Early-stage Idiopathic Parkinson's Disease Research Articles

Role of multimodal advanced biomarkers as potential predictors of cognitive and psychiatric aspects of Parkinson's disease

BackgroundThe value of biomarker research in Parkinson's disease (PD) exists in the early detection and accurate diagnosis of non-motor neuropsychiatric symptoms with implications for future treatment strategies. The aim of the this work was to assess and predict risk for possible cognitive, psychiatric abnormalities in patients with early stage idiopathic PD using a combination of advanced diagnostic biomarkers for early recognition and intervention.MethodsThis cross-sectional case–control study was conducted on 58 eligible idiopathic PD-patients, and 45 age/sex-matched healthy controls. All participants were subjected to neuro-psychiatric-, radiological-, audiological-, and laboratory-evaluations. Cognitive assessment was performed using Montreal Cognitive Assessment, Mattis Dementia, and Parkinson’s Disease-Cognitive scales. Depression was evaluated by Hamilton Depression and Beck Depression Inventory-II rating scales. Radiologically, volumetric-MRI, diffusion tensor imaging (DTI), and susceptibility weighted imaging were done. Audiologically, P300 and cortical auditory evoked potentials were elicited. Laboratory investigations included 24 h-urinary 5-HIAA and serum levels of IL6, BDNF, 5-HT, and aberrant cimiRNA 132-3p expression profile.ResultsNeuropsychological scales revealed mild depression and mild cognitive impairment, with significant differences in PD group. Volumetric-MRI highlighted that PD-patients had a significant bilateral decrease in the mean cortical thickness and thickness/volume of many brain areas. DTI showed a reduction in fractional isotropy and a significant bilateral increase in mean diffusivity through many areas in PD-patients. Patients also had either absent or diminished amplitude of P300,P1, diminished amplitude of N1,P2,N2 and delayed latency of all previous waves. There was a significant reduction of 24 h-urinary 5-HIAA and serum BDNF, with significant elevation of serum IL6, as well as non-significant reduction of serum 5-HT and microRNA-132-3p(2-ΔCt) in PD-patients.ConclusionsEarly stage PD-patients had subtle cognitive impairment and depression as detected by psychometric scales and correlated significantly with the various biomarkers, including advanced neuro-imaging, evoked potential studies, and laboratory markers. The key message of this work include evaluating the high prevalence of cognitive and psychiatric impairment in early idiopathic PD has encouraged research and workup for precision medicine. Proper integration of advanced multimodal biomarkers in this study has led to predict the risk of early mild cognitive and psychiaric affection. This will optimize the health strategies for early proper management to improve quality of life.

Bilirubin-Related Differential Striatal [18F]FP-CIT Uptake in Parkinson Disease.

Oxidative stress is a leading factor in the pathogenesis of idiopathic Parkinson disease (IPD). Two intrinsic antioxidative molecules, bilirubin and uric acid, are known to protect dopaminergic neurons from oxidative stress in IPD. The objective of this study was to determine the relationship between basal serum levels of 2 molecules and dopaminergic deficit assessed by dopamine transporter imaging with F-fluorinated-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl)nortropane ([F]FP-CIT) PET/CT in patients with early-stage drug-naive IPD. Cases of IPD patients who possess the levels of uric acid and bilirubin within a month from [F]FP-CIT PET/CT from January 2011 to December 2016 were retrospectively reviewed. As a control, the same criteria applied to patients with essential tremor (ET). PET images were analyzed using volume-of-interest templates for 12 striatal subregions and 1 occipital area, and the specific-to-nonspecific binding ratio (SNBR) was calculated. One hundred five patients with drug-naive, early-stage IPD and 62 patients with ET were finally included. Levels of bilirubin were significantly higher in the IPD group than in controls (P = 0.026), and bilirubin level was the factor showing the most correlations with SNBR in IPD (P < 0.001), whereas uric acid showed no such difference or relationship. Furthermore, levels of bilirubin showed a positive correlation with SNBR in more affected posterior putamen in the IPD group (Pearson correlation coefficient, ρ = 0.456; P < 0.001), but a negative one in the ET group (ρ = -0.440, P < 0.001). Bilirubin, not uric acid, was the most significant antioxidant marker for dopaminergic deficit in early-stage drug-naive IPD assessed by [F]FP-CIT PET/CT.

Dysregulation of Respiratory Center Drive (P0.1) and Muscle Strength in Patients With Early Stage Idiopathic Parkinson's Disease.

Objective: The goal of this study is to evaluate pulmonary function and respiratory center drive in patients with early-stage idiopathic Parkinson's disease (IPD) to facilitate early diagnosis of Parkinson's Disease (PD).Methods: 43 IPD patients (Hoehn and Yahr scale of 1) and 41 matched healthy individuals (e.g., age, sex, height, weight, BMI) were enrolled in this study. Motor status was evaluated using the Movement Disorders Society-Unified PD Rating Scale (MDS-UPDRS). Pulmonary function and respiratory center drive were measured using pulmonary function tests (PFT). All IPD patients were also subjected to a series of neuropsychological tests, including Non-Motor Symptoms Questionnaire (NMSQ), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Beck Depression Inventory (BDI) and Mini Mental State Examination (MMSE).Results: IPD patients and healthy individuals have similar forced vital capacity (FVC), forced expiratory volume in 1s (FEV1), forced expiratory volume in 1s/forced vital capacity (FEV1/FVC), peak expiratory flow (PEF), and carbon monoxide diffusion capacity (DLCOcSB). Reduced respiratory muscle strength, maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) was seen in IPD patients (p = 0.000 and p = 0.002, respectively). Importantly, the airway occlusion pressure after 0.1 s (P0.1) and respiratory center output were notably higher in IPD patients (p = 0.000) with a remarkable separation of measured values compared to healthy controls.Conclusion: Our findings suggest that abnormal pulmonary function is present in early stage IPD patients as evidenced by significant changes in PImax, PEmax, and P0.1. Most importantly, P0.1 may have the potential to assist with the identification of IPD in the early stage.

Diagnosis of Early-Stage Idiopathic Parkinson's Disease Using High-Resolution Quantitative Susceptibility Mapping Combined with Histogram Analysis in the Substantia Nigra at 3 T.

Background and PurposeTo test whether nigrosome-1 imaging using high-resolution quantitative susceptibility mapping (QSM) combined with histogram analysis can improve the diagnostic accuracy in early-stage idiopathic Parkinson's disease (IPD) patients.MethodsThree-dimensional multiecho gradient-recalled echo images (0.5×0.5×1.0 mm3) were obtained at 3 T for QSM in 38 patients with IPD and 25 healthy subjects. To segment the substantia nigra (SN), regions of interest (ROIs) were semiautomatically drawn at the location below the red nucleus, and the normal-appearing nigrosome-1 was determined by manual correction. QSM histograms were obtained within the ROI. The segmented SN regions on the right and left that had higher mean susceptibility values and fewer voxels with susceptibility values lower than 60, 65, 70, 75, and 80 ppb were chosen for comparisons between the IPD patients and healthy subjects. These results were compared with those of the visual assessments of nigrosome-1 in susceptibility map-weighted imaging (SMWI) by analyzing receiver operating characteristics curves.ResultsThe proportion of voxels with susceptibility values lower than 70 ppb showed the best diagnostic performance, with its value differing significantly between the IPD patients (median=0, interquartile range=0–0.23) and healthy subjects (median=10.67, interquartile range=5.98–21.57) (p<0.0001). The number of voxels with susceptibility values lower than 60, 65, 70, 75, and 80 ppb showed worse diagnostic performances but were still significantly better than that of the mean susceptibility value (p=0.0249, 0.0192, 0.0183, 0.0191, and 0.0186, respectively), which also differed significantly between the two groups: 125.81±16.27 ppb (mean±standard deviation) in IPD versus 98.41±11.70 ppb in healthy subjects (p<0.0001). Additionally, using the proportion of voxels with susceptibility values lower than 70 ppb provided significantly better diagnostic performance than did visual assessments of SMWI (p=0.0143).ConclusionsHigh-spatial-resolution QSM combined with histogram analysis at 3 T can improve the diagnostic accuracy of early-stage IPD.

Differential involvement of nigral subregions in idiopathic parkinson's disease.

In this study, the prevalence of abnormality in putative nigrosome 1 and nigrosome 4 (N1 and N4, respectively) was investigated in early versus late-stage idiopathic Parkinson's disease (IPD) patients. A total of 128 IPD patients (early stage[n = 89]; late stage[n = 39]) and 15 healthy subjects were scanned for high-resolution (0.5 × 0.5 × 1.0mm3 ) multiecho gradient-recalled echo MRI and dopamine transporter PET imaging. The MRI data were processed for susceptibility map-weighted imaging (SMWI) to improve a contrast-to-noise ratio, and the images were resliced at 0.5 mm to define N1 and N4. When each side of N1 and N4 was assessed separately for the loss of hyperintensity by two independent reviewers, the consensus review results showed that in early-stage IPD (178 substantia nigras [SNs]), the loss of hyperintensity was observed more often in only the N1 region (65.2%) when compared to in both N1 and N4 regions (34.8%). In late-stage IPD (78 SNs), on the other hand, the loss in only the N1 region (25.6%) was less prevalent than in both N1 and N4 (74.4%) (P < 0.0001). Additionally, intact SNs (both in N1 and N4) were observed 17 SNs (9.6%) of the early-stage IPD patients, whereas it was not found in any SNs of the late-stage IPD patients (P = 0.005). Moreover, involvement of both N1 and N4 on both sides was found in 19.1% of the early-stage IPD patients, whereas its incidence was higher (61.5%) in the late-stage IPD patients (P < 0.0001), suggesting that the loss of hyperintensity in IPD progresses from N1 to N4 as the disease advances. Hum Brain Mapp 39:542-553, 2018. © 2017 Wiley Periodicals, Inc.

Reduced Rapid Eye Movement Density in Parkinson Disease: A Polysomnography-Based Case-Control Study.

To explore rapid eye movement density (RD) in patients with idiopathic Parkinson disease (IPD) and to investigate its usefulness as surrogate marker of excessive daytime sleepiness, a frequent complaint in IPD patients. Retrospective polysomnography study on 81 subjects without dementia: 29 patients with early stage IPD (disease duration ≤ 3 y), 21 patients with middle- stage IPD (disease duration > 3 and < 8 y) and 31 healthy controls (HC). Rapid eye movement (REM) sleep was defined as any REM episode with > 3 min of continuous REM sleep. RD was defined as number of ocular movements per minute of REM sleep. Patients with early stage IPD and HC fulfilled the PD-specific sleepiness questionnaires Parkinson's Disease Sleep Scale (PDSS) and the Nonmotor Symptoms Questionnaire for Parkinson's disease (NMSQuest). RD was lower in patients with IPD than in HC. The difference was most significant between patients with middle stage IPD and HC (P = 0.001), and most prominent for the third REM episode, again when comparing patients with middle stage IPD and HC (P = 0.03). RD was independent from sex, age, and other sleep parameters. In early stage IPD, RD correlated with the PDSS score (r = -0.63, P = 0.001) and the sleep-related questions of the NMSQuest score (r = 0.48, P = 0.017). REM density is reduced in patients with IPD and correlates with subjective scores on sleep impairment. As an indicator of persistent high sleep pressure, reduced RD in IPD is eligible as a biomarker of excessive daytime sleepiness in IPD. It possibly reflects direct involvement of the brainstem REM generation sites by the disease process. RD is a promising new tool for sleep research in IPD.

Plasma near-infrared spectroscopy for diagnosis of idiopathic Parkinson's disease: the SPIN-PD study.

There are no established chemical biomarkers of idiopathic Parkinson's disease (PD). The results of a prior metabolomics-based biomarker study suggested that near-infrared spectroscopy of blood plasma samples may distinguish idiopathic PD from neurologically normal controls. Near-infrared spectroscopy was used to detect and quantify substrate modifications in blood plasma samples derived from 71 PD subjects enrolled in the PostCEPT observational study and 68 normal control subjects. Near-infrared spectra values were significantly higher in the PD group compared with the control group when adjusted for age and gender (PD: adjusted mean 0.49 [95% CI: 0.45-0.53]; control: adjusted mean 0.40 [95% CI: 0.36-0.44]; p = 0.004, multiple regression). Near-infrared spectra of blood plasma in early-stage idiopathic PD differ from those of non-neurological control subjects. However, the degree of overlap between the groups limits the use of this technique in its present form as a PD biomarker for routine clinical practice.

Relation between Olfactory Dysfunction and Episodic Verbal Memory in Early Parkinson's Disease.

Olfactory dysfunction is an early and common symptom in idiopathic Parkinson's disease (IPD). Recently, the relation between olfactory dysfunction and cognitive loss in IPD has been reported. In our study, we aimed to investigate the relation between olfactory dysfunction and cognitive impairments in early IPD related with this theory. In this study, we included 28 patients with stage 1 and stage 2 IPD according to the Hoehn-Yahr (H-Y) scale and 19 healthy participants. The University of Pennsylvania Smell Identification Test (UPSIT) was performed for evaluating olfactory function. For cognitive investigation in participants, the clock drawing test, Stroop test, verbal fluency test, Benton face recognition test (BFR), Benton line judgment orientation test (BLO), and Auditory Verbal Learning Test (AVLT) were performed. We found significantly lower UPSIT scores in the patient group compared to controls (p=.018). In the neuropsychological investigation, only Stroop test and BLOT test scores were significantly lower in the patient group compared to controls (p=.003, p=.002, respectively). We found a negative correlation between UPSIT scores and Stroop time (p=.033) and Stroop error (p=.037) and a positive correlation between UPSIT scores and SBST long-term memory scores (p=.016) in patients. In our study, we found mild cognitive impairment related with visuospatial and executive functions in early-stage IPD compared to controls. But, in the patient group, we detected a different impairment pattern of memory and frontal functions that correlated with hyposmia. This different pattern might be indicating a subgroup of IPD characterized by low performance in episodic verbal memory, with accompanying olfactory dysfunction in the early stage.

Neuropsychological Deficits Associated with Destruction of the Right Nigrostriatal Pathway

Hemiparkinsonism secondary to a vascular mesencephalic lesion is infrequent; these patients offer an exceptional opportunity to study neuropsychological alterations attributable to unilateral dopaminergic denervation, shedding light on the pathophysiology of cognitive disorders in early-stage idiopathic Parkinson's disease (PD). From the investigation of our case, we conclude that destruction of the right nigrostriatal pathway is accompanied by deficits in executive functioning and verbal/visual memory similar to those observed in many patients with early-stage idiopathic PD. The more complex neuropsychological dysfunction developed by other PD patients must therefore be related to the additional involvement of other brain structures.

Cardiac 123I-MIBG uptake is reduced more markedly in patients with REM sleep behavior disorder than in those with early stage Parkinson's disease

We investigated cardiac uptake of 123I-metaiodobenzylguanidine (MIBG) in patients with REM sleep behavior disorder (RBD) and compared the findings with those of idiopathic Parkinson's disease (IPD). Thirteen RBD, 222 IPD and 50 controls underwent cardiac 123I-MIBG scintigraphy. Resulting heart-to-mediastinum (H/M) ratios were significantly lower in patients with RBD and IPD as compared to the control ratios. H/M ratios were lower for delayed than for early images in patients with RBD and IPD; whereas, the controls had higher ratios for delayed images. H/M ratios were significantly lower for patients with RBD than for those with IPD at Hoehn and Yahr stages 1 and 2. Disease duration did not differ between the two groups. Our study revealed that cardiac 123I-MIBG uptake was more markedly reduced in patients with RBD than in those with early stage IPD. RBD may not necessarily be a prodromal condition of IPD with respect to cardiac 123I-MIBG uptake results.

Ageing and early-stage Parkinson's disease affect separable neural mechanisms of mesolimbic reward processing

The ability to learn stimulus-reward associations on the basis of reward prediction errors critically depends on the mesolimbic dopaminergic system including the dopaminergic midbrain and the ventral striatum. It is known that healthy elderly and patients with Parkinson's disease are less proficient than healthy young adults in learning stimulus-reward contingencies, but it is unclear whether this is due to dysfunctional mesolimbic reward prediction or due to deficiency in processing the rewards per se. We used a well-established event-related fMRI reward-prediction paradigm to address this question. Young adults showed the well-replicated pattern of midbrain and ventral striatal activation for stimuli that predicted monetary reward when compared with stimuli that predicted neutral feedback. Also, as expected, the predicted reward feedback itself did not elicit a mesolimbic response. Healthy elderly subjects and unmedicated early-stage idiopathic Parkinson's disease patients showed the opposite pattern with an absent mesolimbic reward prediction response, but mesolimbic activation to the reward feedback itself. This suggests that the healthy elderly and Parkinson's disease patients were less proficient in learning the predictive value of the reward cues despite preserved mesolimbic processing of reward prediction errors. Parkinson's disease patients additionally displayed a relatively increased response of the anterior cingulate during reward feedback processing and diminished functional connectivity of the midbrain and ventral striatum. Our results are compatible with existing behavioural evidence that both groups exhibit a particularly pronounced deficit in learning from positive feedback and support the view that a tendency to underestimate expected values of reward cues might underlie this deficit. Furthermore, alterations in reward processing in Parkinson's disease extend beyond accelerated ageing effects and include altered connectivity within the mesolimbic system.

Schwarz Pharma and UCB have announced the launch of transdermal rotigotine [Neupro] in the US for the treatment of early-stage idiopathic Parkinson's disease

Schwarz Pharma and UCB have announced the launch of transdermal rotigotine [Neupro] in the US for the treatment of early-stage idiopathic Parkinson's disease

Inversion Recovery MRI in Idiopathic Parkinson Disease Is a Very Sensitive Tool to Assess Neurodegeneration in the Substantia Nigra: Preliminary Investigation

Segmented inversion recovery (IR) ratio imaging (SIRRIM) has been established as a sensitive tool to assess neurodegeneration of the substantia nigra pars compacta (SN(C)) in patients with idiopathic Parkinson disease (IPD). The obtained results suggest the possibility of magnetic resonance imaging (MRI) as a biological marker for IPD. The strength and a parsimonious analysis of the technique are discussed to assess the potential of using MRI as a biological marker for IPD and improve the differential diagnosis of sporadic Parkinson disease. Our hypothesis states that the magnetic resonance SIRRIM technique allows direct visualization and quantitation of neural cell loss in the SN(C) and therefore could become a reliable biological marker for Parkinson disease. To achieve this goal, some key aspects of data acquisition and data analysis need to be addressed. The clinical impact of the SIRRIM technique could be considerable, considering that it might become a viable surrogate to other techniques. Twelve patients with IPD and 12 age-matched control subjects were imaged by using the SIRRIM technique based on two IR imaging sequences that were designed to suppress white and gray matter to assess loss of neural cells in situ by means of a ratio image (white matter suppressed image to gray matter suppressed image). The radiological index was correlated with the Unified Parkinson Disease Rating Scale (UPDRS) for patients with IPD. All patients with IPD were identified correctly, and full dichotomization between healthy volunteers and patients was obtained with our database. Our SIRRIM technique shows that it can be used to rule out Parkinson disease from essential tremor and other forms of Parkinsonism, such as progressive supranuclear palsy and multisystem atrophy. In addition, it is sensitive enough to identify patients with early-stage IPD. The hypothesis of using SIRRIM as a biological marker to assess IPD is supported by excellent correlation with clinical UPDRS scoring and has proved useful for the evaluation and quantitation of neurodegeneration with our SIRRIM technique, showing, in addition, that the differential diagnosis of IPD can be improved. Technical aspects of acquisition and data processing that need to be addressed can be overcome. It ultimately confirms that our objectives can be achieved and allows us to expect assessment of the progressive development of neurodegeneration in longitudinal studies and the putative neuroprotective approaches taken during the evolution of the disease.

Safety, Tolerability, and Efficacy of Continuous Transdermal Dopaminergic Stimulation with Rotigotine Patch in Early-Stage Idiopathic Parkinson Disease

Rotigotine is a new dopamine agonist with transdermal patch formulation for the treatment of Parkinson disease. The aim of this study was to investigate safety and efficacy of rotigotine in patients with early-stage Parkinson disease. In this open-label, dose-escalation, safety and efficacy study, 31 patients in the early stages of idiopathic Parkinson disease received rotigotine to a maximum of 18.0 mg/day. Of the 29 patients who completed the 28-day treatment phase, 24 were maintained at the maximum dose level. The drug was well tolerated, and skin reactions were mild. A statistically significant improvement in UPDRS I, II, and III scores was observed from baseline to end of treatment for the 29 subjects who completed the trial. Mean improvement (+/- standard deviation) was -0.41 +/- 0.78 on UPDRS I (P = 0.0078), -2.76 +/- 3.31 on UPDRS II (P = 0.0001), and -4.62 +/- 5.32 on UPDRS III (P < 0.0001). When results were stratified by maximum dose achieved, significant improvements were seen on all 3 subscores for patients achieving the maximum dose. These data suggest that rotigotine is a safe, well-tolerated, and effective treatment for early-stage Parkinson disease.

Parametric mapping of [18F]FPCIT binding in early stage Parkinson's disease: a PET study.

We have shown that fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane ([(18)F]FPCIT) and PET offer a valuable means of quantifying regional abnormality in dopamine transporter (DAT) imaging associated with Parkinson's disease (PD). The objective of this study was to delineate the topographic distribution of DAT binding in early stage idiopathic PD using statistical parametric analysis of [(18)F]FPCIT PET data. We performed dynamic PET studies in 15 hemi-parkinsonian (Hoehn & Yahr I) patients and 10 age-matched normal volunteers over 100 min and calculated images of [(18)F]FPCIT binding ratios on a pixel-by-pixel basis. Statistical parametric mapping (SPM) was then used to localize binding reductions in PD and to compute the absolute change relative to normal. [(18)F]FPCIT binding decreased significantly in the contralateral posterior putamen of the PD group (P < 0.001, corrected). A significant reduction was also seen in the ipsilateral putamen, which was smaller in extent but localized more posteriorly. A quantitative comparison of DAT binding in the two clusters showed that the onset of motor symptoms in PD was associated with an approximate 70% loss relative to the normal mean in the contralateral posterior putamen. These results suggest that SPM analysis of [(18)F]FPCIT PET data can be used to quantify and map abnormalities in DAT activity within the human striatum. This method provides a useful tool to track the onset and progression of PD at its earliest stages.