Brain MRI Reveals Ascending Atrophy in Parkinson's Disease Across Severity.

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

Over the past two decades, the development of functional imaging methods has greatly promoted our understanding on the changes of neurons following neurodegenerative disorders, such as Parkinson's disease (PD). The application of a spatial covariance analysis on 18F-FDG PET imaging has led to the identification of a distinctive disease-related metabolic pattern. This pattern has proven to be useful in clinical diagnosis, disease progression monitoring as well as assessment of the neuronal changes before and after clinical treatment. It may potentially serve as an objective biomarker on disease progression monitoring, assessment, histological and functional evaluation of related diseases. PD is one of the most common neurodegenerative disorders in the elderly. It is characterized by progressive loss of dopamine neurons in the substantia nigra pars compacta. Throughout the course of disease, the most obvious symptoms are movement-related, such as resting tremor, muscle rigidity, hypokinesia and postural instability (Worth, 2013). Currently, a definite diagnosis of PD is made by clinical evaluation with at least 2 years of follow-up (Hughes et al., 2002; Bhidayasiri and Reichmann, 2013), due to the overlap of motor symptoms between early PD and atypical parkinsonism including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). However, this classic diagnostic criterion does not benefit the early diagnosis of disease. The prognostic outcome and treatment option are substantially different between PD and atypical parkinsonism. Thus it is critical to develop biomarkers for earlier and more accurate diagnosis of PD. Generally, appropriate diagnostic biomarker for PD ought to cover several key characteristics: (i) minimal invasiveness to detect the biomarker in easily accessible body tissue or fluids, (ii) excellent sensitivity to explore the patients with PD, (iii) high specificity to prevent false-positive results in PD-free individuals, and (iv) robustness against potential affecting factors. A PD-related spatial covariance pattern (PDRP) with quantifiable expression on 18F-FDG PET imaging has been gradually detected using a spatial covariance method during the last two decades and it has been demonstrated to be the right diagnostic biomarker for PD (Eidelberg et al., 1994). PDRP has proven not only to be effective in early discrimination of PD from atypical parkinsonian disorders, but also to be able to assess the disease progression and treatment response. Thus it is considered as a multifunctional biomarker. In this review, we aim to provide an overview of the development in pattern-based biomarker for PD.

We have studied focal changes in dopaminergic function throughout the brain volume in early and advanced Parkinson's disease by applying statistical parametric mapping (SPM) to 3D [(18)F]dopa-PET. Data from seven early hemi-Parkinson's disease and seven advanced bilateral Parkinson's disease patients were compared with that from 12 normal controls. Parametric images of [(18)F]dopa influx rate constant (K(i)(o)) were generated for each subject from dynamic 3D [(18)F]dopa datasets and transformed into standard stereotactic space. Significant changes in mean voxel [(18)F]dopa K(i)(o) values between the normal control group and each Parkinson's disease group were localized with SPM. Conventional region of interest analysis was also applied to comparable regions on the untransformed image datasets. In early left hemi-Parkinson's disease, significant extrastriatal increases in [(18)F]dopa K(i)(o) were observed in the left anterior cingulate gyrus and the dorsal midbrain region (P < 0.05, corrected) along with decreases in striatal [(18)F]dopa K(i)(o). In advanced Parkinson's disease, significant extrastriatal decreases in [(18)F]dopa K(i)(o) were observed in the ventral and dorsal midbrain regions (P < 0.05, corrected). No significant changes in [(18)F]dopa K(i)(o) were observed in the anterior cingulate region. In a direct comparison between the early and late Parkinson's disease groups, we observed relative [(18)F]dopa K(i)(o) reductions in ventral and dorsal midbrain, and dorsal pontine regions along with striatal [(18)F]dopa K(i)(o) reductions. Similiar results were found with a region of interest approach, on non-transformed data, except for the focal midbrain [(18)F]dopa K(i)(o) increase seen in early Parkinson's disease. In conclusion, using SPM with [(18)F]dopa-PET, we have objectively localized changes in extrastriatal, pre-synaptic dopaminergic function in Parkinson's disease. The significance of the increased dopaminergic activity of anterior cingulate in early Parkinson's disease remains unclear, but may be compensatory. The [(18)F]dopa signal in dorsal midbrain and pontine regions suggests that [(18)F]dopa is taken up by serotonergic and noradrenergic neurons which also degenerate in advanced Parkinson's disease. This suggests, therefore, that Parkinson's disease is a monoaminergic neurodegenerative disorder.

Forehead sympathetic skin responses in determining autonomic involvement in Parkinson’s disease

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

Bradykinesia in early and advanced Parkinson's disease

Epidermal growth factor (EGF) is a neurotrophic factor that plays an important role in Parkinson's disease (PD). We measured plasma EGF level in PD, essential tremor (ET) and normal controls to investigate whether it changes in PD and whether it is associated with motor and non-motor symptoms of PD. 100 patients with PD, 40 patients with ET as disease control and 76 healthy persons were enrolled in the present study. Motor and non-motor symptoms were assessed by different scales. Plasma EGF levels of three groups were measured by enzyme-linked immunosorbent assay kit. Spearman test and linear logistics regression model were used to test the correlation of EGF with motor and non-motor symptoms of PD. Plasma EGF level was significantly decreased in early PD patients compared with normal control, but not in advanced PD patients. Interestingly, plasma EGF level was significantly increased in advanced PD and total PD patients compared with ET patients, but not in early PD patients. In addition, plasma EGF level was correlated with UPDRS-III scores in PD. Also plasma EGF level was correlated with UPDRS-III scores and NMS scores in early PD. Our results suggested that plasma EGF decreased in the early stage of PD and increased later on in the PD disease course. Also, plasma EGF level was increased significantly in PD compared with ET patients and correlated with motor and non-motor symptoms in early PD.

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

Deep brain stimulation (DBS) is a neurosurgical procedure indicated for patients with advanced Parkinson’s disease (PD). Whether similar benefits may be realized by patients with early PD, however, is currently unclear, especially given the potential risks of the procedure. This systematic review and meta-analysis aimed to investigate the relative efficacy and safety of DBS in comparison to best medical therapy (BMT) in the treatment of PD. It also aimed to compare the efficacy of DBS between patients with early and advanced PD.A systematic search was performed in Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Randomized controlled trials (RCTs) comparing DBS to BMT in PD patients were included. Outcome measures were impairment/disability using the Unified Parkinson’s Disease Rating Scale (UPDRS), quality of life (QoL) using the Parkinson's Disease Questionnaire (PDQ-39), levodopa equivalent dose (LED) reduction, and rates of serious adverse events (SAE).Eight eligible RCTs (n = 1,189) were included in the meta-analysis, two of which recruited early PD patients. Regarding efficacy outcomes, there were significant improvements in UPDRS, PDQ-39, and LED scores in favour of DBS (P < 0.00001). There was a significantly greater reduction of LED in patients with early PD (P < 0.00001), but no other differences between early and advanced PD patients were found. The risk of a patient experiencing an SAE was significantly higher in the DBS group (P = 0.005), as was the total number of SAEs (P < 0.00188).Overall, DBS was superior to BMT at improving impairment/disability, QoL, and reducing medication doses, but these benefits need to be weighed against the higher risk of SAEs. There was insufficient evidence to determine the impact of the PD stage on the efficacy of DBS.

Advances in functional magnetic resonance imaging data analysis methods using Empirical Mode Decomposition to investigate temporal changes in early Parkinson's disease

To detect abnormal eye movements in Parkinson's disease and explore its correlation with clinical characteristics and their value for diagnosis. We recruited forty-nine Parkinson's disease patients, including 35 early Parkinson's disease patients (Hoehn-Yahr: 1 to 2 stage) and 14 advanced Parkinson's disease patients (Hoehn-Yahr: 3 to 5 stage) and 23 healthy controls. Clinical manifestations in Parkinson's disease patients were recorded. Oculomotor performances including fixation, gaze, saccade in horizontal and vertical direction, and smooth pursuit in horizontal and vertical direction were measured by video-oculography. We found that five oculomotor parameters, namely square wave jerk frequency, latency of downward saccade, latency of upward saccade, accuracy of upward saccade, and gain of horizontal smooth pursuit were significantly different in Parkinson's disease patients and controls. When combining all these five parameters, we got the diagnostic sensitivity of 78.3% and specificity of 95.2%. More deficits in upward saccade than in other directions were associated with disease duration and progression of Parkinson's disease. Our primary study suggests that oculomotor examination might serve as an aid in the clinical assessment of Parkinson's disease patients and differentiating between early Parkinson's disease and normal controls.

A prediction model for the walking and balance milestone in Parkinson's disease

Are dopaminergic pathways involved in theory of mind? A study in Parkinson's disease

Ropinirole (Requip®, GlaxoSmithKline) is a novel nonergoline dopamine D2 agonist indicated for the treatment of early and advanced Parkinson's disease. It is mainly metabolized by the liver and its elimination half-life is approximately 5.8 h. When used as monotherapy in early Parkinson's disease, ropinirole improves signs and symptoms of the disorder. When used as an adjunct to levodopa in advanced Parkinson's disease patients with motor fluctuations, ropinirole reduces off time and allows a reduction of levodopa dose. The initial use of ropinirole in early Parkinson's disease to which levodopa is added when necessary, has been demonstrated to lead to a lower incidence of dyskinesias compared with treatment with levodopa alone. An 18F-dihydroxyphenylalanine positron emission tomography study suggested the possibility that ropinirole could slow the progression of loss of dopamine neurons compared with treatment with levodopa but this remains to be proven. Side effects of ropinirole include nausea, somnolence, edema, orthostatic hypotension, hallucinations and dyskinesia. A once-daily formulation of ropinirole is currently in development that has the potential for greater convenience, improved tolerability and greater efficacy.

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.