Postural Instability Gait Difficulty Subtype Research Articles

Wearable sensor-based quantitative gait analysis in Parkinson’s disease patients with different motor subtypes

Gait impairments are among the most common and disabling symptoms of Parkinson’s disease and worsen as the disease progresses. Early detection and diagnosis of subtype-specific gait deficits, as well as progression monitoring, can help to implement effective and preventive personalized treatment for PD patients. Yet, the gait features have not been fully studied in PD and its motor subtypes. To characterize comprehensive and objective gait alterations and to identify the potential gait biomarkers for early diagnosis, subtype differentiation, and disease severity monitoring. We analyzed gait parameters related to upper/lower limbs, trunk and lumbar, and postural transitions from 24 tremor-dominant (TD) and 20 postural instability gait difficulty (PIGD) dominant PD patients who were in early stage and 39 matched healthy controls (HC) during the Timed Up and Go test using wearable sensors. Results show: (1) Both TD and PIGD groups showed restricted backswing range in bilateral lower extremities and more affected side (MAS) arm, reduced trunk and lumbar rotation range in the coronal plane, and low turning efficiency. The receiver operating characteristic (ROC) analysis revealed these objective gait features had high discriminative value in distinguishing both PD subtypes from the HC with the area under the curve (AUC) values of 0.7~0.9 (p < 0.01). (2) Subtle but measurable gait differences existed between TD and PIGD patients before the onset of clinically apparent gait impairment. (3) Specific gait parameters were significantly associated with disease severity in TD and PIGD subtypes. Objective gait biomarkers based on wearable sensors may facilitate timely and personalized gait treatments in PD subtypes through early diagnosis, subtype differentiation, and disease severity monitoring.

Exploring obstructive sleep apnea and sleep architecture in Parkinson's disease motor subtypes

IntroductionParkinson's disease (PD) can be divided into motor subtypes: postural instability/gait difficulty (PIGD), tremor dominant, and indeterminate. This study aimed to assess differences in sleep structure and obstructive sleep apnea (OSA) between the PIGD and non-PIGD subtypes. MethodsPD participants with or without OSA (defined as apnea-hypopnea index (AHI) ≥ 15 events/hour on overnight polysomnography) were included. Patients were separated into two groups: PIGD and non-PIGD. Linear regression was used to explore differences in sleep, AHI, and other respiratory parameters between groups (adjusted for variables determined a priori). Logistic regression adjusted for the same variables was used to determine if the proportion of patients with OSA differed across groups. Subset analyses were performed: subset 1 excluding patients on psychoactive medication; subset 2 excluding patients taking levodopa or dopaminergic agonists (DAs) at nighttime and subset 3 excluding patients on either of the abovementioned drugs. Results146 participants were studied. The non-PIGD group had less N3 sleep compared to the PIGD group (12.4% vs 16.9% p = 0.06), reaching significance in subsets 1 and 3. The AHI was significantly lower in the PIGD group (p = 0.047), including when medication effects were removed (p < 0.05). OSA was more frequent in the non-PIGD group, but only significantly in subset 3 (adjusted OR 0.3, p = 0.04). ConclusionOSA may be more severe in non-PIGD subtypes, and more frequent, in a subset free of psychoactive medication, and of levodopa and DAs, possibly owing to motor complications and dyskinesia. Future studies are required to confirm this.

Altered connectivity between frontal cortex and supplementary motor area in various types of Parkinson's disease.

Tremor-dominant (TD) and postural instability/gait difficulty (PIGD) are common subtypes of Parkinson's disease, each with distinct clinical manifestations and prognoses. The neural mechanisms underlying these subtypes remain unclear. This study aimed to investigate the altered connectivity of the frontal cortex and supplementary motor area (SMA) in different types of Parkinson's disease. Data of 173 participants, including 41 TD patients, 65 PIGD patients, and 67 healthy controls, were retrospectively analyzed. All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) and clinical assessments. Differences in amplitude of low frequency fluctuation (ALFF), voxel-wise functional connectivity (FC), and functional network connectivity (FNC) among the three groups were compared, followed by partial correlation analysis. Compared to healthy controls, the left dorsolateral superior frontal gyrus (DLSFG) ALFF was significantly increased in both PIGD and TD patients. The FC between the left DLSFG and the left SMA, as well as between the left paracentral lobule and the right DLSFG, was significantly decreased. Similarly, the FNC between the visual network and the auditory network was reduced. Compared to TD patients, PIGD patients showed a significantly higher ALFF in the left DLSFG and a notably reduced FC between the left DLSFG and left SMA. Additionally, the FC of the left DLSFG-SMA was inversely correlated with the PIGD score exclusively in PIGD patients. The FNC of the visual-auditory network was inversely associated with the tremor score only in TD patients. Decreases in the left DLSFG-SMA connectivity may be a key feature of the PIGD subtype, while reduced VN-AUD connectivity may characterize the TD subtype.

Correlation Between Substantia Nigra Hyperechogenicity and Iron Metabolism in the Postural Instability Gait Difficulty Subtype of Parkinson's Disease.

The correlation between substantia nigra (SN) hyperechogenicity on transcranial sonography (TCS) and serum iron metabolism parameters in patients with the postural instability gait difficulty (PIGD) subtype of Parkinson's disease (PD) was investigated so as to explore the pathological mechanism of SN hyperechogenicity. The study enrolled 95 PIGD patients recruited by the Parkinson's Disease Specialty in the Second Affiliated Hospital of Soochow University during June 2019-2021. On the basis of the TCS results, the PIGD patients were assigned to the PD with SN hyperechogenicity (SN+) group (n=60) and PD without SN hyperechogenicity (SN-) group (n=35). Meanwhile, 49 sex- and age-matched healthy individuals were included in the control group. All participants underwent blood tests. Differences in the iron metabolism parameters among the three groups and the correlation between SN hyperechogenicity and serum iron metabolism parameters were analyzed. Serum ferritin, ceruloplasmin and transferrin levels were lower in the SN+ and SN- groups than in the control group (all p values <0.001). The serum ceruloplasmin level was lower in the SN+ group (0.23 [0.20, 0.25] g/L) than in the SN- group (0.25 [0.22, 0.29] g/L) (p=0.001), and the proportion of patients with an abnormal ceruloplasmin level was higher in the SN+ group than in the SN- group (43.3% [26/60] vs. 14.3% [5/35], χ2=8.484, p=0.004). Moreover, the SN hyperechogenicity area was negatively correlated with the serum transferrin level (r=-0.428, p < 0.001). Decreased serum ceruloplasmin levels may be associated with SN hyperechogenicity development in PIGD patients. The SN hyperechogenicity area is negatively correlated with the serum transferrin level.

Altered functional connectivity of the primary motor cortex in tremor dominant and postural instability gait difficulty subtypes of early drug-naive Parkinson's disease patients.

The primary motor cortex (M1) is an important hub in the motor circuitry of Parkinson's disease (PD), but the subregions' function and their correlation to tremor dominant (TD) and postural instability and gait disturbance (PIGD) with PD remain unclear. This study aimed to determine whether the functional connectivity (FC) of the M1 subregions varied between the PD and PIGD subtypes. We recruited 28 TD patients, 49 PIGD patients, and 42 healthy controls (HCs). M1 was divided into 12 regions of interest using the Human Brainnetome Atlas template to compare FC among these groups. Compared with HCs, TD and PIGD patients exhibited increased FC between the left upper limb region (A4UL_L) and the right caudate nucleus (CAU)/left putamen (PUT), between the right A4UL (A4UL_R) and the left anterior cingulate and paracingulate gyri (ACG)/bilateral cerebellum4_5 (CRBL4_5)/left PUT/right CAU/left supramarginal gyrus/left middle frontal gyrus (MFG), as well as decreased connectivity between the A4UL_L and the left postcentral gyrus and the bilateral cuneus, and between the A4UL_R and the right inferior occipital gyrus. TD patients showed increased FC between the right caudal dorsolateral area 6 (A6CDL_R) and the left ACG/right MFG, between the A4UL_L and the right CRBL6/right middle frontal gyrus, orbital part/bilateral inferior frontal gyrus, and orbital part (ORBinf), and between the A4UL_R and the left ORBinf/right MFG/right insula (INS). PIGD patients displayed increased connectivity between the A4UL_L and the left CRBL4_5. Compared with PIGD patients, TD patients exhibited increased connectivity between the A6CDL_R and the left ACG/right MFG and between the A4UL_R and the left ACG/left ORBinf/right INS/right MFG. Furthermore, in TD and PIGD groups, the FC strength between the A6CDL_R and right MFG was negatively correlated with PIGD scores, while the FC strength between the A4UL_R and left ORBinf/right INS was positively correlated with TD scores and tremor scores. Our results demonstrated that early TD and PIGD patients share some common injury and compensatory mechanisms. TD patients occupied more resources in the MFG, ORBinf, INS, and ACG, which can be used as biomarkers to distinguish them from PIGD patients.

Serum neurofilament light chain and postural instability/gait difficulty (PIGD) subtypes\xa0of Parkinson\u2019s disease in the MARK-PD study

The PIGD (postural instability / gait difficulty) subtype of Parkinson´s disease (PD) is associated with faster cognitive and motor decline. So far, there are no quantifiable biomarkers to aid clinical subtyping. Neurofilament light chain (NfL) is a highly specific marker of neuro-axonal damage and can be assessed in blood. Here, we investigated if serum NfL concentrations are associated with PIGD subtype and PIGD scores in PD patients at advanced disease stages. Furthermore, we evaluated if serum NfL is associated with motor and cognitive function assessed with MDS-UPDRS part III and Montreal cognitive assessment (MoCA). Serum NfL levels were analyzed with Single Molecule Assays (Simoa) in blood of 223 PD patients from the bioMARKers in Parkinson’s Disease (MARK-PD) study. Serum NfL concentrations were higher in PIGD patients independent of age, sex and disease duration. In linear regression analysis, serum NfL levels were associated with MoCA, MDS-UPDRS III and PIGD scores in unadjusted models, but remained significant after adjustment only with PIGD scores. In conclusion, increased serum NfL levels were associated with PIGD subtype and PIGD scores in patients with advanced PD.

Sensor-Based and Patient-Based Assessment of Daily-Living Physical Activity in People with Parkinson's Disease: Do Motor Subtypes Play a Role?

The benefits of daily-living physical activity are clear. Nonetheless, the relationship between physical activity levels and motor subtypes of Parkinson’s disease (PD), i.e., tremor dominant (TD) and postural instability gait difficulty (PIGD), have not been well-studied. It is also unclear if patient perspectives and motor symptom severity are related to objective, sensor-based assessment of daily-living activity in those subtypes. To address these questions, total daily-living physical activity was quantified in 73 patients with PD and 29 healthy controls using a 3D-accelerometer worn on the lower back for at least three days. We found that individuals with the PIGD subtype were significantly less active than healthy older adults (p = 0.007), unlike individuals with the TD subtype. Among the PIGD subtype, higher daily physical activity was negatively associated with more severe ON bradykinesia (rS = -0.499, p = 0.002), motor symptoms (higher ON MDS-UPDRS (Unified Parkinson’s Disease Rating Scale motor examination)-III scores), gait difficulties (rS = -0.502, p = 0.002), motor complications (rS = 0.466, p = 0.004), and balance (rS = 0.519, p = 0.001). In contrast, among the TD subtype, disease-related characteristics were not related to daily-living physical activity. Intriguingly, physical activity was not related to self-report of ADL difficulties (scores of the MDS-UPDRS Parts I or II) in both motor subtypes. These findings highlight the importance of objective daily-living physical activity monitoring and suggest that self-report does not necessarily reflect objective physical activity levels. Furthermore, the results point to important differences in factors related to physical activity in PD motor subtypes, setting the stage for personalized treatment programs.

Alteration of Tremor Dominant and Postural Instability Gait Difficulty Subtypes During the Progression of Parkinson's Disease: Analysis of the PPMI Cohort.

Background: Classifying PD into tremor dominant (TD) and postural instability gait difficulty (PIGD) subtypes may have several limitations, such as its diagnostic inconsistency and inability to reflect disease stage. In this study, we investigated the patterns of progression and dopaminergic denervation, by prospective evaluation at regular time intervals.Methods: 325 PD dopamine replacement drug-naïve patients (age 61.2 ± 9.7, M:F = 215:110) were enrolled. Patients were grouped into TD, indeterminant, and PIGD subtypes. Clinical parameters and I-123 FP-CIT SPECT images of each groups were analyzed and compared at baseline, 1, 2, and 4 years of follow up periods.Results: Baseline I-123 FP-CIT uptakes of the striatum were significantly higher in the TD group compared with the indeterminant group and PIGD group (p < 0.01). H & Y stage and MDS-UPDRS part III scores of the indeterminant group were significantly worse at baseline, compared with the TD and PIGD groups (p < 0.001 and p < 0.01, respectively), and MDS-UPDRS part II scores of the indeterminant group were significantly worse than the PIGD group (p < 0.001). There were no other significant differences of age, gender, weight, duration of PD, SCOPA-AUT, MOCA, usage of dopamine agonists, and levodopa equivalent daily doses at baseline. After 4 years of follow up, there were no differences of I-123 FP-CIT uptakes or clinical parameters, except for the MDS-UPDRS part II between the TD and indeterminant group (p < 0.05). The motor-subtypes were reevaluated at the 4 years period, and the proportion of patients grouped to the PIGD subtype increased. In the reevaluated PIGD group, MDS-UPDRS part II score (p < 0.001), SCOPA-AUT (p < 0.001), the proportion of patients who developed levodopa induced dyskinesia were higher than the reevaluated TD group, and the striatal I-123 FP-CIT uptakes were significantly lower (p < 0.01).Conclusion: There are no significant differences of symptoms and dopaminergic innervation between the TD and PIGD group after a certain period of follow up. Significant portion of patients switched from the TD subtype to the PIGD subtype during disease progression, and had a worse clinical prognosis.

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

ObjectiveUric 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. MethodsFasting 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. ResultsMost 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). ConclusionHigher 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.

Interoceptive processing deficit: A behavioral marker for subtyping Parkinson’s disease

BackgroundNon-motor symptoms in Parkinson's disease (PD), such as cognitive, emotional, autonomic and somatosensory alterations, are not ubiquitous but vary between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes of the syndrome. Non-motor phenomena (e.g., anxiety, depression and apathy) have been related to representation of autonomic and somatosensory sensations (interoception), and recent findings suggest interoceptive deficits in PD. ObjectivesTo test whether interoceptive processing is differently affected in TD and PIGD phenotypes, by assessing both interoceptive accuracy and sensibility in PD patients with TD and PIGD subtypes, and in healthy controls. MethodsInteroceptive accuracy was measured by the heartbeat perception task requiring participants to count their own heartbeats in a given time interval. A time-estimation, control task was also administered asking participants to count the seconds in a set period of time. Interoceptive sensibility was assessed by a questionnaire of subjective interoception. Finally, the patients underwent measures of anxiety, depression, apathy and anhedonia, and impulsive-compulsive disturbances. ResultsThe main results showed reduced interoceptive accuracy and sensibility in TD patients relative to both PIGD patients and healthy controls. Reduced interoceptive accuracy of TD group was a reliable result since their performance on the time estimation control task was comparable to that of both PIGD patients and healthy controls. ConclusionsThese findings demonstrate that the behavioural assessment of different aspects of interoceptive processing can provide with a further marker for subtyping patients with PD.

Do cognition and other non-motor symptoms decline similarly among patients with Parkinson's disease motor subtypes? Findings from a 5-year prospective study.

Among patients with Parkinson's disease (PD), a wide range of motor and non-motor symptoms (NMS) are evident. PD is often divided into tremor dominant (TD) and postural instability gait difficulty (PIGD) motor subtypes. We evaluated the effect of disease duration and aimed to characterize whether there are differences in the deterioration of cognitive function and other NMS between the PIGD and TD subtypes. Sixty-three subjects were re-evaluated at the follow-up visit about 5years after baseline examination. Cognitive function and other NMS were assessed. At follow-up, the PIGD and TD groups were similar with respect to medications, comorbidities and disease-related symptoms. There was a significant time effect for all measures, indicating deterioration and worsening in both groups. However, cognitive scores, particularly those related to executive function, became significantly worse in the PIGD with a more moderate decrease in the TD group. For example, the computerized global cognitive score declined in the PIGD group from 94.21±11.88 to 83.91±13.76, p<0.001. This decline was significantly larger (p=0.03) than the decrease observed in the TD group (96.56±10.29 to 92.21±14.20, p=0.047). A significant group×time interaction effect was found for the change in global cognitive score (p=0.047), the executive function index (p=0.002) and accuracy on a motor-cognitive catch game (p=0.008). In contrast, several NMS including depression, health-related quality of life and fear of falling deteriorated in parallel in both subtypes, with no interaction effect. The present findings highlight the difference in the natural history of the disease between the two PD "motor" subtypes. While the PIGD group demonstrated a significant cognitive decline, especially in executive functions, a more favorable course was observed in the TD subtype. This behavior was not seen in regards to the other NMS.

Subtypes evaluation of motor dysfunction in Parkinson’s disease using neuromelanin-sensitive magnetic resonance imaging

Parkinson’s disease (PD) is characterized by the loss of neuromelanin (NM)-containing neurons in the substantia nigra pars compacta (SNc), and it is divided into two motor subtypes: the postural instability gait difficulty (PIGD) and the tremor dominant (TD) subtypes. With NM-sensitive Magnetic Resonance Imaging (NM-MRI), investigators have been able to accurately detect signal attenuation in SNc of PD; however, the difference of NM loss between PIGD and TD subtypes is still unclear. Thus, the aim of this study was to evaluate the differences in NM-MRI between PD motor subtypes. PD patients were classified into PIGD (n=14) and TD groups (n=9); 20 age and sex matched controls were recruited. We compared the signal intensity contrast ratios in medial and lateral regions of the SNc using NM-MRI in PIGD, TD, and controls, respectively. Remarkable signal attenuation was observed in the lateral part of SNc in PD when compared with the controls, and we were able to detect more severe signal attenuation in the medial part of SNc in PIGD patients in comparison with that in the TD group. Also, the medial part of SNc, ipsilateral to the most clinically affected side, showed the highest power to discriminate the PD motor subtypes (AUC, 81%; sensitivity, 71.4%; specificity, 77.8%). Our results indicated a potential diagnostic value of NM-MRI to discriminate the PD motor subtypes, providing new evidence for the neuropathology-based differences between the two subtypes.

Relationship between the plasma levels of neurodegenerative proteins and motor subtypes of Parkinson's disease.

The aim of our study is to examine the plasma levels of the four kinds of neurodegenerative proteins in plasma: α-syn, T-tau, P-tau181, and Aβ-42 in Parkinson's disease (PD) and to evaluate the relationship between their plasma levels and PD motor subtypes. 84 patients with PD were enrolled in our study, and finally, 73 of them were classified into the tremor-dominant subtype (TD) and the postural instability gait difficulty subtype (PIGD). Their motor performance was evaluated by a series of clinical assessments: Freezing of Gait Questionnaire (FOGQ), Timed Up and Go (TUGs), Tinetti balance, and Tinetti gait. Plasma levels of these proteins were measured by enzyme-linked immunosorbent assay (ELISA). The plasma level of α-syn was significantly higher in PD patients when compared to controls (p=0.004), and significantly higher in the PIGD group when compared to the TD group (p=0.03). While the plasma level of Aβ-42 was significantly lower in PD patients than in controls (p=0.002), and significantly lower in the PIGD group than in the TD group (p=0.05). In PD patients, the plasma level of α-syn (r=-0.355, p<0.001) was significantly related to the severity of Tenitti Gait score, even after performing multiple linear regression (p=0.002). While the plasma level of Aβ-42 (r=-0.261, p<0.05) was significantly associated with the severity of PIGD score and remained correlate when performed multiple linear regression (p=0.005). The patients with PIGD subtype are characterized with a lower level of plasma Aβ-42 and a higher plasma level of α-syn, which may be used as biomarkers for diagnosis and progression of the subtypes of PD.

Subcortical Volumes Differ in Parkinson's Disease Motor Subtypes: New Insights into the Pathophysiology of Disparate Symptoms.

Objectives: Patients with Parkinson’s disease (PD) can be classified, based on their motor symptoms into the Postural Instability Gait Difficulty (PIGD) subtype or the Tremor Dominant (TD) subtype. Gray matter changes between the subtypes have been reported using whole brain Voxel-Based Morphometry (VBM), however, the evaluation of subcortical gray matter volumetric differences between these subtypes using automated volumetric analysis has only been studied in relatively small sample sizes and needs further study to confirm that the negative findings were not due to the sample size. Therefore, we aimed to evaluate volumetric changes in subcortical regions and their association with PD motor subtypes.Methods: Automated volumetric magnetic resonance imaging (MRI) analysis quantified the subcortical gray matter volumes of patients with PD in the PIGD subtype (n = 30), in the TD subtype (n = 30), and in 28 healthy controls (HCs).Results: Significantly lower amygdala and globus pallidus gray matter volume was detected in the PIGD, as compared to the TD subtype, with a trend for an association between globus pallidus degeneration and higher (worse) PIGD scores. Furthermore, among all the patients with PD, higher hippocampal volumes were correlated with a higher (better) dual tasking gait speed (r = 0.30, p < 0.002) and with a higher global cognitive score (r = 0.36, p < 0.0001). Lower putamen volume was correlated with a higher (worse) freezing of gait score (r = −0.28, p < 0.004), an episodic symptom which is common among the PIGD subtype. As expected, differences detected between HCs and patients in the PD subgroups included regions within the amygdala and the dorsal striatum but not the ventral striatum, a brain region that is generally considered to be more preserved in PD.Conclusions: The disparate patterns of subcortical degeneration can explain some of the differences in symptoms between the PD subtypes such as gait disturbances and cognitive functions. These findings may, in the future, help to inform a personalized therapeutic approach.

White matter changes and the development of motor phenotypes in de novo Parkinson's Disease

BackgroundParkinson's Disease (PD) patients are usually divided into Tremor Dominant (TD) and Postural Instability/Gait Difficulty (PIGD) subtypes. The latter is characterized by axial motor symptoms and worse outcomes, possibly also because of comorbid white matter disease. Therefore, the current study investigated the importance of Age-Related White Matter Changes (ARWMCs) in the development of different PD motor phenotypes. MethodsThe present 4-year longitudinal study recruited 63 de novo PD patients, who underwent MRI at the time of the diagnosis to rate ARWMCs. Motor subtypes (PIGD or TD) were evaluated at baseline visit, and after 2 and 4years. Age, gender, UPDRS part III total score, comorbidities and ARWMC total score were included in a mixed effect logistic regression model for repeated measures. ResultsThe likelihood of being PIGD subtype during the study period was associated with higher ARWMC total score (OR=2.743; 95%CI=1.137–7.802), but not with age (OR=0.967; 95%CI=0.818–1.143), female gender (OR=0.169; 95%CI=0.014–1.970), UPDRS part III total score (OR=1.942; 95%CI=0.888–13.470), and comorbidities (OR=2.979; 95%CI=0.560–15.849). ConclusionMotor dysfunction in PD is apparently multifactorial and, in particular, comorbid white matter disease might concur in the development of axial impairment.

Microstructural Changes within the Basal Ganglia Differ between Parkinson Disease Subtypes.

Diffusion tensor imaging (DTI) of the substantia nigra has shown promise in detecting and quantifying neurodegeneration in Parkinson disease (PD). It remains unknown, however, whether differences in microstructural changes within the basal ganglia underlie PD motor subtypes. We investigated microstructural changes within the basal ganglia of mild to moderately affected PD patients using DTI and sought to determine if microstructural changes differ between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes. Fractional anisotropy, mean diffusivity, radial, and axial diffusivity were obtained from bilateral caudate, putamen, globus pallidus, and substantia nigra of 21 PD patients (12 TD and 9 PIGD) and 20 age-matched healthy controls. T-tests and ANOVA methods were used to compare PD patients, subtypes, and controls, and Spearman correlations tested for relationships between DTI and clinical measures. We found our cohort of PD patients had reduced fractional anisotropy within the substantia nigra and increased mean and radial diffusivity within the substantia nigra and globus pallidus compared to controls, and that changes within those structures were largely driven by the PIGD subtype. Across all PD patients fractional anisotropy within the substantia nigra correlated with disease stage, while in PIGD patients increased diffusivity within the globus pallidus correlated with disease stage and motor severity. We conclude that PIGD patients have more severely affected microstructural changes within the substantia nigra compared to TD, and that microstructural changes within the globus pallidus may be particularly relevant for the manifestation of the PIGD subtype.

Regional homogeneity alterations differentiate between tremor dominant and postural instability gait difficulty subtypes of Parkinson's disease.

Parkinson's disease (PD) can be classified into the tremor dominant (TD) subtype and the postural instability gait difficulty (PIGD) subtype, which present with different clinical courses and prognoses. However, the symptom-specific intrinsic neural mechanisms underlying the subtypes of PD still remain elusive. In the current study, we utilized resting-state fMRI (rs-fMRI) combined with the regional homogeneity (ReHo) method to investigate the modulations of neural activity in 13 patients with predominantly PIGD (p-PIGD) and 15 patients with predominantly TD (p-TD) in the resting state. Compared with healthy controls, the p-PIGD and the p-TD groups both displayed ReHo changes in the default mode network (DMN). By contrast, the p-TD group exhibited more ReHo alterations in the cerebellum involved in the cerebello-thalamo-cortical (CTC) loops, whilst the p-PIGD group in extensive cortical and sub-cortical areas, including the frontal, parietal, occipital, temporal, limbic lobes, basal ganglia and thalamus, which are involved in the striatal-thalamo-cortical (STC) loops. Direct comparison between the two groups showed significant ReHo alterations in the primary visual cortex. Our findings underscore the differential involvement of the STC and CTC circuits underlying the two subtypes of PD. Moreover, relatively widespread neural activity abnormality, especially in the motor-related regions as well as the visual network, is apparently a characteristic feature of PIGD symptoms. This study could shed light on the underlying pathophysiology and clinical heterogeneity of PD presentation.

Sexual dysfunction is associated with postural instability gait difficulty subtype of Parkinson's disease.

The pathophysiology of the postural instability gait difficulty (PIGD) subtype of Parkinson's disease (PD) is unclear. Information on the spectrum of non-motor symptoms (NMS) in PIGD phenotype is limited. Our objective is to compare the spectrum of NMS in PIGD subtype compared to non-PIGD subgroup in PD patients and to determine predictive factors that are associated with PIGD phenotype. A total of 432 PD patients comprising 158 PIGD and 274 non-PIGD patients were recruited. NMS burden (frequency and severity) was assessed using non-motor symptom scale (NMSS). In the univariable analysis, NMSS total score (P=0.0132), NMSS domain 3 (mood/apathy) score (P=0.0108), NMSS domain 5 (attention/memory) score (P=0.0048) and NMSS domain 8 (sexual function) score (P=0.0052) were significantly higher in the PIGD group than in the non-PIGD group. Using multivariable logistic regression, UPDRS tremor score, UPDRS PIGD score, H&Y staging score and NMSS domain 8 (sexual function) score were found to be significantly different in the PIGD group compared to the non-PIGD group. We disclosed for the first time that PIGD patients demonstrated a greater overall NMS burden and sexual dysfunction and was an independent predictor of PIGD phenotype. Early intervention of sexual dysfunction symptoms in PIGD patients may improve their clinical management.

Cognitive function and other non-motor features in non-demented Parkinson's disease motor subtypes.

Among patients with Parkinson's disease (PD), a wide range of non-motor symptoms (NMS) are evident. We assessed markers of NMS and explored their behavioral correlates with the tremor-dominant (TD) and postural instability gait difficulty (PIGD) subtypes. 110 non-demented patients with PD were evaluated and stratified into the PIGD and TD subtypes and, using stricter criteria, into predominant subgroups: p-PIGD (n = 31) and p-TD (n = 32). Non-motor signs that were assessed included cognitive function (pen and paper and a computerized battery), autonomic function (NMSQest and SCOPA-AUT), mood, and sleep. Health-related quality of life was evaluated using the PDQ-39. The p-PIGD subgroup had a higher score on the NMSQest (p = 0.033) and a higher score (i.e., worse) on the PDQ-39 (p-PIGD: 26.28 ± 12.47; p-TD: 16.93 ± 12.22; p = 0.004), compared to the p-TD subgroup, while these measures did not differ in the larger PIGD and TD group. The p-PIGD subgroup used more sleep medications compared to the p-TD subgroup (1.0 ± 1.39 vs. 0.41 ± 0.94, p = 0.05, respectively). Most cognitive scores were similar in both subgroups; however, the visuospatial components of the Montreal Cognitive Assessment and the computerized catch game were significantly worse among the p-PIGD subgroup. Mild associations were found between certain non-motor symptoms, but not cognitive function, and the PIGD score. Non-demented patients from the PIGD subtype experience more non-motor symptoms and poorer quality of life compared to the TD subtype. These findings suggest that the clinical management of non-motor and motor symptoms in patients with PD may be enhanced by a personalized approach.

Gait and balance in Parkinson's disease subtypes: objective measures and classification considerations.

Parkinson's disease (PD) is often divided into tremor dominant (TD) and postural instability gait difficulty (PIGD) subtypes. However, objective measures of gait (e.g., stride length, variability) and balance have not been well studied in these subtypes. To better understand these motor subtypes, we objectively quantified gait and balance and their behavioral correlates. 110 patients with PD underwent a clinical evaluation and were stratified into PIGD and TD subtypes. Participants walked under single and dual task conditions while wearing a single body-fixed sensor, both "OFF" and "ON" medications and at home for 3 days. We also examined performance-based tests of mobility, balance, and fall risk. Stricter criteria were also applied, dividing the subjects into predominant representative subgroups: p-PIGD and p-TD. Both the PIGD (n = 62) and TD (n = 42) groups and the p-PIGD (n = 31) and p-TD (n = 32) subgroups were similar with respect to basic disease characteristics (e.g., disease duration, p > 0.69). Surprisingly gait speed, stride length, and variability did not differ between the PIGD and TD groups (p > 0.05). In contrast, the p-PIGD group had reduced gait speed (under single and dual task conditions), shorter strides, increased stride variability, and decreased stride regularity (regularity: p-PIGD 0.66 ± 0.10; p-TD 0.74 ± 0.08; p = 0.003). The p-PIGD group also scored worse on performance-based tests, compared to the p-TD. Clinical assessments of the disturbances seen in patients with the PIGD subtype are not consistent with objective measures; overlapping between the groups is seen in many objective features of gait and balance. These findings suggest that the proposed alternate classification scheme may be useful.