Analysis of gait characteristics and related factors in patients with Parkinson's disease based on wearable devices.

BACKGROUND: Postural instability and gait disorder dominant (PIGD) is one of the most common disabling symptoms of Parkinson's disease (PD), which seriously affects patients' quality of life. Therefore, it is essential to identify PIGD and develop targeted interventions to reduce the risk of PIGD in PD patients. AIM: This study aimed to investigate the gait characteristics of PD patients based on wearable devices and to establish a predictive model for their related influencing factors. METHODS: The retrospective medical records of patients from January 2020 to September 2023 were collected, including 159 patients with PD (divided into PIGD [n = 73] and non-PIGD [n = 86] groups) and 200 healthy patients (as the healthy control group). Information from social demographic data, a blood test, scale scores, gait analysis based on wearable devices, white matter lesions, and the Fazekas scale was extracted and analyzed. RESULTS: Compared with the healthy control group, the mean step length, mean rate, mean angular velocity, and step length were lower in the PD group, while the mean steps were higher in the turning test. The incidence of PIGD was 46% in PD patients, and PD patients with the non-tremor onset mode were more likely to develop PIGD than those with the tremor onset mode. Compared to the non-PIGD group, the PIGD group showed more serious gait problems in different experimental tasks and had a higher Hoehn and Yahr (H-Y) stage, Hamilton Anxiety Scale (HAMA) score, Hamilton Depression Scale score, periventricular white matter (PVWM) score, deep white matter score, and Fazekas scale score, but they had lower hemoglobin levels, D-dimer levels, Tinetti Balance scores, Tinetti Gait scores, Berg Balance Scale scores, and Mini-Mental State Examination (MMSE) scores. Logistic regression analysis showed that the MMSE score was negatively correlated with the occurrence of PIGD, while the HAMA score, H-Y stage, PVWM score, and non-tremor form of onset were positively correlated with the occurrence of PIGD CONCLUSION: The incidence of gait disorder in PD patients is higher than that in the normal population. Moreover, cognitive dysfunction, anxiety state, H-Y stage, PVWM score, and the non-tremor mode of onset can be considered independent risk factors for PIGD.

Neuroimaging correlates of postural instability in Parkinson's disease.

BACKGROUND: Postural instability (PI) is a common disabling symptom in Parkinson's disease (PD), but little is known on its pathophysiological basis. OBJECTIVE: In this study, we aimed to identify the brain structures associated with PI in PD patients, using different MRI approaches. METHODS: We consecutively enrolled 142 PD patients and 45 control subjects. PI was assessed using the MDS-UPDRS-III pull-test item (PT). A whole-brain regression analysis identified brain areas where grey matter (GM) volume correlated with the PT score in PD patients. Voxel-based morphometry (VBM) and Tract-Based Spatial Statistics (TBSS) were also used to compare unsteady (PT ≥ 1) and steady (PT = 0) PD patients. Associations between GM volume in regions of interest (ROI) and several clinical features were then investigated using LASSO regression analysis. RESULTS: PI was present in 44.4% of PD patients. The whole-brain approach identified the bilateral inferior frontal gyrus (IFG) and superior temporal gyrus (STG) as the only regions associated with the presence of postural instability. VBM analysis showed reduced GM volume in fronto-temporal areas (superior, middle, medial and inferior frontal gyrus, and STG) in unsteady compared with steady PD patients, and the GM volume of these regions was selectively associated with the PT score and not with any other motor or non-motor symptom. CONCLUSIONS: This study demonstrates a significant atrophy of fronto-temporal regions in unsteady PD patients, suggesting that these brain areas may play a role in the pathophysiological mechanisms underlying postural instability in PD. This result paves the way for further studies on postural instability in Parkinsonism.

Free water imaging unravels unique patterns of longitudinal structural brain changes in Parkinson's disease subtypes.

Background: Research shows that individuals with Parkinson's disease (PD) who have a postural instability and gait difficulties (PIGD) subtype have a faster disease progression compared to those with a tremor dominant (TD) subtype. Nevertheless, our understanding of the structural brain changes contributing to these clinical differences remains limited, primarily because many brain imaging techniques are only capable of detecting changes in the later stages of the disease. Objective: Free water (FW) has emerged as a robust progression marker in several studies, showing increased values in the posterior substantia nigra that predict symptom worsening. Here, we examined longitudinal FW changes in TD and PIGD across multiple brain regions. Methods: Participants were TD and PIGD enrolled in the Parkinson's Progression Marker Initiative (PPMI) study who underwent diffusion MRI at baseline and 2 years later. FW changes were quantified for regions of interest (ROI) within the basal ganglia, thalamus, brainstem, and cerebellum. Results: Baseline FW in all ROIs did not differ between groups. Over 2 years, PIGD had a greater percentage increase in FW in the putamen, globus pallidus, and cerebellar lobule V. A logistic regression model incorporating percent change in motor scores and FW in these brain regions achieved 91.4% accuracy in discriminating TD and PIGD, surpassing models based solely on clinical measures (74.3%) or imaging (76.1%). Conclusion: The results further suggest the use of FW to study disease progression in PD and provide insight into the differential course of brain changes in early-stage PD subtypes.

Association of Plasma and Electroencephalography Markers With Motor Subtypes of Parkinson's Disease.

Objective: The aim of this study was to investigate the correlations of plasma neurodegenerative proteins and electroencephalography (EEG) dynamic functional network (DFN) parameters with disease progression in early Parkinson's disease (PD) with different motor subtypes, including tremor-dominant (TD) and postural instability and gait disorder (PIGD). Methods: In our study, 33 patients with PD (21 TD and 12 PIGD) and 33 healthy controls (HCs) were enrolled. Plasma neurofilament light chain (NfL), α-synuclein (α-syn), total-tau (t-tau), ß-amyloid 42 (Aß42), and ß-amyloid 40 (Aß40) levels were measured using an ultrasensitive single-molecule array (Simoa) immunoassay. All the patients with PD underwent EEG quantified by DFN analysis. The motor and non-motor performances were evaluated by a series of clinical assessments. Subsequently, a correlation analysis of plasma biomarkers and EEG measures with clinical scales was conducted. Results: In the TD group, plasma NfL exhibited a significant association with MDS-UPDRS III and Montreal Cognitive Assessment (MoCA). A higher Aß42/40 level was significantly related to a decrease in Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA) in the PIGD group. In terms of the correlation between EEG characteristic parameters and clinical outcomes, trapping time (TT) delta was positively correlated with MDS-UPDRS III and MoCA scores in the TD group, especially in the prefrontal and frontal regions. For other non-motor symptoms, there were significant direct associations of k PLI theta with HAMD and HAMA, especially in the prefrontal region, and k PLI gamma was particularly correlated with Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ) scores in the prefrontal, frontal, and parietal regions in the TD group. Furthermore, there was a significant positive correlation between plasma t-tau and k PLI , and pairwise correlations were found among plasma NfL, theta TT, and MoCA scores in the TD group. Conclusion: These results provide evidence that plasma neurodegenerative proteins and EEG measures have great potential in predicting the disease progression of PD subtypes, especially for the TD subtype. A combination of these two kinds of markers may have a superposition effect on monitoring and estimating the prognosis of PD subtypes and deserves further research in larger, follow-up PD cohorts.

Zonisamide improves axial symptoms in dementia with Lewy bodies with parkinsonism: Post hoc analysis of clinical trials.

Patients with dementia with Lewy bodies (DLB) experience worsening axial symptoms with disease progression, which can negatively affect quality of life. Previous phase 2 and 3 clinical trials conducted in Japan showed that zonisamide improved parkinsonism in patients with DLB. In the present study, we performed a post hoc analysis of pooled data from the previous phase 2 and 3 trials to examine the effect of zonisamide on axial symptoms in this patient group. In our pooled analysis, the primary outcome was the change from baseline to 12 weeks in axial symptom score, measured as the sum of Unified Parkinson's Disease Rating Scale Part III items relevant to gait/balance/midline function. A total of 498 patients were included in this analysis. Zonisamide 25 mg and 50 mg significantly reduced the axial symptom score at week 12 compared with placebo (p < 0.01 and p < 0.001, respectively, by mixed model of repeated measures). Our findings indicate that zonisamide may improve axial symptoms in DLB with parkinsonism and, thus, may potentially reduce the risk of falls and improve quality of life in this vulnerable patient population.

Predicting Axial Impairment in Parkinson's Disease through a Single Inertial Sensor.

BACKGROUND: Current telemedicine approaches lack standardised procedures for the remote assessment of axial impairment in Parkinson's disease (PD). Unobtrusive wearable sensors may be a feasible tool to provide clinicians with practical medical indices reflecting axial dysfunction in PD. This study aims to predict the postural instability/gait difficulty (PIGD) score in PD patients by monitoring gait through a single inertial measurement unit (IMU) and machine-learning algorithms. METHODS: Thirty-one PD patients underwent a 7-m timed-up-and-go test while monitored through an IMU placed on the thigh, both under (ON) and not under (OFF) dopaminergic therapy. After pre-processing procedures and feature selection, a support vector regression model was implemented to predict PIGD scores and to investigate the impact of L-Dopa and freezing of gait (FOG) on regression models. RESULTS: Specific time- and frequency-domain features correlated with PIGD scores. After optimizing the dimensionality reduction methods and the model parameters, regression algorithms demonstrated different performance in the PIGD prediction in patients OFF and ON therapy (r = 0.79 and 0.75 and RMSE = 0.19 and 0.20, respectively). Similarly, regression models showed different performances in the PIGD prediction, in patients with FOG, ON and OFF therapy (r = 0.71 and RMSE = 0.27; r = 0.83 and RMSE = 0.22, respectively) and in those without FOG, ON and OFF therapy (r = 0.85 and RMSE = 0.19; r = 0.79 and RMSE = 0.21, respectively). CONCLUSIONS: Optimized support vector regression models have high feasibility in predicting PIGD scores in PD. L-Dopa and FOG affect regression model performances. Overall, a single inertial sensor may help to remotely assess axial motor impairment in PD patients.

Disentangling the PIGD classification for the prediction of cognitive impairment in de novo Parkinson's disease.

BACKGROUND: Postural Instability and Gait difficulties (PIGD) subtype has been associated with worse cognitive performance in Parkinson's disease (PD). OBJECTIVE: To investigate whether PIGD subtype classification or PIGD-related clinical features predict the development of cognitive decline in de novo PD patients. METHODS: Data from 422 PD patients with de novo PD were obtained from the PPMI database. At follow-up (up to 6 years), patients were categorized as having cognitive impairment or not. Multivariate Cox survival analysis was carried out including motor subtype and individual MDS-UPDRS items defining PIGD phenotype as predictors. Previously validated clinical predictors of cognitive impairment were included in the model as covariates. Occurrence of cognitive impairment at follow-up was used as the time-to-event and Kaplan-Meier curve was generated. RESULTS: At baseline, 76 patients were classified as PIGD, 299 tremor-dominant and 47 as indeterminate. Development of cognitive impairment was not associated with PIGD subtype (p = 0.252). When individual MDS-UPDRS items were interrogated in the model, postural instability proved to be an independent predictor of cognitive impairment (HR = 2.045; 95%CI: 1.068-3.918; p = 0.031), while gait difficulties were not associated with cognitive decline (p = 0.870). CONCLUSIONS: Our findings suggest that postural instability, as assessed by MDS-UPDRS III, may serve as a possible indicator of the risk of developing cognitive impairment in de novo PD patients rather than the PIGD phenotype.

Diplopia Is Frequent and Associated with Motor and Non-Motor Severity in Parkinson's Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up.

BACKGROUND AND OBJECTIVE: Diplopia is relatively common in Parkinson's disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. PATIENTS AND METHODS: PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as "with diplopia" or "without diplopia" according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls. RESULTS: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269-4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012-1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson's Disease Rating Scale-III (OR = 1.039; 95%CI, 1.023-1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001-1.057; p = 0.049) scores were independent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716). CONCLUSIONS: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity.

Differentiating Parkinson's disease motor subtypes: A radiomics analysis based on deep gray nuclear lesion and white matter.

OBJECTIVE: To investigate the feasibility of radiomics analysis of brain MR images to differentiate Parkinson's disease motor subtypes. METHODS: 42 postural instability gait difficulty (PIGD) patients, 92 tremor-dominant (TD) patients and 96 healthy controls were included from the Parkinson's Progressive Marker Initiative public database. For each subject, 4850 radiomic features from 148 cortical and 14 subcortical brain regions were extracted. The variance threshold and the least absolute shrinkage and selection operator were used to select the optimal features. Classification models based on Support Vector Machine, Logistic Regrcession, and Multi-Layer Perceptron were constructed to assess the performance of optimal features in the discrimination of the two subtypes. Correlations between radiomic features and clinical scores of the two subtypes were estimated. RESULTS: The Support Vector Machine demonstrated the best performance in discriminating between the two subtypes, and the mean area under the curve was 0.833 (specificity = 83.3%, sensitivity = 75.0%, and accuracy = 80.7%). For the postural instability gait difficulty patients, these optimal features in the hippocampal showed closed correlations with the Montreal Cognitive Assessment scores (P < 0.05). CONCLUSION: The results of our study provide preliminary evidence that radiomics analysis of brain MR images could allow discrimination between patients with TD, PIGD and control subjects and has great potential value in the clinical practice.

Serum NFL levels predict progression of motor impairment and reduction in putamen dopamine transporter binding ratios in de novo Parkinson's disease: An 8-year longitudinal study.

Neurofilament light chain (NFL) level in biofluids is a sensitive measure of axonal damage and a promising biomarker in neurodegenerative diseases. In Parkinson's disease (PD), NFL can distinguish PD from other parkinsonian disorders, and NFL concentration is associated with disease severity, risk of progression, and survival. To determine whether serum NFL at baseline in de novo PD predicts motor decline, differentially impacts specific motor features, predicts cognitive decline, and predicts loss of dopamine terminals, here we evaluated 376 de novo PD patients from the PPMI database and analyzed the effect of baseline serum NFL levels on progression over eight years of motor impairment measured with the UPDRS, cognitive function measured with the MoCA, and putamen dopamine transporter (DAT) binding ratio measured with DaTscan. In longitudinal mixed effects models that controlled for age, gender, disease duration, and levodopa equivalent drug dose, higher levels of serum NFL at baseline were associated with greater increases of UPDRS-III and total UPDRS scores, with greater worsening of postural instability and gait disorder (PIGD) scores but not tremor scores over time. In contrast, baseline serum NFL was not associated with significant progression of MoCA scores in this de novo PD cohort. Higher baseline serum NFL was associated with greater reduction of putamen DAT binding ratio over time. Together, these findings show that baseline serum NFL levels predict the rate of motor decline, the accumulation of PIGD clinical features, and the progression of dopamine transporter loss in the early stage of PD.

Is Cortical Activation During Walking Different Between Parkinson's Disease Motor Subtypes?

Parkinson's disease (PD) is often classified into tremor dominant (TD) and postural instability gait disorder (PIGD) subtypes. Degeneration of subcortical/cortical pathways is different between PD subtypes, which leads to differences in motor behavior. However, the influence of PD subtype on cortical activity during walking remains poorly understood. Therefore, we aimed to investigate the influence of PD motor subtypes on cortical activity during unobstructed walking and obstacle avoidance. Seventeen PIGD and 19 TD patients performed unobstructed walking and obstacle avoidance conditions. Brain activity was measured using a mobile functional near-infrared spectroscopy-electroencephalography (EEG) systems, and gait parameters were analyzed using an electronic carpet. Concentrations of oxygenated hemoglobin (HbO2) of the prefrontal cortex (PFC) and EEG absolute power from alpha, beta, and gamma bands in FCz, Cz, CPz, and Oz channels were calculated. These EEG channels correspond to supplementary motor area, primary motor cortex, posterior parietal cortex, and visual cortex, respectively. Postural instability gait disorder patients presented higher PFC activity than TD patients, regardless of the walking condition. Tremor dominant patients presented reduced beta power in the Cz channel during obstacle avoidance compared to unobstructed walking. Both TD and PIGD patients decreased alpha and beta power in the FCz and CPz channels. In conclusion, PIGD patients need to recruit additional cognitive resources from the PFC for walking. Both TD and PIGD patients presented changes in the activation of brain areas related to motor/sensorimotor areas in order to maintain balance control during obstacle avoidance, being that TD patients presented further changes in the motor area (Cz channel) to avoid obstacles.

Executive function network's white matter alterations relate to Parkinson's disease motor phenotype.

Parkinson's disease (PD) patients with postural instability and gait disorder phenotype (PIGD) are at high risk of cognitive deficits compared to those with tremor dominant phenotype (TD). Alterations of white matter (WM) integrity can occur in patients with normal cognitive functions (PD-N). However, the alterations of WM integrity related to cognitive functions in PD-N, especially in these two motor phenotypes, remain unclear. Diffusion tensor imaging (DTI) is a non-invasive neuroimaging method to evaluate WM properties and by applying DTI tractography, one can identify WM tracts connecting functional regions. Here, we 1) compared the executive function (EF) in PIGD phenotype with normal cognitive functions (PIGD-N) and TD phenotype with normal cognitive functions (TD-N) phenotypes; 2) used DTI tractography to evaluated differences in WM alterations between these two phenotypes within a task-based functional network; and 3) examined the WM integrity alterations related to EF in a whole brain network for PD-N patients regardless of phenotypes. Thirty-four idiopathic PD-N patients were classified into two groups based on phenotypes: TD-N and PIGD-N, using an algorithm based on UPDRS part III. Neuropsychological tests were used to evaluate patients' EF, including the Trail making test part A and B, the Stroop color naming, the Stroop word naming, the Stroop color-word interference task, as well as the FAS verbal fluency task and the animal category fluency tasks. DTI measures were calculated among WM regions associated with the verbal fluency network defined from previous task fMRI studies and compared between PIGD-N and TD-N groups. In addition, the relationship of DTI measures and verbal fluency scores were evaluated for our full cohort of PD-N patients within the whole brain network. These values were also correlated with the scores of the FAS verbal fluency task. Only the FAS verbal fluency test showed significant group differences, having lower scores in PIGD-N when compared to TD-N phenotype (p < 0.05). Compared to the TD-N, PIGD-N group exhibited significantly higher MD and RD in the tracts connecting the left superior temporal gyrus and left insula, and those connecting the right pars opercularis and right insula. Moreover, compared to TD-N, PIGD-N group had significantly higher RD in the tracts connecting right pars opercularis and right pars triangularis, and the tracts connecting right inferior temporal gyrus and right middle temporal gyrus. For the entire PD-N cohort, FAS verbal fluency scores positively correlated with MD in the superior longitudinal fasciculus (SLF). This study confirmed that PIGD-N phenotype has more deficits in verbal fluency task than TD-N phenotype. Additionally, our findings suggest: (1) PIGD-N shows more microstructural changes related to FAS verbal fluency task when compared to TD-N phenotype; (2) SLF plays an important role in FAS verbal fluency task in PD-N patients regardless of motor phenotypes.

Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson's disease.

BACKGROUND: The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD. METHODS: Plasma NfL was measured in 199 participants (149 PD and 50 healthy controls, HC) using an ultrasensitive single molecule array. Patients were classified into TD or PIGD based on MDS-UPDRS components. After 2 years, 115 patients were reassessed. Association between NfL and clinical measures in PIGD and TD at baseline and at 2-year follow-up were analysed. RESULTS: At baseline, plasma NfL levels were higher in PD than HC (8.8 ± 3.4 vs 16.2 ± 7.6 pg/ml, p < 0.0001), and differentiated PD from HC with a good diagnostic accuracy (AUC = 0.833, p < 0.001). At 2 years, NfL was higher in PIGD than TD (18.4 ± 14.5 vs 12.6 ± 4.4 pg/ml, p = 0.039). Within the PIGD group, higher NfL associated significantly with worse global cognition and UPDRS motor scores at baseline, and was able to predict motor and cognitive decline at a mean follow-up duration of 1.9 years, controlled for age, sex and disease duration. CONCLUSIONS: In this longitudinal study, we demonstrated for the first time the potential utility of plasma NfL as a diagnostic and prognostic biomarker in PIGD even at early stages of PD. These important novel findings will require further confirmation in larger, longitudinal PD cohorts.

Analysis of related factors affecting motor subtypes of Parkinson’s disease / 中风与神经疾病杂志

@#Objective　To investigate the differences between the subtypes of postural instability gait difficulty （PIGD） subtypes. in Parkinson’s disease and the subtypes of tremor and the related factors affecting the phenotypes of Parkinson’s disease. Methods　Collect hospital between January 2019 and January 2020 in our hospital nursing of 69 patients with Parkinson’s disease，Parkinson’s disease is divided into PIGD and TD groups to evaluate clinical data acquisition and scale，scale including Hoehn-Yahr scale，MDS - UPDRS scale，non-motor symptoms scale （NMSS），Parkinson’s disease sleep scale （PDSS），Mini-mental State Examination （MMSE） and Hamilton Depression Scale （HAMD），Hamilton anxiety scale （HAMA），Parkinson’s life quality evaluation scale （PDQ-39）.The collected data were statistically analyzed. Results　There was no statistically significant difference between the two groups in age of onset，course of disease，equivalent dose of levodopa，HAMA，HAMD，MMSE，PDSS，NMSS and PDQ-39 scores. Differences were statistically significant in age of onset，education，medical comorbidities，UPDRS score，H-Y rating，stiffness，bradykinesia，tremor，and gait abnormalities. The next step of correlation analysis found that patients’ age of onset，comorbidity severity，H-Y classification，UPDRS score，and exercise symptoms were correlated with PD subtypes. Conclusion　The age of onset，the severity of medical comorbidities，disease severity，and motor subtypes of PD patients were related factors affecting the PIGD subtypes.

Amyloid-ß and Parkinson's disease.

Parkinson's disease (PD) is the second commonest neurodegenerative disorder in the world with a rising prevalence. The pathophysiology is multifactorial but aggregation of misfolded α-synuclein is considered to be a key underpinning mechanism. Amyloid-ß (Aß) and tau deposition are also comorbid associations and especially Aß deposition is associated with cognitive decline in PD. Some existing evidence suggests that low cerebrospinal fluid (CSF) Aß42 is predictive of future cognitive impairment in PD. Recent studies also show that CSF Aß is associated with the postural instability and gait difficulties (PIGD) or the newly proposed cholinergic subtype of PD, a possible risk factor for cognitive decline in PD. The glial-lymphatic system, responsible for convective solute clearance driven by active fluid transport through aquaporin-4 water channels, may be implicated in brain amyloid deposition. A better understanding of the role of this system and more specifically the role of Aß in PD symptomatology, could introduce new treatment and repurposing drug-based strategies. For instance, apomorphine infusion has been shown to promote the degradation of Aß in rodent models. This is further supported in a post-mortem study in PD patients although clinical implications are unclear. In this review, we address the clinical implication of cerebral Aß deposition in PD and elaborate on its metabolism, its role in cognition and motor function/gait, and finally assess the potential effect of apomorphine on Aß deposition in PD.

Effect of unilateral subthalamic deep brain stimulation in highly asymmetrical Parkinson's disease: 7-year follow-up.

OBJECTIVEFor patients with highly asymmetrical Parkinson's disease (PD), unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) has been suggested as a reasonable treatment. However, the results of a previous 2-year follow-up study involving patients with prominently asymmetrical PD who had unilateral STN DBS suggested that simultaneous bilateral surgery should be performed. In the present study, the authors analyze 7-year follow-up data from the same patient group to examine changes in motor benefit from unilateral STN DBS over time and the interval between initial unilateral surgery and a second (contralateral) STN DBS surgery.METHODSEight patients with highly asymmetrical parkinsonism who underwent unilateral STN DBS were evaluated. The factors measured were scores on the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III), Hoehn and Yahr (HY) stage, and levodopa equivalent daily dose (LEDD). Evaluations occurred at 3, 6, and 12 months after the initial surgery and annually thereafter.RESULTSThe mean follow-up period was 91.5 months (range 36-105 months). Three years after the initial unilateral surgery, motor benefits on the contralateral side continued; however, an aggravation of the ipsilateral parkinsonism attenuated the improvement in total UPDRS III scores, which reverted to baseline. Axial motor score, LEDD, and HY stage did not differ from the baseline. Seven of 8 patients (87.5%) were considered candidates for a second surgery to offer additional motor benefits. Of the 7 candidates, 4 patients (50% of total patients) underwent the second surgery at 58.5 ± 11.6 (mean ± SD) months after the initial surgery. Three patients were not able to have the second surgery: one patient died of gastric cancer, one patient was severely immobilized by an accident, and one patient could not afford the second surgery. One patient remained content with the initial unilateral surgery throughout the follow-up period.CONCLUSIONSSeven of 8 patients with unilateral STN DBS became candidates for second surgery before battery replacement surgery of the first implanted device. Baseline asymmetry alone may not predict appropriate candidates for unilateral STN DBS. This study provides further evidence that, from a long-term perspective, initial simultaneous bilateral STN DBS should be considered for PD patients with prominently asymmetrical motor symptoms.

Effects of spinal cord stimulation on postural control in Parkinson's disease patients with freezing of gait.

Freezing of gait (FoG) in Parkinson's disease (PD) is an incapacitating transient phenomenon, followed by continuous postural disorders. Spinal cord stimulation (SCS) is a promising intervention for FoG in patients with PD, however, its effects on distinct domains of postural control is not well known. The aim of this study is to assess the effects of SCS on FoG and distinct domains of postural control. Four patients with FoG were implanted with SCS systems in the upper thoracic spine. Anticipatory postural adjustment (APA), reactive postural responses, gait and FoG were biomechanically assessed. In general, the results showed that SCS improved FoG and APA. However, SCS failed to improve reactive postural responses. SCS seems to influence cortical motor circuits, involving the supplementary motor area. On the other hand, reactive posture control to external perturbation that mainly relies on neuronal circuitries involving the brainstem and spinal cord, is less influenced by SCS.

Disease progression in Parkinson subtypes: the PPMI dataset.

INTRODUCTION: Discrete patterns of progression have been suggested for patients with Parkinson disease and presenting tremor dominant (TD) or postural instability gait disorders (PIGD). However, longitudinal prospective assessments need to take into consideration the variability in clinical manifestations and the evidence that only 40% of initially classified PIGD remain in this subtype at subsequent visits. METHODS: We analyzed clinical progression of PIGD compared to TD using longitudinal clinical data from the PPMI. Given the reported instability of such clinical classification, we only included patients who were reported as PIGD/TD at each visit during the 4-year observation. We used linear mixed-effects models to test differences in progression in these subgroups in 51 dependent variables. RESULTS: There were 254 patients with yearly assessment. The number of PIGD was 36/254 vs 144/254 TD. PIGD had more severe motor disease at baseline but progressed faster than TD only in three non-motor items of the MDS-UPDRS: cognitive impairment, hallucinations, and psychosis plus features of DDS. Our analysis also showed in PIGD faster increase in the average time with dyskinesia. CONCLUSIONS: PIGD are characterized by more severe disease manifestations at diagnosis and greater cognitive progression, more frequent hallucinations, psychosis as well as features of DDS than TD patients. We interpret these findings as expression of greater cortical and subcortical involvement in PIGD already at onset. Since PIGD/TD classification is very unstable at onset, our analysis based on stricter definition criteria provides important insight for clinical trial stratification and definition of related outcome measures.

Analysis of the clinical features of early Parkinson's disease with comparatively integrated intestinal function.

OBJECTIVE: Constipation is among the most frequently delineated nonmotor symptoms (NMS) with a high occurrence in Parkinson's disease (PD). The purpose of our study was to investigate whether PD with comparatively integrated intestinal function (without constipation) in the early stage had different clinical features compared to constipated PD. METHOD: We conducted a study of 105 consecutive de novo as well as early treated (treated for shorter than 3 months), aged 50 years or older outpatients. Subjects were administered motor and nonmotor questionnaires as well as constipation associated examinations. Then, we explored the distinctive features of nonconstipated contrasted to constipated PD by using univariate, multiple regression analysis and correlation analysis. RESULTS: Nonconstipated PD tended to have fewer motor deficits, as well as lower Hoehn and Yahr (H&Y) stage and they mainly presented as tremor-dominant (TD), while constipated group had a higher occurrence of posture instability and gait difficulty (PIGD); nonconstipated patients were inclined to live in urban area, the NMSloads and prevalence of NMS were lower compared to constipated ones. Correlation analysis found a discord between NMSloads and disease severity based on H&Y stage and motor scores in nonconstipated PD. CONCLUSIONS: These results suggest that PD without constipation in early stage may represent a unique clinical phenotype, which may be more benign than PD with constipation.

Serum uric acid level and its association with motor subtypes and non-motor symptoms in early Parkinson's disease: PALS study.

OBJECTIVE: Uric acid has been found to be potentially neuroprotective in Parkinson's disease (PD). We investigated the relationship between serum uric acid levels and both motor and non-motor features in a prospective early PD cohort study. METHODS: Fasting serum uric acid levels were measured from 125 early PD patients. Demographic, clinical characteristics, motor and non-motor assessments were performed. Patients were categorized into three motor subtypes: tremor-dominant (TD), postural instability/gait difficulty (PIGD), and mixed. Non-motor symptoms were classified as present or absent based on the appropriate cut-offs for each non-motor instrument. RESULTS: Most patients had TD (n = 51, 40.8%) and mixed (n = 63, 50.4%) motor subtypes, while a minority had PIGD (n = 11, 8.8%) motor subtype. The mean serum uric acid levels were significantly different between the three motor subtypes (p = 0.0106), with the mixed subtype having the lowest serum uric acid levels. Using the TD subtype as reference, patients with higher serum uric acid levels were less likely to have the mixed (OR = 0.684; p = 0.0312) subtype as opposed to the TD subtype. Uric acid levels were not significantly different between the TD and PIGD subtypes. For non-motor symptoms, higher serum uric acid levels were significantly associated with less fatigue (OR = 0.693; p = 0.0408). CONCLUSION: Higher serum uric acid levels were associated with TD motor subtype and less fatigue in early PD, which could be related to its anti-oxidative properties. Uric acid could be an important biomarker for specific motor features and symptoms of fatigue in PD.