Untreated Parkinson's Disease Research Articles

Cortical beta burst dynamics are altered in Parkinson's disease but normalized by deep brain stimulation

Exaggerated subthalamic beta oscillatory activity and increased beta range cortico-subthalamic synchrony have crystallized as the electrophysiological hallmarks of Parkinson's disease. Beta oscillatory activity is not tonic but occurs in ‘bursts’ of transient amplitude increases. In Parkinson's disease, the characteristics of these bursts are altered especially in the basal ganglia. However, beta oscillatory dynamics at the cortical level and how they compare with healthy brain activity is less well studied. We used magnetoencephalography (MEG) to study sensorimotor cortical beta bursting and its modulation by subthalamic deep brain stimulation in Parkinson's disease patients and age-matched healthy controls. We show that the changes in beta bursting amplitude and duration typical of Parkinson's disease can also be observed in the sensorimotor cortex, and that they are modulated by chronic subthalamic deep brain stimulation, which, in turn, is reflected in improved motor function at the behavioural level. In addition to the changes in individual beta bursts, their timing relative to each other was altered in patients compared to controls: bursts were more clustered in untreated Parkinson's disease, occurring in ‘bursts of bursts’, and re-burst probability was higher for longer compared to shorter bursts. During active deep brain stimulation, the beta bursting in patients resembled healthy controls’ data. In summary, both individual bursts’ characteristics and burst patterning are affected in Parkinson's disease, and subthalamic deep brain stimulation normalizes some of these changes to resemble healthy controls’ beta bursting activity, suggesting a non-invasive biomarker for patient and treatment follow-up.

Relationship between Apathy and Subjective Poor Night-time Sleep in de novo, Untreated Parkinson's Disease.

Sleep disturbance is one of the most common non-motor symptoms of Parkinson's disease (PD). However, the confounding effects of dopaminergic medication on sleep are a major challenge in understanding the impact of sleep disturbance in PD. We investigated the sleep disturbance and associated clinical features in patients with de novo, untreated PD. One-hundred-eight patients with de novo, untreated PD were included. Night sleep disturbance was evaluated using the night sleep subscale of the Scales for Outcomes in Parkinson's Disease (SCOPA-Sleep). Depression, anxiety, and apathy were assessed using the Geriatric Depression Scale (GDS), Beck Anxiety Inventory (BAI), and Apathy Evaluation Scale (AES), respectively. Early perfusion and dopamine transporter imaging of F-18 FP-CIT PET/CT were performed together with statistical parametric mapping analysis. The night sleep SCOPA-Sleep sub-score was correlated with the AES (p = 0.014), BAI (p = 0.014), and GDS (p = 0.023) scores. Patients with poor night sleep were more apathetic (p = 0.013). Additionally, there was increased perfusion in the left posterior cingulate in patients with sleep disturbance and apathy compared to those with sleep disturbance only. Night sleep disturbance was related to mood disorders, particularly apathy, in patients with de novo, untreated PD.

Toward Automated Articulation Rate Analysis via Connected Speech in Dysarthrias.

This study aimed to evaluate the reliability of different approaches for estimating the articulation rates in connected speech of Parkinsonian patients with different stages of neurodegeneration compared to healthy controls. Monologues and reading passages were obtained from 25 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD), 25 de novo patients with Parkinson's disease (PD), 20 patients with multiple system atrophy (MSA), and 20 healthy controls. The recordings were subsequently evaluated using eight syllable localization algorithms, and their performances were compared to a manual transcript used as a reference. The Google & Pyphen method, based on automatic speech recognition followed by hyphenation, outperformed the other approaches (automated vs. hand transcription: r > .87 for monologues and r > .91 for reading passages, p < .001) in precise feature estimates and resilience to dysarthric speech. The Praat script algorithm achieved sufficient robustness (automated vs. hand transcription: r > .65 for monologues and r > .78 for reading passages, p < .001). Compared to the control group, we detected a slow rate in patients with MSA and a tendency toward a slower rate in patients with iRBD, whereas the articulation rate was unchanged in patients with early untreated PD. The state-of-the-art speech recognition tool provided the most precise articulation rate estimates. If speech recognizer is not accessible, the freely available Praat script based on simple intensity thresholding might still provide robust properties even in severe dysarthria. Automated articulation rate assessment may serve as a natural, inexpensive biomarker for monitoring disease severity and a differential diagnosis of Parkinsonism.

Reply to: Correlation of Antidepressant Use and Symptom Time Period in Dream Enactment Behaviors.

Firstly, I would like to thank Sumi et al.1 for showing interest in my recently published study2 and providing the opportunity to expand the discussion on this fascinating topic, that has both clinical and theoretical relevance. Sumi et al. had concerns about possible confounding due to medication use. Although all participants in the Parkinson's Progression Markers Initiative (PPMI) database were untreated for Parkinson's disease (PD) at baseline, which is important to highlight, since dopaminergic medications have previously been associated with dream alterations3; I do nevertheless agree that given the frequent comorbidity of depression and REM sleep behavior disorder in people with PD, that the effects of antidepressants and clonazepam used to treat these, ought to be considered. In fact, a previous study identified that 41.2% of PD participants in PPMI reported using antidepressants during the course of the study and 14.2% reported having used clonazepam.4 However, Sumi et al.'s statement that neither PPMI nor the study evaluated the presence of depression, is not entirely correct. In the study, total number of depressive symptoms, assessed using the extensively validated Geriatric Depression Scale,5 was included as a covariate in one of the sensitivity analyses.2 Crucially, the inclusion of depressive symptoms as a covariate did not alter the association between aggressive dream content and either motor or cognitive decline.2 Nonetheless, to ensure that the results were not confounded by antidepressant use specifically, I have now conducted two further analyses. First, I repeated the primary analyses after adjusting for antidepressant use at any time from baseline to the most recent study visit. Second, I repeated the analyses after including self-reported past or present depression (obtained from item 10 of the REM sleep behavior disorder screening questionnaire), as an additional covariate. Neither antidepressant use nor a history of depression attenuated the association between dream content and motor or cognitive decline (P's < 0.05). Similarly, after adjusting for clonazepam use, the associations between aggressive dream content and both outcomes remained significant (P's < 0.05). Finally, with respect to Sumi et al.'s third concern regarding fluctuation of aggressive dreams over time, it is pertinent to emphasize that these participants were all newly diagnosed at baseline, with a mean duration of 6.3 months since diagnosis. As such, it is unlikely that sufficient time had passed for there to be a significant group for whom “aggressive dreams [had] disappeared” during the course of PD. In any case, if such a group were to exist, it could actually have led to an underestimation of the association, since individuals who once had aggressive dreams would have been included in the non-aggressive dream group. Therefore, whilst the insightful concerns raised by Sumi et al are important to consider, I do not believe they challenge the core conclusions of this study, namely, that people with newly diagnosed, untreated PD who report having frequent aggressive dreams, may be at higher risk of early motor and cognitive decline than those who do not report having them. Data used in the preparation of this article were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. Data were downloaded from the PPMI database on December 22, 2020. 1. Research Project: Conception, Organization, Execution; 2. Statistical Analysis: Design, Execution; 3. Manuscript Preparation AIO: 1,2,3. Each Parkinson's Progression Markers Initiative site received approval from a local ethical committee on human experimentation before commencement of the study. Written informed consent was obtained from all individuals who participated in the study. I confirm that I have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. I declare that there are no conflicts of interest relevant to this work. The author is funded by a National Institute for Health Research academic clinical fellowship.

Validation of cepstral peak prominence in assessing early voice changes of Parkinson's disease: Effect of speaking task and ambient noise.

Although the cepstral peak prominence (CPP) and its variant, the cepstral peak prominence smooth (CPPS), are considered to be robust acoustic measures for the evaluation of dysphonia, whether they are sensitive to capture early voice changes in Parkinson's disease (PD) has not yet been explored. This study aimed to investigate the voice changes via the CPP measures in the idiopathic rapid eye movement sleep behavior disorder (iRBD), a special case of prodromal neurodegeneration, and recently diagnosed and advanced-stage Parkinson's disease (AS-PD) patients using different speaking tasks across noise-free and noisy environments. The sustained vowel phonation, reading of passages, and monologues of 60 early stage untreated PD, 30 advanced-stage Parkinson's disease, 60 iRBD, and 60 healthy control (HC) participants were evaluated. Significant differences were found between the PD groups and controls in sustained phonation via the CPP (p < 0.05) and CPPS (p < 0.01) and the monologue via the CPP (p < 0.01), although neither the CPP nor CPPS measures were sufficiently sensitive to capture the possible prodromal dysphonia in the iRBD. The quality of the CPP and CPPS measures was influenced substantially by the addition of ambient noise. It was anticipated that the CPP measures might serve as a promising digital biomarker in assessing the dysphonia from the early stages of PD.

Automated speech analysis in early untreated Parkinson's disease: Relation to gender and dopaminergic transporter imaging.

The mechanisms underlying speech abnormalities in Parkinson's disease (PD) remain poorly understood, with most of the available evidence based on male patients. This study aimed to estimate the occurrence and characteristics of speech disorder in early, drug-naive PD patients with relation to gender and dopamine transporter imaging. Speech samples from 60 male and 40 female de novo PD patients as well as 60 male and 40 female age-matched healthy controls were analyzed. Quantitative acoustic vocal assessment of 10 distinct speech dimensions related to phonation, articulation, prosody, and speech timing was performed. All patients were evaluated using [123]I-2b-carbomethoxy-3b-(4-iodophenyl)-N-(3-fluoropropyl) nortropane single-photon emission computed tomography and Montreal Cognitive Assessment. The prevalence of speech abnormalities in the de novo PD cohort was 56% for male and 65% for female patients, mainly manifested with monopitch, monoloudness, and articulatory decay. Automated speech analysis enabled discrimination between PD and controls with an area under the curve of 0.86 in men and 0.93 in women. No gender-specific speech dysfunction in de novo PD was found. Regardless of disease status, females generally showed better performance in voice quality, consonant articulation, and pauses production than males, who were better only in loudness variability. The extent of monopitch was correlated to nigro-putaminal dopaminergic loss in men (r=0.39, p=0.003) and the severity of imprecise consonants was related to cognitive deficits in women (r=-0.44, p=0.005). Speech abnormalities represent a frequent and early marker of motor abnormalities in PD. Despite some gender differences, our findings demonstrate that speech difficulties are associated with nigro-putaminal dopaminergic deficits.

Sex-based differences in the activation of peripheral blood monocytes in early Parkinson disease

Increasing evidence supports the role of brain and systemic inflammation in the etiology of Parkinson disease (PD). We used gene expression profiling to examine the activation state of peripheral blood monocytes in 18 patients with early, untreated PD and 16 healthy control (HC) subjects. Monocytes were isolated by negative selection, and gene expression studied by RNA-seq and gene set enrichment analysis. A computational model that incorporated case/control status, sex, and the interaction between case/control status and sex was utilized. We found that there was a striking effect of sex on monocyte gene expression. There was inflammatory activation of monocytes in females with PD, with enrichment of gene sets associated with interferon gamma stimulation. In males, the activation patterns were more heterogeneous. These data point to the importance of systemic monocyte activation in PD, and the importance of studies which examine the differential effects of sex on pathophysiology of the disease.

Electrogastrography for diagnosis of early-stage Parkinson's disease

IntroductionPatients with Parkinson's disease (PD) often present with gastric symptoms. Electrogastrography (EGG) can noninvasively assess gastric electric activity and may be useful for early PD diagnosis. The present study aimed to compare the efficacy of EGG in early PD diagnosis with those of 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy and odor stick identification test –Japanese version (OSIT-J). MethodsThirty-seven untreated PD patients (mean age ± SD, 66 ± 8years; disease duration < 3 years) and 20 healthy control subjects (68 ± 6.9 years) were recruited. EGG and OSIT-J were performed in both groups, and MIBG scintigraphy in the PD group. EGG parameters were assessed in the preprandial and early and late postprandial segments using power spectrum analysis. ResultsIrregular EGG waves were observed in PD patients. The preprandial instability coefficient of dominant frequency (ICDF), an index of EGG irregularity, in PD patients (9.5% [6.3%]) was higher than that in controls (3.9% [3.9%], p = 0.00005). The OSIT-J score was also lower in PD patients (4.6 [3.3]) than in controls (7.7 [3.3], p = 0.006). In receiver operating characteristics analyses, the areas under the curves of preprandial ICDF and OSIT-J were 0.83 and 0.72, respectively. The sensitivities of preprandial ICDF and MIBG (delayed-phase) scintigraphy were 73% and 70%, respectively. ConclusionsEarly and untreated PD patients showed irregular EGG waves and high ICDF. EGG showed better accuracy than the olfactory test for early PD diagnosis and similar sensitivity to MIBG scintigraphy.

Does Gut Microbiota Influence the Course of Parkinson's Disease? A 3-Year Prospective Exploratory Study in de novo Patients.

Although abnormalities in gut microbiota are hypothesized to influence the pathogenesis and clinical phenotype of Parkinson's disease (PD), prospective studies on de novo patients are lacking. To preliminarily investigate whether gut microbiota in early untreated PD may predict motor and non-motor features progression over a 3-year period. 16S ribosomal RNA gene amplicons were sequenced on fecal samples of 39 de novo PD patients. Multiple confounders were taken into account, including dietary habits. Motor and non-motor symptoms were assessed using validated scales at baseline and followed-up yearly for 3 years. At last follow-up, a detailed neuropsychological assessment was additionally performed. A general linear model for repeated measurements- adjusted by dopaminergic therapy at follow-up- was used to investigate the relationship between bacterial taxa abundance at baseline (stratified by the median of distribution at baseline) and outcome variables. Twenty-five patients were included (11 refused, 2 lost at follow-up, 1 died). Lower abundance of Roseburia (Firmicutes phylum) at baseline was associated with worse evolution of motor, non-motor and cognitive functions at 3-year follow-up. Similarly, lower abundance of Ruminococcaceae and Actinobacteria at baseline was associated with faster worsening of global cognitive functions. At follow-up, frontal lobe functions were the features most robustly associated with baseline microbial abnormalities. In the present exploratory study on de novo PD, we found an association between abnormal distribution of specific bacterial taxa and the progression of motor and non-motor features over a 3-year period. This proof-of-principle study supports the design of a larger observational study aiming to determine whether these differences survive multiple-comparison correction and define microbiota-specific subgroups suitable for therapeutic targeting.

Sex differences in underweight and body mass index in Chinese early de novo patients with Parkinson's disease.

ObjectiveThere have been studies investigating sex differences in clinical manifestation of Parkinson's disease (PD). However, sex differences in underweight and body mass index (BMI) in de novo PD patients lacked systematic study. We aimed to compare sex differences in clinical features and related factors of underweight and BMI in Chinese de novo PD patients.Materials and MethodsA total of 253 untreated PD inpatients and 218 controls were recruited from Ningbo. BMI, demographics, Montreal Cognitive Assessment (MoCA), supine and upright blood pressure, Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), homocysteine (HCY), uric acid, glycated hemoglobin, and lipid parameters were examined. Patients were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and Hoehn and Yahr (HY) Rating Scale.ResultsFemale patients had a significantly lower incidence of underweight and higher BMI than male patients, and there were sex differences in serum lipids, HCY levels, and depression severity. Binary regression analysis showed that only in male patients was underweight associated with the UPDRS motor score and lower ΔSBP and ΔDBP values (all p < .05). Further multiple regression analysis indicated, in addition to the correlations between BMI and ΔSBP and ΔDBP values in both sexes (all p < .001), BMI was also associated with MoCA and lower UPDRS motor scores in male patients and lower HAMD scores in female patients.ConclusionOur study suggests that there are significant sex differences in the prevalence of underweight, BMI, and factors associated with underweight and BMI among de novo PD patients.

Identified biomarkers for the development of cognitive impairment in Parkinson's disease

As part of an international prospective study, scientists analyzed the data of 423 patients with newly diagnosed and untreated Parkinson's disease who did not show signs of cognitive impairment. Three years after the detection of the disease, 15-38% (depending on the criteria used) of these patients began to develop cognitive impairment. Scientists performed brain scans, genetic tests, and cerebrospinal fluid analysis and found that a decrease in mental ability correlated with several biomarkers.

Ultrasonic stimulation of the brain to enhance the release of dopamine - A potential novel treatment for Parkinson's disease.

Parkinson's disease (PD) is characterized by the decrease of dopamine (DA) production and release in the substantia nigra and striatum regions of the brain. Transcranial ultrasound has been exploited recently for neuromodulation of the brain in a number of fields. We have stimulated DA release in PC12 cells using low-intensity continuous ultrasound (0.1W/cm2-0.3W/cm2, 1MHz), 12h after exposure at 0.2W/cm2, 40s, the amount of DA content eventually increased 78.5% (p=0.004). After 10-day ultrasonic treatment (0.3W/cm2, 5min/d), the DA content in the striatum of PD mice model restored to 81.07% of the control (vs 43.42% in the untreated PD mice model). In addition to this the locomotion activity was restored to the normal level after treatment. We suggest that the low intensity ultrasound-induced DA release can be attributed to a combination of neuron regeneration and improved membrane permeability produced by the mechanical force of ultrasound. Our study indicates that the application of transcranial ultrasound applied below FDA limits, could provide a candidate for relatively safe and noninvasive PD therapy through an amplification of DA levels and the stimulation of dopaminergic neuron regeneration without contrast agents.

Neuropsychological Test Performances and Depression in Early-Stage De Novo Parkinson's Disease.

Evaluate neuropsychological test performance in depressed patients with early-stage Parkinson's disease. Data from 422 participants from the Parkinson's Progression Marker Initiative were examined. The Geriatric Depression Scale-15 was used to categorize depressed and non-depressed participants. Neuropsychological tests measured verbal learning/memory, processing speed, visuospatial ability, verbal fluency, and working memory. Demographic and clinical variables were compared using independent samples t tests and chi-square analyses.Linear regression models were fit to adjust for age, years of education, and symptom duration. The non-depressed group (n=280) was significantly older; t(246.08)=2.25, p=.026 and had higher education; t(420)=2.35, p=.019; and longer duration of PD symptoms; t(170.58)=-2.13, p=.035 than the depressed group (n=142). The non-depressed group performed better on a working memory task than the depressed group, t(420)=2.05, p=.041, but the results did not appear to be of clinical significance. There was no significant difference between other cognitive domains. The results were not influenced by age, education, or disease duration. Among patients with early-stage, untreated Parkinson's disease, depression does not appear to affect neuropsychological test performance. Clinicians should demonstrate caution in over-interpreting the influence of depression on cognition in this population.

Dopaminergic urethral closure mechanisms in a rat model of Parkinson's disease.

Urinary incontinence is prevalent among patients with Parkinson's disease (PD). In the present study, we investigated urethral functions in a rat model of PD induced by 6-hydroxydopamine injection at their substantia nigra pars compacta as well as the roles of selective agonists/antagonist of dopamine D1- and D2-like receptors in active urethral closure mechanisms. We measured changes in the urethral pressure amplitude during electrical stimulation, urethral baseline pressure, and leak point pressure after intravenous administration of selective agonists or antagonists of the dopamine D1- and D2-like receptors in a rat model of PD. The mean leak point pressure and the mean active urethral response values were significantly smaller for the untreated PD rat group compared with the control group. In PD model, the active urethral response increased significantly after treatment with the dopamine D1-like receptor agonist, whereas that induced by the dopamine D2-like receptor agonist decreased significantly. The response to the D2-like receptor agonist was suppressed in the PD rat by the dopamine D2-like receptor antagonist. Our results suggest that the active urethral closure mechanisms are significantly impaired when dopamine is depleted. In the PD rat, dopamine D1-like receptor activity on the central nervous system appear to partially compensate for urethral functions negatively impacted by the lack of dopamine, whereas dopamine D2-like receptor activity might exacerbate urinary leakage owing to the negative effect of this activated receptor on urethral pressure under increased intra-abdominal pressure.

Assessment of Motor Impairments in Early Untreated Parkinson's Disease Patients: The Wearable Electronics Impact.

The complex nature of Parkinson's disease (PD) makes difficult to rate its severity, mainly based on the visual inspection of motor impairments. Wearable sensors have been demonstrated to help overcoming such a difficulty, by providing objective measures of motor abnormalities. However, up to now, those sensors have been used on advanced PD patients with evident motor impairment. As a novelty, here we report the impact of wearable sensors in the evaluation of motor abnormalities in newly diagnosed, untreated, namely de novo, patients. A network of wearable sensors was used to measure motor capabilities, in 30 de novo PD patients and 30 healthy subjects, while performing five motor tasks. Measurement data were used to determine motor features useful to highlight impairments and were compared with the corresponding clinical scores. Three classifiers were used to differentiate PD from healthy subjects. Motor features gathered from wearable sensors showed a high degree of significance in discriminating the early untreated de novo PD patients from the healthy subjects, with 95% accuracy. The rates of severity obtained from the measured features are partially in agreement with the clinical scores, with some highlighted, though justified, exceptions. Our findings support the feasibility of adopting wearable sensors in the detection of motor anomalies in early, untreated, PD patients. This work demonstrates that subtle motor impairments, occurring in de novo patients, can be evidenced by means of wearable sensors, providing clinicians with instrumental tools as suitable supports for early diagnosis, and subsequent management.

Complexity of electrocortical activity as potential biomarker in untreated Parkinson’s disease

In Parkinson's disease (PD), the identification of instrumental biomarkers is crucial to evaluate disease susceptibility and motor stage. We evaluated self-similarity of electrocortical activity as expression of brain signal complexity in untreated PD, to investigate its possible role as a neurophysiological biomarker. We analyzed the data of 34 untreated PD subjects and 18 group-matched controls who underwent standardized electroencephalography. A Welch's periodogram was applied to site-specific electroencephalographic signal epochs. To investigate self-similarity of electrocortical activity, the power law exponent β was computed for each selected coordinate. In both PD subjects and controls, β values at each coordinate increased with an antero-posterior gradient, changing from values around one in fronto-temporal sites to values around two among parieto-occipital sites. PD subjects presented overall lower β values among different sites compared to controls, with significant differences for the left fronto-temporal sites. Our findings suggest an increased level of fronto-temporal neuronal organization in untreated PD. We hypothesize a possible role of β as a neurophysiological biomarker for early untreated PD.

The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort.

ObjectiveThe Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker‐defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease‐modifying therapeutic trials.MethodsA total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org.ResultsApproximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS‐UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α‐synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t‐tau (45/53) and p‐tau (16/18) were reduced in PD versus HC (P < 0.01),Interpretation PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.

Is hyperhomocysteinemia associated with the structural changes of the substantia nigra in Parkinson's disease? A two-year follow-up study

ObjectiveIt was recently found that structural changes in the substantia nigra (SN) and motor symptoms become more prominent in Parkinson's disease (PD) patients with striatal silent lacunar infarction (SSLI) than in those without SSLI. Hyperhomocysteinemia (HHCY) was an independent risk factor for SSLI in PD patients. In this follow-up study, we investigated the relationship between HHCY and structural changes of the SN in PD patients. MethodsA total of 72 untreated early PD patients without SSLI, divided into control and HHCY groups, were enrolled in this study. All participants underwent conventional MRI and diffusion kurtosis imaging (DKI) twice; at baseline and at the 2-year visit. The differences of the following variables between the two groups were analyzed: mean kurtosis (MK) values of the SN, the severity of disease, daily dosage of levodopa, and the variation of these indexes from baseline to 2-year visit. Logistic regression analysis was used to identify the relationship between HHCY and structural changes of the SN in PD patients. Results1.All variables mentioned above showed significant differences between the two groups. 2. The variation in MK values of the SN were positively correlated with the variation in the severity of disease. 3. HHCY was an independent risk factor for the variation in MK values of the SN in PD patients. ConclusionHHCY is associated with the structural changes of the SN in PD patients. As PD progresses, motor symptoms become aggravated with increased structural changes to the SN, especially in patients with HHCY.

Functional monoamine oxidase B gene intron 13 polymorphism predicts putaminal dopamine turnover in de novo Parkinson's disease.

The objective of this study was to evaluate the effects of common functional polymorphisms in genes involved in dopamine metabolism on striatal dopamine turnover in de novo Parkinson's disease (PD). This was an observer-blinded cohort study investigating effects of common functional polymorphisms in dopa decarboxylase (DDC, rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT, rs4680), and dopamine transporter/solute carrier family 6 member 3 (DAT/SLC6A3, variable number tandem repeats) genes on 18 F-fluorodopa uptake and an effective distribution volume ratio (inverse of dopamine turnover) measured by 18 F-fluorodopa PET in 28 untreated PD patients. Patients carrying the MAOBCC/(C)/CT genotype (low/intermediate enzyme activity) had a lower dopamine turnover in the putamen (higher mean effective distribution volume ratio) when compared with patients with MAOBTT/(T) genotype (high enzyme activity). Striatal PET measures were not different between variants in the remaining genes. The MAOB (rs1799836) polymorphism predicts putaminal dopamine turnover in early PD with the MAOBTT allele linked to high enzyme activity leading to higher intrinsic dopamine turnover, which has been demonstrated to constitute a risk factor for motor complications. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Upgraded Methodology for the Development of Early Diagnosis of Parkinson's Disease Based on Searching Blood Markers in Patients and Experimental Models.

Numerous attempts to develop an early diagnosis of Parkinson's disease (PD) by searching biomarkers in biological fluids were unsuccessful. The drawback of this methodology is searching markers in patients at the clinical stage without guarantee that they are also characteristic of either preclinical stage or prodromal stage (preclinical-prodromal stage). We attempted to upgrade this methodology by selecting only markers that are found both in patients and in PD animal models. HPLC and RT-PCR were used to estimate the concentration of amino acids, catecholamines/metabolites in plasma and gene expression in lymphocytes in 36 untreated early-stage PD patients and 52 controls, and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice at modeling the clinical ("symptomatic") stage and preclinical-prodromal ("presymptomatic") stage of PD. It was shown that among 13 blood markers found in patients, 7 markers are characteristic of parkinsonian symptomatic mice and 3 markers of both symptomatic and presymptomatic mice. According to our suggestion, the detection of the same marker in patients and symptomatic animals indicates adequate reproduction of pathogenesis along the corresponding metabolic pathway, whereas the detection of the same marker in presymptomatic animals indicates its specificity for preclinical-prodromal stage. This means that the minority of markers found in patients-decreased concentration of L-3,4-dihydroxyphenylalanine (L-DOPA) and dihydroxyphenylacetic acid (DOPAC) and increased dopamine D3 receptor gene expression-are specific for preclinical-prodromal stage and are suitable for early diagnosis of PD. Thus, we upgraded a current methodology for development of early diagnosis of PD by searching blood markers not only in patients but also in parkinsonian animals.