Parkinson's Disease Motor Subtypes Research Articles

Olfactory dysfunction and striatal dopamine transporter binding in motor subtypes of Parkinson's disease.

Olfactory dysfunction is one of the earliest non-motor symptoms (NMS) in Parkinson's disease (PD). There are contradictory results regarding the association of olfactory dysfunction and dopamine uptake in striatal nuclei among PD patients. It has been suggested that different motor subtypes of PD vary in the disease pathophysiology and progression. Thus, we hypothesized that there might be different associations between olfactory dysfunction and striatal dopaminergic neuronal loss among three motor subtypes of PD, namely, indeterminate, postural instability and gait difficulty (PIGD), and tremor-dominant (TD). We recruited 162 healthy controls (HCs) and 464 drug-naïve PD patients from PPMI who underwent common PD scaling tests. Striatal binding ratios (SBRs) of DaTSCAN images in caudate and putamen nuclei were calculated. To assess the olfactory function, the University of Pennsylvania Smell Identification Test (UPSIT) was carried out. The UPSIT score was significantly correlated with MDS-UPDRS part I (p value: 0.002, correlation coefficient: - 0.160), MDS-UPDRS part III (p value: 0.000, correlation coefficient: - 0.248), and SBR score in right (p value: 0.000, correlation coefficient: 0.240) and left caudate (p value: 0.000, correlation coefficient: 0.221) and right (p value: 0.000, correlation coefficient: 0.323) and left putamen (p value: 0.000, correlation coefficient: 0.335) nucleus in TD subtype. There were no significant correlations in HC, PIGD, and indeterminate subjects. The olfactory dysfunction was correlated with dopamine transporter activity in striatal nuclei only in the TD subtype. Therefore, the olfactory dysfunction in PIGD and indeterminate subtype may not be a predictive factor for the future decrease in dopamine uptake.

Differential Effects of Subthalamic Nucleus and Globus Pallidus Internus Deep Brain Stimulation on Motor Subtypes in Parkinson's Disease

To investigate differences in motor symptom change outcomes following bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in well-defined motor subtypes of Parkinson's disease (PD) to improve clinical decision making. We included 114 patients undergoing STN-DBS and 65 patients undergoing GPi-DBS. The patients were classified as akinetic-rigid type (ART), tremor-dominant type (TD), and mixed type (MT) based on the preoperative the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part-Ⅲ (MDS-UPDRS-III) scores in the medication-off state. Outcome measures included the med-off MDS-UPDRS-III and its subscores changes at the last follow-up after surgery. Outcomes were compared among different motor subtypes and between STN-DBS and GPi-DBS. At the last follow-up (14.92 ± 8.35 months), TD patients had greater median overall motor improvement in med-off MDS-UPDRS-III scores compared with ART patients (62.90% vs 46.67%, P < 0.001), regardless of stimulation target. ART patients showed greater improvement after STN-DBS compared with GPi-DBS (54.44% vs 37.21%, P < 0.001), with improvement in rigidity, akinesia, and posture and gait disorders accounting for this difference. Our results suggest that the different PD motor subtypes show differential responses to STN-DBS and GPi-DBS, that TD patients have greater improvement than ART patients, and STN-DBS has a better effect in ART patients than GPi-DBS. Besides, different motor symptoms among different motor subtypes may respond differently to STN-DBS vs GPi-DBS. All above may reflect the heterogeneity of PD. Longer-term outcomes across different motor subtypes and stimulation targets should be further studied.

Parkinson's Disease Motor Subtypes Change with the Progression of the Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up.

Motor phenotype (MP) can be associated with a different prognosis in Parkinson's disease (PD), but it is not fixed and can change over time. Our aim was to analyze how the MP changed over time and to identify factors associated with the changes in PD patients from a multicenter Spanish PD cohort. 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 study.MP was calculated at both visits based on Jankovic classification in TD (tremor dominant), IND (indeterminate), or PIGD (postural instability and gait difficulty). Sociodemographic and clinical data were collected, including serum biomarkers. Five hundred eleven patients (62.57±8.59 years old; 59.2%males) were included in the study. At V0, MP was: 47.4%(242/511) TD; 36.6%(187/511) PIGD; 16%(82/511) IND. Up to 38%(194/511) of the patients changed their phenotype from V0 to V2, being the most frequent from TD to IND (8.4%) and from TD to PIGD (6.7%). A worse cognitive status (OR = 0.966) and less autonomy for activities of daily living (OR = 0.937) at V0 and a greater increase in the globalNMS burden (OR = 1.011) from V0 to V2 were associated with changing from TD to another phenotype after 2-year follow-up. The MP in PD can change over time. With disease progression, the percentage of cases with non-tremoric MP increases. PD patients who changed from TD to postural instability and gait difficulty increased NMS burden significantly.

Olfactory dysfunction is associated with motor function only in tremor-dominant Parkinson's disease.

The prevalence of olfactory impairment in patients with Parkinson's disease (PD) is 50-90%, and therefore, olfactory dysfunction is one of the most prevalent non-motor symptoms (NMSs) in patients with PD. Numerous studies have evaluated the association between motor and non-motor symptoms and olfactory dysfunction in PD. In this study, we investigated the relationship between olfactory dysfunction, which is measured using the UPSIT test, with other motor and non-motor symptoms separately in three motor subtypes of PD, including tremor dominant (TD), postural instability and gait difficulty (PIGD), and indeterminate and healthy subjects. We recruited 487 early-stage PD patients (43 PIGD, 406 TD, and 38 indeterminate) and healthy controls (HCs) (n = 197) from the Parkinson Progression Markers Initiative (PPMI). All participants completed motor and non-motor tests at baseline visit and after 4years of follow-up. Subjects underwent common PD scaling tests. Olfactory dysfunction was significantly correlated with declined motor functions only in the TD subtype. Also, significant correlations were noticed between olfactory dysfunction and speed-attention processing and executive function in the HCs as well. Finally, no significant or meaningful association was observed in the PIGD and indeterminate subtype. Anosmia and hyposmia subjects in the TD group had the worse motor and non-motor scores compared to normosmia subjects after 4years. Olfactory dysfunction was significantly correlated with declined motor functions in the TD subtype. This is indicating that olfactory dysfunction may be an early motor and non-motor biomarker only in the TD subtype. However, it is possible that the involvement of olfactory function in other subtypes is not strong enough to make it a useful marker of diseases progression.

Distinct hippocampal subfield atrophy in Parkinson's disease regarding motor subtypes

IntroductionGlobal hippocampal atrophy has been repeatedly reported in patients with Parkinson's disease (PD). However, there is limited literature on the differential involvement of hippocampal subfields among PD motor subtypes. This study aimed to investigate hippocampal subfield alterations in patients with PD based on their predominant symptoms. MethodWe enrolled 31 PD patients with the tremor-dominant (TD) subtype, 27 PD patients with postural instability and gait disturbance-dominant (PIGD) subtype, and 40 healthy controls (HCs). All participants underwent high-spatial-resolution T1-weighted magnetic resonance imaging. The volume of hippocampal subfields was measured using FreeSurfer software, compared across groups, and correlated with clinical features. ResultsWe found volumetric reductions in the hippocampal subfield in both patient subtypes compared to HCs, which were more pronounced in the PIGD subtype. The PIGD subtype had accelerated age-related alterations in the hippocampus compared to the TD subtype. Bilateral hippocampal volumes were positively associated with cognitive performance levels, but not with disease severity and duration in patients. ConclusionsAlterations in the hippocampal subfields of patients with PD differed based on their predominant symptoms. These findings are of relevance for understanding the pathophysiology of the increased risk of cognitive impairment in PIGD.

Autonomic symptoms in motor subtypes of Parkinson's disease

Background: Parkinson's Disease (PD) patients suffer from a wide range of motor symptoms and PD motor subtypes, including tremor-dominant (TD) and non-tremor dominant (nTD) (characterized by postural instability and gait difficulty and known as PIDG) have been described. Heterogeneity have been observed in non-motor symptoms of PD patients, but reports on this topic are conflicting. Aim: We aimed to investigate autonomic dysfunction in PD motor subtypes by scales for outcomes in PD-autonomic symptoms (SCOPA-AUT).

Stability of MDS-UPDRS Motor Subtypes Over Three Years in Early Parkinson's Disease.

Background: Various classifications have been proposed to subtype Parkinson's disease (PD) based on their motor phenotypes. However, the stability of these subtypes has not been properly evaluated.Objective: The goal of this study was to understand the distribution of PD motor subtypes, their stability over time, and baseline factors that predicted subtype stability.Methods: Participants (n = 170) from two prospective cohorts were included: the Early PD Longitudinal Singapore (PALS) study and the National Neuroscience Institute Movement Disorders Database. Early PD patients were classified into tremor-dominant (TD), postural instability and gait difficulty (PIGD), and indeterminate subtypes according to the Movement Disorder Society's Unified PD Rating Scale (MDS-UPDRS) criteria and clinically evaluated for three consecutive years.Results: At baseline, 60.6% patients were TD, 12.4% patients were indeterminate, and 27.1% patients were PIGD subtypes (p < 0.05). After 3 years, only 62% of patients in TD and 50% of patients in PIGD subtypes remained stable. The mean levodopa equivalent daily dose (LEDD) was higher in the PIGD subtype (276.92 ± 232.91 mg; p = 0.01). Lower LEDD [p < 0.05, odds ratio (OR) 0.99, 95% confidence interval (CI): 0.98–0.99] and higher TD/PIGD ratios (p < 0.05, OR 1.77, 95% CI: 1.29–2.43) were independent predictors of stability of TD subtype with an area under the curve (AUC) of 0.787 (95%CI: 0.669–0.876), sensitivity = 57.8%, and specificity = 89.7%.Conclusion: Only 50–62% of PD motor subtypes as defined by MDS-UPDRS remained stable over 3 years. TD/PIGD ratio and baseline LEDD were independent predictors for TD subtype stability over 3 years.

The inconsistency and instability of Parkinson's disease motor subtypes

IntroductionTremor-dominant (TD), indeterminate/mixed (ID/M) and postural instability gait difficulty/akinetic-rigid (PIGD/AR) are commonly used subtypes to categorize Parkinson's disease (PD) patients based on their most prominent motor signs. Three different algorithms to determine these motor subtypes are used. Here, we examined if PD subtypes are consistent among algorithms and if subtype stability over time depends on the applied algorithm. MethodsUsing a large longitudinal PD database, we applied 3 published algorithms of PD motor subtype classification in two sets of analyses: 1) cross-sectional analysis in 1185 patients, determining the prevalence of subtypes in 5-year intervals of disease duration; 2) longitudinal analysis of 178 patients, comparing subtypes of individual patients at baseline (within 5 years of diagnosis) and at follow-up ≥ 5 years after baseline. ResultsCross-sectionally, prevalence of subtypes varied widely among the 3 algorithms: 5–32% TD, 9–31% ID/M, and 59–75% PIGD/AR. For all 3 algorithms, cross-sectional analysis showed a marked decline of TD prevalence with disease duration and a corresponding increase in PIGD/AR prevalence, driven by increasing gait/balance scores over time. Longitudinally, only 15–36% of baseline TD patients were still categorized as TD at 6.2 ± 1.0 years of follow-up. In 15–39% of baseline TD patients, the subtype changed to ID/M, and 46–50% changed to PIGD/AR. This shift was observed using all 3 algorithms. ConclusionPD motor subtypes determined by different established algorithms are inconsistent and unstable over time. Lack of subtype fidelity should be considered when interpreting biomarker-subtype correlation and highlights the need for better definition of PD subtypes.

Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes.

ObjectiveTo discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.MethodsIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.ResultsAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = −0.04, 95% confidence interval = −0.07–0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6 × 10−7), which harbors an independent risk allele for essential tremor.ConclusionsMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

Efficacy of short-term multidisciplinary intensive rehabilitation in patients with different Parkinson's disease motor subtypes: a prospective pilot study with 3-month follow-up.

Parkinson's disease (PD) can be classified into three motor-based subtypes: postural instability/gait difficulty (PIGD), tremor dominant (TD), and indeterminate. The neuropathophysiological mechanisms of the three motor subtypes are different, which may lead to different responses to therapy. Sixty-nine patients with idiopathic Parkinson's disease (Hoehn-Yahr stage ≤ 3) were screened from 436 patients with Parkinsonism recruited through outpatient services and the internet. According to the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) TD/PIGD ratio, the patients were divided into PIGD (TD/PIGD ≤ 0.09; n = 36), TD (TD/PIGD ≥1.15; n = 19), and indeterminate (TD/PIGD = 0.90-1.15; n = 14) groups. All patients received 2 weeks of multidisciplinary intensive rehabilitation treatment (MIRT) during hospitalization, as well as a remote home rehabilitation health education class. Compared with the scores at admission, all patients showed significant improvements in their MDS-UPDRS III score, walking ability, balance, and posture control at discharge. Moreover, the MDS-UPDRS III score improvement was greater in the PIGD group than in the TD group. The follow-up data, collected for 3 months after discharge, showed that overall symptom improvement in each group was maintained for 1-3 months. Furthermore, there were no significant differences in the duration or grade effects of symptom improvement among the three groups. These findings suggest that 2 weeks of MIRT is effective for improving motor performance in all three motor subtypes. Patients in the PIGD group had a better response after hospitalization than those in the TD group. This study was approved by the Institutional Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University of China (approval No. 2018bkky022) on May 7, 2018 and registered with the Chinese Clinical Trial Registry (registration No. ChiCTR1900020771) on January 19, 2019.

Neuroimaging Detectable Differences between Parkinson's Disease Motor Subtypes: A Systematic Review.

ABSTRACTBackgroundThe neuroanatomical substrates of Parkinson's disease (PD) with tremor‐dominance (TD) and those with non‐tremor dominance (nTD), postural instability and gait difficulty (PIGD), and akinetic‐rigid (AR) are not fully differentiated. A better understanding of symptom specific pathoanatomical markers of PD subtypes may result in earlier diagnosis and more tailored treatment. Here, we aim to give an overview of the neuroimaging literature that compared PD motor subtypes.MethodsA systematic literature review on neuroimaging studies of PD subtypes was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Search terms submitted to the PubMed database included: “Parkinson's disease”, “MRI” and “motor subtypes” (TD, nTD, PIGD, AR). The results are first discussed from macro to micro level of organization (i.e., (1) structural; (2) functional; and (3) molecular) and then by applied imaging methodology.FindingsSeveral neuroimaging methods including diffusion imaging and positron emission tomography (PET) distinguish specific PD motor subtypes well, although findings are mixed. Furthermore, our review demonstrates that nTD‐PD patients have more severe neuroalterations compared to TD‐PD patients. More specifically, nTD‐PD patients have deficits within striato‐thalamo‐cortical (STC) circuitry and other thalamocortical projections related to cognitive and sensorimotor function, while TD‐PD patients tend to have greater cerebello‐thalamo‐cortical (CTC) circuitry dysfunction.ConclusionsBased on the literature, STC and CTC circuitry deficits seem to be the key features of PD and the subtypes. Future research should make greater use of multimodal neuroimaging and techniques that have higher sensitivity in delineating subcortical structures involved in motor diseases.

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.

The Relationship Between Speech Characteristics and Motor Subtypes of Parkinson's Disease

Purpose The aim of this study was to examine whether acoustic dysarthria characteristics align with overall motor profile in individuals with Parkinson's disease (PD). Potential speech differences between tremor-dominant and non-tremor-dominant subtypes are theoretically motivated but empirically inconclusive. Method Twenty-seven individuals with dysarthria from PD provided a contextual speech sample. Participants were grouped into non-tremor-dominant (n = 12) and tremor-dominant (n = 15) motor subtypes according to the Unified Parkinson Disease Rating Scale. Dependent speech variables included fundamental frequency range, average pause duration, cepstral peak prominence, stuttering dysfluencies, and maze dysfluencies. Results There were no significant differences between the speech of the tremor-dominant and non-tremor-dominant groups. High within-group variability existed across parameters and motor subtypes. Conclusion Speech characteristics across the areas of phonation, prosody, and fluency did not differ appreciably between PD motor subtypes.

Parkinson's disease motor subtypes and bilateral GPi deep brain stimulation: One-year outcomes

ObjectiveWe aimed to explore the differences in motor symptoms and quality of life (QOL) outcomes following bilateral globus pallidus internus deep brain stimulation (GPi DBS), across well-defined motor subtypes of Parkinson's disease (PD), to improve clinical decision making. MethodsThis single-center retrospective study investigated bilateral GPi DBS outcomes in 65 PD patients. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire (PDQ-39) before and one year after surgery. Outcomes were compared between the tremor-dominant (TD) and postural instability and gait difficulty (PIGD) subtypes and between the TD and akinetic-rigid (AR) subtypes. ResultsFor the entire cohort, motor function (UPDRS III) in the Off-medication state, motor complications (UPDRS IV), activities of daily living (ADL, UPDRS II), and the ADL and discomfort domains of PDQ-39 significantly improved one year following GPi implantation compared to baseline (effect size = 1.32, 1.15, 0.25, 0.45, and 0.34, respectively). GPi DBS improved the Off-medication UPDRS III scores regardless of the motor subtypes. However, compared to the PIGD and AR patients, the TD patients showed greater improvement in overall UPDRS III postoperatively primarily due to greater tremor improvement in the Off-medication state. The outcomes in akinesia, rigidity, axial symptoms and QOL were similar among all subtypes. ConclusionBilateral GPi DBS was effective for advanced PD patients regardless of motor subtypes. Greater tremor improvement in the TD patients accounted for greater Off-medication motor improvement. Longer-term GPi DBS outcomes across different motor subtypes and brain targets should be further studied.

The role of the motor subtypes on the relationship between anxiety and cognitive dysfunctions in Parkinson's disease.

Anxiety is a common neuropsychiatric symptom in Parkinson's disease (PD). Until now, anxiety has been consistently related to cognitive deficits and severity of motor symptoms, whereas the association between anxiety and motor subtypes (TD-PD, tremor dominant and PIGD-PD, postural instability/gait disturbances dominant) revealed contrasting results. The present study aims to investigate the relationship between PD motor subtypes and anxiety and to explore whether the relationship between anxiety and cognitive deficits occurs in a specific PD motor subtype. Consecutive PD outpatients were recruited and divided into TD-PD and PIGD-PDgroups according to Jankovic et al.'s criteria. All participants underwent a neuropsychological battery to evaluate anxiety, apathy, the global cognitive functioning, memory abilities, executive and visuo-constructional functions. Thirty-six patients with TD-PD and 35 patients with PIGD-PD were enrolled. The two groups did not differ on demographical and clinical variables. As for theseverity of anxiety, no significant difference between the two groups was found. Regression analysis revealed that higher anxiety score was associated with poorer performance on constructional visuospatial test in both TD-PD and PIGD-PD. Clinical variables were not associated with anxiety in the two groups. Our findings indicated that the severity of anxiety was not associated with any PD motor subtypes. Moreover, regression analysis revealed that impaired visuo-constructional abilities are related to anxiety independently of PD motor subtypes. Since altered fronto-parietal network might be one of the pathogenetic mechanisms underpinning anxiety and constructional visuospatial deficits, thetreatment of cognitive dysfunctions might reduce anxious symptoms.

Serum Uric Acid, Serum Uric Acid to Serum Creatinine Ratio and Serum Bilirubin in Patients With Parkinson's Disease: A Case-Control Study.

BackgroundStudies have shown that a low serum uric acid (SUA) level associates with Parkinson’s disease (PD), but many of them did not exclude patients with impaired renal function. Studies on the association between serum bilirubin level and PD also are limited. This study determined the association between SUA level, SUA/serum creatinine (SCr) ratio and serum bilirubin levels in PD patients with normal renal and liver functions.MethodsThe PD patients from a neurological clinic, and the controls from the club for the elderly, were recruited into this study. The PD stage and motor and non-motor function were determined by the Hoehn-Yahr (H&Y) scale and unified Parkinson’s disease rating scale (UPDRS), respectively.ResultsSixty-one PD patients and 135 controls participated. The SUA/SCr ratio, but not SUA, was significantly lower in the PD patients than in the controls (4.12 ± 0.90 vs. 4.59 ± 1.04, P = 0.003). Serum total bilirubin (TB) and indirect bilirubin (IDB) were significantly higher in the PD patients (7.92 ± 3.67 µmol/L vs. 6.59 ± 2.78 µmol/L, P = 0.003 and 4.52 ± 2.48 µmol/L vs. 3.26 ± 1.82 µmol/L, P < 0.001), respectively. Serum TB and IDB, but not SUA or SUA/SCr ratio, were associated negatively with PD stages (P = 0.010 and P = 0.014, respectively). There was no association between TB, IDB, SUA or SUA/SCr ratio and PD disease duration or motor subtypes. No significant correlation was found between SUA or SUA/SCr ratio, serum TB and IDB.ConclusionThe SUA/SCr ratio is more sensitive than SUA in determining their association with PD. The high serum TB and IDB levels in PD patients compared with the controls suggest that serum bilirubin might play a role in the pathogenesis of PD. However, the lack of association between SUA or the SUA/SCr ratio and serum TB or IDB suggests that these two biomarkers play a different role in the etiopathogenesis of PD.

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.

Parkinson's disease motor subtype changes during 20 years of follow-up

•Tremor dominant, postural instability/gait dominant, and intermediate type categories are reproducible subtypes of Parkinson’s disease. •Parkinson's disease subtypes continuously vary with disease duration. •Intermediate subtypes require further delineation.

Parkinson's Disease Motor Subtypes Show Different Responses to Long-Term Subthalamic Nucleus Stimulation.

Background and purpose: Subthalamic nucleus deep brain stimulation (STN DBS) is well established for the treatment of advanced Parkinson’s disease (PD), substantially improving motor symptoms, quality of life, and reducing the long-term need for dopaminergic medication. However, whether chronic STN DBS produces different effects on PD motor subtypes is unknown. This retrospective study aimed to evaluate the long-term effects of STN DBS on the PD motor subtypes.Methods: Eighty patients undergoing STN DBS were included. The Unified Parkinson’s Disease Rating Scale (UPDRS) analysis was performed in “On” and “Off” medication/“On” and “Off” stimulation conditions. The patients were classified as akinetic-rigid type (ART), tremor-dominant type (TDT), and mixed type (MT) based on the preoperative UPDRS III subscores in the “Off” medication state. Preoperative and postoperative comparisons were performed.Results: After 4.9 years, STN DBS produced significant improvement in the UPDRS III total scores and subscores of tremor, rigidity, and bradykinesia in the “Off” medication state in the ART group, less improvement in the MT group, and the least improvement in the TDT group. The UPDRS II and III total scores and other subscores failed to improve during the “On” medication state. However, all groups improved substantially, and the improvement in tremor was sustained for both the “On” and “Off” medication states after years. Long-term STN DBS failed to improve swallowing and speech in all the subtypes.Conclusion: The data confirms that PD is heterogeneous. Long-term STN DBS produced the best effects on bradykinesia/rigidity in the “Off” medication state and on tremor in the “On” and “Off” medication states. There were differences in the response by each group, but some of the differences could be explained by the fact that more severe symptoms at baseline tend to have greater improvement. The findings support the idea that ART mainly involves the basal ganglia-thalamo-cortical pathway, whereas TDT involves a different circuit, likely the cerebellar-thalamo-cortical pathway.

Local field potentials of subthalamic nucleus contain electrophysiological footprints of motor subtypes of Parkinson’s disease

Although motor subtypes of Parkinson's disease (PD), such as tremor dominant (TD) and postural instability and gait difficulty (PIGD), have been defined based on symptoms since the mid-1990s, no underlying neural correlates of these clinical subtypes have yet been identified. Very limited data exist regarding the electrophysiological abnormalities within the subthalamic nucleus (STN) that likely accompany the symptom severity or the phenotype of PD. Here, we show that activity in subbands of local field potentials (LFPs) recorded with multiple microelectrodes from subterritories of STN provide distinguishing neurophysiological information about the motor subtypes of PD. We studied 24 patients with PD and found distinct patterns between TD (n = 13) and PIGD (n = 11) groups in high-frequency oscillations (HFOs) and their nonlinear interactions with beta band in the superior and inferior regions of the STN. Particularly, in the superior region of STN, the power of the slow HFO (sHFO) (200-260 Hz) and the coupling of its amplitude with beta-band phase were significantly stronger in the TD group. The inferior region of STN exhibited fast HFOs (fHFOs) (260-450 Hz), which have a significantly higher center frequency in the PIGD group. The cross-frequency coupling between fHFOs and beta band in the inferior region of STN was significantly stronger in the PIGD group. Our results indicate that the spatiospectral dynamics of STN-LFPs can be used as an objective method to distinguish these two motor subtypes of PD. These observations might lead to the development of sensing and stimulation strategies targeting the subterritories of STN for the personalization of deep-brain stimulation (DBS).