=0.47, p=0.01). However, OABSS showed no significant correlation with tremor score, age, or duration of PD. Conclusions: Higher OABSS was consistently associated with increase in severity of motor disorders, especially akinetic-rigid score, in the study participants.

Homocysteine Concentration Correlates with Baseline Clinical Status and Predicts Outcomes in a Large, Early Parkinson's Disease Cohort (DATATOP)

OBJECTIVETo determine the prevalence of elevated homocysteine (Hcy) concentration and its association with cognitive and motor function measurements in early untreated Parkinson's disease (PD).BACKGROUNDPrevious studies have identified a relationship of elevated circulating Hcy levels with the development of cognitive impairment in aging but this relationship has not been established in early PD. We sought to determine the prevalence of elevated Hcy status in a cohort with early untreated PD and whether it was associated with greater initial and subsequent morbidity.DESIGN/METHODSWe measured Hcy using 677 baseline samples from the DATATOP cohort of patients with early, untreated PD. Elevated Hcy status was defined as mildly elevated (&gt;11 μM) and moderately elevated (&gt;15 μM). Outcomes included motor assessments by Unified Parkinson's Disease Rating Scale (UPDRS scores) and cognitive assessments (Mini‐Mental Status test (MMSE) and Symbol Digits Modalities Test (SDMT)) at baseline and follow‐up, calculated as an annualized rate of change for those who participated for 6 months to 2 years. Baseline analyses were adjusted for sex, age, baseline B12 levels and treatment assignment. Change analyses were also adjusted for baseline value of the outcome.RESULTSThe geometric mean Hcy level was 9.5 μM and was mildly elevated in 26% (179/677) and moderately elevated in 7% (46/677) of subjects. Analysis of baseline features showed lower MMSE and SDMT scores in those with moderately elevated Hcy. Analysis of outcomes showed greater decline in MMSE scores in those with moderately elevated Hcy. No associations were observed between mildly elevated Hcy and the baseline or outcome UPDRS motor scores.CONCLUSIONSIn this cohort of early, untreated PD subjects, 1 in 4 had mildly elevated Hcy. Moderately elevated baseline Hcy levels correlated with lower baseline cognitive measures and greater rate of cognitive decline. Because B vitamin supplementation can lower Hcy levels, this data raises the possibility that prevention or early correction of mild to moderate hyperhomocyteinemia through vitamin supplementation may slow the onset of cognitive decline in PD.Support or Funding InformationMJFOX Foundation

Effects of dopaminergic replacement therapy on motor speech disorders in Parkinson's disease: longitudinal follow-up study on previously untreated patients.

Although speech disorders represent an early and common manifestation of Parkinson's disease (PD), little is known about their progression and relationship to dopaminergic replacement therapy. The aim of the current study was to examine longitudinal motor speech changes after the initiation of pharmacotherapy in PD. Fifteen newly-diagnosed, untreated PD patients and ten healthy controls of comparable age were investigated. PD patients were tested before the introduction of antiparkinsonian therapy and then twice within the following 6 years. Quantitative acoustic analyses of seven key speech dimensions of hypokinetic dysarthria were performed. At baseline, PD patients showed significantly altered speech including imprecise consonants, monopitch, inappropriate silences, decreased quality of voice, slow alternating motion rates, imprecise vowels and monoloudness. At follow-up assessment, preservation or slight improvement of speech performance was objectively observed in two-thirds of PD patients within the first 3-6 years of dopaminergic treatment, primarily associated with the improvement of stop consonant articulation. The extent of speech improvement correlated with L-dopa equivalent dose (r = 0.66, p = 0.008) as well as with reduction in principal motor manifestations based on the Unified Parkinson's Disease Rating Scale (r = -0.61, p = 0.02), particularly reflecting treatment-related changes in bradykinesia but not in rigidity, tremor, or axial motor manifestations. While speech disorders are frequently present in drug-naive PD patients, they tend to improve or remain relatively stable after the initiation of dopaminergic treatment and appear to be related to the dopaminergic responsiveness of bradykinesia.