Postural Instability Gait Disorder Research Articles

Association of Dizziness-Related Handicap or Disability with Clinical Features in Patients with Early Parkinson's Disease.

Complaining of dizziness is common in patients with Parkinson's disease (PD) even at the early phase of the disease. Therefore, regarding motor or non-motor symptoms, clinical implication of subjective dizziness in early Parkinsonian patients is needed to be explored. Eighty patients diagnosed with early PD (defined by disease duration of five years or less) were retrospectively enrolled for the study. Dizziness handicap inventory (DHI), the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Functional Level Scale (FLS), and clinical features of parkinsonian motor and non-motor symptoms using representative measurements. Through simple and multiple linear regression analyses, we found that both DHI and FLS were significantly and positively correlated with postural instability/gait disorder (PIGD) score but negatively with the Montreal cognitive assessment (MoCA) score. We found that subjective dizziness in patients with early PD was related to not only axial symptoms of PIGD, but also global cognitive function of MoCA. Further research is required to confirm our results.

Distribution pattern of iron deposition in the basal ganglia of different motor subtypes of Parkinson's disease

ObjectiveThe quantitative susceptibility mapping (QSM) technique was used to analyze the distribution pattern of iron deposition in the basal ganglia region of patients with motor subtypes of Parkinson’s disease (PD) and to explore the difference in iron content in the basal ganglia region of PD motor subtypes on the major motor symptomatic side. MethodsThe study included 76 patients with PD and 37 healthy controls (HC). Patients with PD were divided into two groups: postural instability/gait disorder (PIGD)(n = 48), and tremor dominance (TD)(n = 28). We classified patients with PD according to the side of the major motor symptoms as left PIGD (n = 23), left TD (n = 14), right PIGD (n = 25), and right TD (n = 14). All subjects underwent brain magnetic resonance scanning to obtain QSM and susceptibility values in the corresponding regions of interest (ROI). Results(1) Compared with the HC, the bilateral SN in the PD-PIGD and TD group showed greater susceptibility values. The susceptibility values in the left CN, bilateral PUT were also greater in the PD-PIGD group than the HC. (2) Compared with the TD, the left PUT susceptibility values were greater in the PIGD group, especially in patients whose major symptomatic side were on the right limb. (3) Correlation analysis showed that in the PD group, bilateral SN was positively correlated with the unified Parkinson's disease rating scale III part scores of the Movement Disorder Society (MDS-UPDRS III) and the Hoehn-Yahr stage. Bilateral dentate nucleus (DN) susceptibility values were significantly positively correlated with TD scores, and left PUT susceptibility values were positively correlated with PIGD scores. The left SN within the PIGD group was positively correlated with the PIGD score. ConclusionThere were different iron deposition patterns in the basal ganglia between the PD-PIGD and TD groups. There also seems to be a difference in iron deposition in PD motor subtypes on different major motor symptom sides.

Speech and gait abnormalities in motor subtypes of de-novo Parkinson's disease.

To investigate the presence and relationship of temporal speech and gait parameters in patients with postural instability/gait disorder (PIGD) and tremor-dominant (TD) motor subtypes of Parkinson's disease (PD). Speech samples and instrumented walkway system assessments were acquired from a total of 60 de-novo PD patients (40 in TD and 20 in PIGD subtype) and 40 matched healthy controls. Objective acoustic vocal assessment of seven distinct speech timing dimensions was related to instrumental gait measures including velocity, cadence, and stride length. Compared to controls, PIGD subtype showed greater consonant timing abnormalities by prolonged voice onset time (VOT) while also shorter stride length during both normal walking and dual task, while decreased velocity and cadence only during dual task. Speaking rate was faster in PIGD than TD subtype. In PIGD subtype, prolonged VOT correlated with slower gait velocity (r=-0.56, p=0.01) and shorter stride length (r=-0.59, p=0.008) during normal walking, whereas relationships were also found between decreased cadence in dual task and irregular alternating motion rates (r=-0.48, p=0.04) and prolonged pauses (r=-0.50, p=0.03). No correlation between speech and gait was detected in TD subtype. Our findings suggest that speech and gait rhythm disorder share similar underlying pathomechanisms specific for PIGD subtype.

Effects of the combined treatment of bilateral subthalamic nucleus stimulation and levodopa on balance and mobility in Parkinson's disease.

<p>Background and purpose &ndash; To evaluate the efficacy of the combined therapy of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and dopaminergic medication on balance and mobility in patients with Parkinson&rsquo;s disease (PD).</p>. <p>Eighteen PD patients under bilateral STN-DBS stimulation therapy, were enrolled in this study. Unified Parkinson&rsquo;s Disease Rating Scale (UPDRS) was applied to assess the patients&rsquo; clinical characteristics. UPDRS part III postural instability/gait disorder (PIGD) scores (sum of items 3.9-3.13) and UPDRS part III postural stability item (item 3.12) were calculated separately. Patients were evaluated with Berg Balance Scale (BBS), Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go (TUG) test, dual-task TUG test, and Forward Functional Reach (FFR) Test in two conditions: Stimulation-ON (stim-ON)/Medication-ON (Med-ON) and Stimulation-OFF (Stim-OFF)/Med-ON.</p>. <p>The mean age of patients was 59.5&plusmn;9.1 (R: 41-71) years. The UPDRS part III total score and PIGD subsection score significantly improved after stimulation (p=0.001), but the postural instability item of the UPDRS part III did not change significantly (p=0.1). There were no significant differences between the Stim-ON/Med-ON and Stim-OFF/Med-ON conditions, in terms of total Mini-BESTest total scores, total BBS score, FFR test score (p&gt;0.05 for all of them). TUG test was significantly improved in the Stim-ON/Med-ON condition compared to Stim-OFF/Med-ON condition (p=0.03), but DT-TUG test did not change (p=0.1).&nbsp;</p>. <p>Combined bilateral STN-DBS and dopaminergic medication therapy had an additional improvement on motor symptoms and mobility performance, but not on balance and dual-task mobility.&nbsp;</p>.

Determinants of cognitive impairment in multiple system atrophy: Clinical and genetic study.

Classically, cognitive impairment (CI) was not considered as a paramount feature of multiple system atrophy(MSA) in both parkinsonian(MSA-P) and cerebellar(MSA-C) motor-subtypes. Yet, growing evidence indicates currently the commonness of such deficits among MSA patients in different populations. Our aim was to evaluate the cognitive profile of MSA Tunisian patients and to analyze the underlying clinical and genetic determinants. In a retrospective cross-sectional study, clinically-diagnosed MSA patients were included. All subjects underwent clinical and neuropsychological assessments to characterize their cognitive profile. The associations with their APOE genotype status were analyzed. Determinant of CI were specified. We included 71 MSA patients. Female gender(sex-ratio = 0.65) and MSA-P subtype(73%) were predominant. Mean age of disease onset was 59.1years. CI was found in 85.7% of patients(dementia in 12.7% and Mild cognitive impairment(MCI) in 73% of patients mainly of multiple-domain amnestic type(37.3%)). Mean MMSE score was lower among MSA-P compared to MSA-C(23.52 vs. 26.47;p = 0.027). Higher postural instability gait disorder(PIGD) and MDS-UPDRS-III scores were noted in demented MSA patients(p = 0.019;p = 0.015 respectively). The main altered cognitive domain was attention(64.8%). Executive functions and mood disorders were more affected in MSA-P(p = 0.029,p = 0.035 respectively). Clinical and neurophysiological study of dysautonomia revealed no differences across cognitive subtypes. APOE genotyping was performed in 51 MSA patients with available blood samples. Those carrying APOEε4 had 1.32 fold higher risk to develop CI, with lower MMSE score(p = 0.0001). Attention and language were significantly altered by adjusting the p value to APOEɛ4 carriers(p = 0.046 and p = 0.044 respectively). Executive dysfunction was more pronounced among MSA-PAPOEε4 carriers(p = 0.010). In this study, the main determinants of CI in Tunisian MSA patients were MSA-P motor-subtype, mainly of PIGD-phenotype, disease duration and APOEε4 carrying status, defining a more altered cognitive phenotype. This effect mainly concerned executive, attention and language functions, all found to be more impaired in APOEε4 carriers with variable degrees across MSA motor-subtypes.

Gut Microbial Ecosystem in Parkinson Disease: New Clinicobiological Insights from Multi-Omics.

Gut microbiome alterations in Parkinson disease (PD) have been reported repeatedly, but their functional relevance remains unclear. Fecal metabolomics, which provide a functional readout of microbial activity, have scarcely been investigated. We investigated fecal microbiome and metabolome alterations in PD, and their clinical relevance. Two hundred subjects (104 patients, 96 controls) underwent extensive clinical phenotyping. Stool samples were analyzed using 16S rRNA gene sequencing. Fecal metabolomics were performed using two platforms, nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry. Fecal microbiome and metabolome composition in PD was significantly different from controls, with the largest effect size seen in NMR-based metabolome. Microbiome and NMR-based metabolome compositional differences remained significant after comprehensive confounder analyses. Differentially abundant fecal metabolite features and predicted functional changes in PD versus controls included bioactive molecules with putative neuroprotective effects (eg, short chain fatty acids [SCFAs], ubiquinones, and salicylate) and other compounds increasingly implicated in neurodegeneration (eg, ceramides, sphingosine, and trimethylamine N-oxide). In the PD group, cognitive impairment, low body mass index (BMI), frailty, constipation, and low physical activity were associated with fecal metabolome compositional differences. Notably, low SCFAs in PD were significantly associated with poorer cognition and low BMI. Lower butyrate levels correlated with worse postural instability-gait disorder scores. Gut microbial function is altered in PD, characterized by differentially abundant metabolic features that provide important biological insights into gut-brain pathophysiology. Their clinical relevance further supports a role for microbial metabolites as potential targets for the development of new biomarkers and therapies in PD. ANN NEUROL 2021;89:546-559.

Association Analyses of Autonomic Dysfunction and Sympathetic Skin Response in Motor Subtypes of Parkinson's Disease.

Introduction: Autonomic dysfunction is a common and disabling non-motor symptom of Parkinson's disease (PD). We aimed to understand autonomic dysfunction in PD motor subtypes, the pattern of sympathetic skin response (SSR) to motor asymmetry, and the association of SSR with autonomic and motor dysfunctions.Methods: A total of 101 PD patients of Han Chinese were included. Unified PD rating scale (UPDRS), scales for outcomes in PD-autonomic symptoms (SCOPA-AUT), orthostatic hypotension, and SSR were evaluated.Results: SCOPA-AUT and incidences of orthostatic hypotension and absent SSR were worse in the subtype of postural instability gait disorder (PIGD) than the subtypes of tremor dominant and intermediate. SSR latency and amplitude were asymmetrical corresponding to the accentuation of motor severity. Patients with absent SSR had worse UPDRS and SCOPA-AUT scores. SSR parameters of the severe side in patients with SSR showed no independent association with the scores.Conclusion: Our results support that autonomic dysfunction is more severe in the PIGD than other subtypes and demonstrate an asymmetry of SSR in PD patients. Absent SSR may indicate worse autonomic and motor symptoms, but SSR parameters are not sufficient to evaluate the severity of the dysfunctions.

Therapy of Parkinson's Disease Subtypes.

Early descriptions of subtypes of Parkinson's disease (PD) are dominated by the approach of predetermined groups. Experts defined, from clinical observation, groups based on clinical or demographic features that appeared to divide PD into clinically distinct subsets. Common bases on which to define subtypes have been motor phenotype (tremor dominant vs akinetic-rigid or postural instability gait disorder types), age, nonmotor dominant symptoms, and genetic forms. Recently, data-driven approaches have been used to define PD subtypes, taking an unbiased statistical approach to the identification of PD subgroups. The vast majority of data-driven subtyping has been done based on clinical features. Biomarker-based subtyping is an emerging but still quite undeveloped field. Not all of the subtyping methods have established therapeutic implications. This may not be surprising given that they were born largely from clinical observations of phenotype and not in observations regarding treatment response or biological hypotheses. The next frontier for subtypes research as it applies to personalized medicine in PD is the development of genotype-specific therapies. Therapies for GBA-PD and LRRK2-PD are already under development. This review discusses each of the major subtyping systems/methods in terms of its applicability to therapy in PD, and the opportunities and challenges designing clinical trials to develop the evidence base for personalized medicine based on subtypes.

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.

Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson\u2019s disease

BackgroundThe 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.MethodsPlasma 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.ResultsAt 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.ConclusionsIn 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.

Use of Functional Magnetic Resonance Imaging to Assess How Motor Phenotypes of Parkinson’s Disease Respond to Deep Brain Stimulation

Deep brain stimulation (DBS) is a well-accepted treatment of Parkinson's disease (PD). Motor phenotypes include tremor-dominant (TD), akinesia-rigidity (AR), and postural instability gait disorder (PIGD). The mechanism of action in how DBS modulates motor symptom relief remains unknown. Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to determine whether the functional activity varies in response to DBS depending on PD phenotypes. Subjects underwent an fMRI scan with DBS cycling ON and OFF. The effects of DBS cycling on BOLD activation in each phenotype were documented through voxel-wise analysis. For each region of interest, ANOVAs were performed using T-values and covariate analyses were conducted. Further, a correlation analysis was performed comparing stimulation settings to T-values. Lastly, T-values of subjects with motor improvement were compared to those who worsened. As a group, BOLD activation with DBS-ON resulted in activation in the motor thalamus (p < 0.01) and globus pallidus externa (p < 0.01). AR patients had more activation in the supplementary motor area (SMA) compared to PIGD (p < 0.01) and TD cohorts (p < 0.01). Further, the AR cohort had more activation in primary motor cortex (MI) compared to the TD cohort (p = 0.02). Implanted nuclei (p = 0.01) and phenotype (p = <0.01) affected activity in MI and phenotype alone affected SMA activity (p = <0.01). A positive correlation was seen between thalamic activation and pulse-width (p = 0.03) and between caudate and total electrical energy delivered (p = 0.04). These data suggest that DBS modulates network activity differently based on patient motor phenotype. Improved understanding of these differences may further our knowledge about the mechanisms of DBS action on PD motor symptoms and to optimize treatment.

Use of Functional Magnetic Resonance Imaging to Assess How Motor Phenotypes of Parkinson's Disease Respond to Deep Brain Stimulation

Abstract INTRODUCTION Deep brain stimulation (DBS) is a well-accepted treatment of Parkinson's disease (PD). Motor phenotypes include tremor-dominant (TD), akinesia-rigidity (AR), and postural instability gait disorder (PIGD). The mechanism of action in how DBS modulates symptom relief remains unknown. METHODS Subjects who were classified into TD, AR, or PIGD cohorts underwent task-based fMRI. The effects of the task [DBS (ON/OFF)] on BOLD activation in each phenotype were documented through general linear voxel-wise analysis. For group analysis, t-values were compared using ANOVA in regions of interest, including the primary motor cortex (MI), motor thalamus, primary somatosensory cortex (SI), globus pallidum externus (GPe), anterior and posterior cerebella, supplementary motor area (SMA), and caudate and putamen. A 2-way ANOVA analysis was performed to assess the impact of age, phenotype, and target nuclei. RESULTS BOLD activation with DBS-ON compared to the OFF state resulted in activation in the motor thalamus (P &lt; .01) and GPe (P &lt; .01) when analyzed as a group. Among phenotype, age of PD onset, and target nuclei, phenotype was most effective in determining activation levels. Specifically, AR patients had more activation in the SMA than PIGD patients (P = .002) and in MI compared to TD and PIGD subjects (P = .001 and P = .017, respectively). Further analysis demonstrated that the implant brain region affected activation patterns only in PIGD patients. Specifically, globus pallidum internus (GPi) DBS resulted in MI and SMA deactivation, while STN DBS led to MI activation with no changes in the SMA. CONCLUSION These data suggest that DBS modulates network activity differently based on patient motor phenotype. The nuclei where DBS is implanted affected activation patterns in the PIGD cohort. An improved understanding of these differences may allow us to further our knowledge about the mechanisms of DBS action on PD motor symptoms and to exploit connections to optimize treatment.

Differentiating Parkinson's disease motor subtypes using automated volume-based morphometry incorporating white matter and deep gray nuclear lesion load.

BackgroundPeriventricular leukoaraiosis may be an important pathological change in postural instability gait disorder (PIGD), a motor subtype of Parkinson's disease (PD). Clinical diagnosis of PIGD may be challenging for the general neurologist.PurposeTo evaluate 1) the utility of a fully automated volume‐based morphometry (Vol‐BM) in characterizing imaging diagnostic markers in PD and PIGD, including, 2) novel deep gray nuclear lesion load (GMab), and 3) discriminatory performance of a Vol‐BM model construct in classifying the PIGD subtype.Study TypeProspective.SubjectsIn all, 23 PIGD, 21 PD, and 20 age‐matched healthy controls (HC) underwent MRI brain scans and clinical assessments.Field Strength/Sequence3.0T, sagittal 3D‐magnetization‐prepared rapid gradient echo (MPRAGE), and fluid‐attenuated inversion recovery imaging (FLAIR) sequences.AssessmentClinical assessment was conducted by a movement disorder neurologist. The MR brain images were then segmented using an automated multimodal Vol‐BM algorithm (MorphoBox) and reviewed by two authors independently.Statistical TestingBrain segmentation and clinical parameter differences and dependence were assessed using analysis of variance (ANOVA) and regression analysis, respectively. Logistic regression was performed to differentiate PIGD from PD, and discriminative reliability was evaluated using receiver operating characteristic (ROC) analysis.ResultsSignificantly higher white matter lesion load (WMab) (P < 0.01), caudate GMab (P < 0.05), and lateral and third ventricular (P < 0.05) volumetry were found in PIGD, compared with PD and HC. WMab, caudate and putamen GMab, and caudate, lateral, and third ventricular volumetry showed significant coefficients (P < 0.005) in linear regressions with balance and gait assessments in both patient groups. A model incorporating WMab, caudate GMab, and caudate GM discriminated PIGD from PD and HC with a sensitivity = 0.83 and specificity = 0.76 (AUC = 0.84).Data ConclusionFast, unbiased quantification of microstructural brain changes in PD and PIGD is feasible using automated Vol‐BM. Composite lesion load in the white matter and caudate, and caudate volumetry discriminated PIGD from PD and HC, and showed potential in classification of these disorders using supervised machine learning. Level of Evidence: 1 Technical Efficacy: Stage 1J. Magn. Reson. Imaging 2020;51:748–756.

Association of homocysteine, folate, and white matter hyperintensities in Parkinson's patients with different motor phenotypes.

To investigate the association of homocysteine (Hcy), folate, and white matter hyperintensities in Parkinson's disease (PD) with different motor phenotypes. Of the PD patients, 176 were included. Based on the Unified Parkinson's Disease Rating Scale, the PD patients were classified into postural instability gait disorder (PIGD) and non-PIGD phenotypes. According to the Fazekas score, patients were divided into the none/mild white matter hyperintensity (WMH) group and the moderate/severe WMH group. The relationship of Hcy, folate, and white matter hyperintensities (WMHs), and the motor phenotype of PD were analyzed. PD-PIGD patients had higher proportion of moderate/severe WMHs, Hcy levels, and lower folate levels than PD-non-PIGD patients (p all ≤ 0.001). In the subgroup analysis, patients with both PD-PIGD and moderate/severe WMHs had the highest Hcy and lowest folate levels compared with others. Binary logistic regression analysis showed that age, folate, and Hcy were independent risk factors for WMHs. In an a priori-determined stratified analysis, after adjustment for confounding factors, the odds ratio of WMHs was 8.01 (95% CI 2.700-23.767, p trend = 0.001) in the patients with Hcy levels in the highest quintile compared with the lowest quintile and 16.81 (95% CI 4.74-59.65, p trend < 0.001) in the patients with folate levels in the lowest quintile compared with the highest quintile. Our data showed a close association between WMHs and Hcy, folate especially in PD-PIGD patients. It can be speculated that higher Hcy and lower folate probably played important roles in the development of WMHs and motor heterogeneity in PD.

Periventricular White Matter Abnormalities on Diffusion Tensor Imaging of Postural Instability Gait Disorder Parkinsonism.

Postural instability gait disorder is a motor subtype of Parkinson disease associated with predominant gait dysfunction. We investigated the periventricular white matter comprising longitudinal, thalamic, and callosal fibers using diffusion tensor MR Imaging and examined clinical correlates in a cohort of patients with Parkinson disease and postural instability gait disorder and healthy controls. All subjects underwent the Tinetti Gait and Balance Assessment and brain MR imaging. The DTI indices (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) from ROIs dropped over the superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior and posterior limbs of the internal capsule, and the genu and body of corpus callosum were evaluated. Our findings showed that the superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, genu of the corpus callosum, and body of the corpus callosum are more affected in postural instability gait disorder than in those with Parkinson disease or healthy controls, with more group differences among the longitudinal fibers. Only the callosal fibers differentiated the postural instability gait disorder and Parkinson disease groups. DTI measures in the superior longitudinal fasciculus, frontostriatal fibers (anterior thalamic radiation, anterior limb of the internal capsule), and genu of the corpus callosum fibers correlated with clinical gait severity. Findings from this case-control cohort lend further evidence to the role of extranigral pathology and, specifically, the periventricular fibers in the pathophysiology of postural instability gait disorder.

Evaluation of dysphagia in different phenotypes of early and idiopathic Parkinsonism

BackgroundParkinsonism (PD) is a common neurodegenerative disorders into which dysphagia occurs mainly in the late stage and to a lesser extent in an early stage. Diagnosis of dysphagia particularly in early idiopathic Parkinson’s disease (IPD) is important as dysphagia affects the quality of life of patients and most of the patients are unaware of this important symptom.MethodFifty-four patients were enrolled in this study presented with early IPD attending to the outpatient clinic of Sohag University Hospital. All PD patients were assessed by using Unified Parkinson’s Disease Rating Scale (UPDRS) and modified Hoehn and Yahr scale. IPD patients were classified into tremor dominant (TD) and postural instability/gait disorder (PIGD) phenotypes. Swallowing disturbance questionnaire (SDQ) and fiberoptic endoscopic evaluation of swallowing (FEES) were used to evaluate dysphagia.ResultsThirty-five percent of patients experienced dysphagia when the patients were questioned, and this percent rises to 40% on using FEES. The results of SDQ were significantly correlated to the results of more accurate FEES. The percentage of dysphagia was higher in patients with PIGD than TD phenotype. Dysphagia was significantly associated with the mean of the Mini-Mental State Examination (MMSE), UPDRS, and modified Hoehn and Yahr scale.ConclusionsDysphagia is a prevalent symptom in early IPD and significantly correlated with Parkinsonism phenotype, UPDRS, and modified Hoehn and Yahr scale.

Importance of Balance-Gait Disorder as a Risk Factor for Cognitive Impairment, Dementia and Related Non-Motor Symptoms in Parkinson's Disease.

In Parkinson's disease (PD), postural instability-gait disorder (PIGD) has been associated with more rapid cognitive decline, dementia, and greater non-motor symptom (NMS) burden. To assess the importance of balance-gait disorder, relative to and in combination with other clinical measures, as a risk factor for cognitive impairment, dementia and NMS burden in PD. 164 PD subjects were evaluated in a retrospective cross-sectional study using the MDS-UPDRS scale, MMSE and Clinical Dementia Rating Scale. Using univariate comparisons followed by multiple stepwise regression, we identified factors most closely associated with NMS burden and concurrent dementia. Nominal logistic regression and linear discriminant analysis was used to compute receiver operating characteristic curves and to measure sensitivity and specificity of predictors of dementia. Dementia was more frequent in those with the PIGD phenotype (χ2 = 11.49, p = 0.003). The MDS-UPDRS balance-gait measure, excluding freezing of gait, was the single best predictor not only of concurrent cognitive impairment and dementia (F = 37.16, p < 0.001) but also of NMS burden, predicting 29% of the MDS-UPDRS total non-motor experiences of daily living score (F = 67.14, p < 0.0001). This measure, together with combined severity of hallucinations/psychosis, daytime sleepiness and urinary problems, a closely correlated symptom cluster (r = 0.63 p < 0.0001), accurately classified 84% of patients with dementia. In PD, balance-gait impairment is closely associated with dementia and NMS burden, particularly the linked symptoms of cognitive impairment, psychosis, daytime sleepiness and urinary dysfunction. This phenotype characterizes patients likely to require closer surveillance and more comprehensive care. Confirmation of these findings in prospective longitudinal studies might help refine predictive algorithms designed to identify PD patients more likely to progress from mild cognitive impairment to dementia.

Mortality from Parkinson's disease in China: Findings from a ten-year follow up study in Shanghai

BackgroundStandardized mortality ratio (SMR) is the most frequently used index in Parkinson's disease (PD) survival survey. However, there is little SMR data in PD from China. ObjectiveTo examine the outcome, including overall and cause-specific mortality, of PD patients subsequent to 10 years of surveillance in Shanghai, China. This is an extension study of our previous investigation on mortality. MethodsOne hundred fifty-seven PD patients recruited from the movement disorder clinic of Rui Jin Hospital in 2006 were followed up until December 31, 2016 or death, representing a follow-up period of up to 10 years. Overall and cause-specific standardized mortality ratios (SMR) were calculated, and predictors for survival at disease onset were estimated. ResultsThirty one patients had died by December 31, 2016, and the SMR at 10 years of follow-up was 0.87 (0.59–1.25). The primary direct cause of death was respiratory disease (SMR = 3.52, 95% CI 1.98–5.78). Employing Cox's proportional hazard modeling, postural instability gait disorder (PIGD) type and older age at onset predicted poor survival in this cohort. ConclusionsThis finding confirms the similar survival of patients with PD to the control population in the post-levodopa era. PIGD type and older age at onset had a negative impact on survival.

Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype.

ObjectiveParkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression.MethodsWe screened 10 SNPs, previously associated with PD risk, for association with tremor‐dominant (TD) versus postural‐instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi‐site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross‐sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha‐synuclein (SNCA) expression in the GTEx (Genotype‐Tissue Expression project) consortium database.ResultsGenotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni‐corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor‐predominant phenotype and predicted a slower rate of motor progression (1‐point difference in annual rate of UPDRS‐III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005).InterpretationOur study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor‐predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

Susceptibility-weighted MRI of extrapyramidal brain structures in Parkinsonian disorders.

Susceptibility-weighted MRI (SWI) is sensitive to T2∗ effects and mineralization.We investigated differences in the extrapyramidal brain structures on SWI between Parkinson disease (PD) and postural instability gait disorder (PIGD) patients and correlated the SWI values with the degree of gait dysfunction.Forty patients diagnosed with PD and PIGD underwent 3 Tesla magnetic resonance imaging (MRI) brain study. An SWI sequence (TE/TR/FA 20/33/15) was used. Ten regions of interest were placed in the midbrain and basal ganglia by 2 independent raters blinded to subject data and quantitatively evaluated.The inter-rater reliability between the raters was excellent (interclass correlation coefficient >0.8). The SWI intensity values in all regions were on average lower in PIGD than in PD patients, with the lowest results found in globus pallidus.Multivariate analysis showed a lower SWI hypointensity in the putamen and globus pallidus in PIGD compared with PD patients, with a similar trend for the other basal ganglia nuclei. Pearson correlation analysis showed a statistically significant positive correlation between SWI putaminal hypointensity and the Tinetti total score (r = 0.39, P = 0.01) in both PD and PIGD.SWI putaminal hypointensity may be a useful imaging marker in prospective evaluation for clinical progression for Parkinsonian disorders.