Tremor Dominant Subtype Research Articles

Inhibitory motor dysfunction in parkinson's disease subtypes.

Parkinson's disease (PD) is divided into postural instability gait difficulty (PIGD) and tremor-dominant (TD) subtypes. Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of PD. To evaluate the differences of GABA levels between PD motor subtypes using MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS). COHORT.: SUBJECTS: PD patients were classified into PIGD (n = 13) and TD groups (n = 9); 16 age- and sex-matched healthy controls were also recruited. All subjects were right-handed. All subjects underwent an magnetic resonance spectroscopy scan including MEGA-PRESS at 3.0T. The detected GABA signal also contains signal from macromolecules (MM) and homocarnosine, so it is referred to as GABA+. GABA + levels and Creatine (Cr) levels were quantified in the left basal ganglia (BG) using Gannet 2.0 by Tao Gong. Differences in GABA + levels between the three groups were analyzed using analysis of covariance. The relationship between GABA levels and a unified PD rating scale (UPDRS) was also analyzed. GABA + levels were significantly lower in left BG regions of PD patients compared with healthy controls (P < 0.001). In PD patients, the GABA concentration was lower in the TD group than the PIGD group (P = 0.019). Cr levels in PIGD and TD were lower than controls (P = 0.020; P = 0.002). A significant negative correlation was found in PIGD between GABA levels and UPDRS (r = -0.572, P = 0.041), while no correlation was found in TD (r = -0.339, P = 0.372). Low BG GABA levels in PD patients, and differences between PIGD/TD patients, suggest that GABAergic dysfunction may play an important role in the pathogenesis of Parkinson's disease. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1610-1615.

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.

Motor subtype changes in early Parkinson's disease

IntroductionDistinct motor subtypes of Parkinson's disease (PD) have been described through both clinical observation and through data-driven approaches. However, the extent to which motor subtypes change during disease progression remains unknown. Our objective was to determine motor subtypes of PD using an unsupervised clustering methodology and evaluate subtype changes with disease duration. MethodsThe Parkinson's Progression Markers Initiative database of 423 newly diagnosed PD patients was utilized to retrospectively identify unique motor subtypes through a data-driven, hierarchical correlational clustering approach. For each patient, we assigned a subtype to each motor assessment at each follow-up visit (time points) and by using published criteria. We examined changes in PD subtype with disease duration using both qualitative and quantitative methods. ResultsFive distinct motor subtypes were identified based on the motor assessment items and these included: Tremor Dominant (TD), Axial Dominant, Appendicular Dominant, Rigidity Dominant, and Postural and Instability Gait Disorder Dominant. About half of the patients had consistent subtypes at all time points. Most patients met criteria for TD subtype soon after diagnosis. For patients with inconsistent subtypes, there was an overall trend to shift away from a TD phenotype with disease duration, as shown by chi-squared test, p < 0.001, and linear regression analysis, p < 0.05. ConclusionThese results strongly suggest that classification of motor subtypes in PD can shift with increasing disease duration. Shifting subtypes is a factor that should be accounted for in clinical practice or in clinical trials.

Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype.

Parkinson’s disease (PD) patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA), a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT) availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36), intermediate (I, n = 22), and tremor-dominant (TD, n = 17) subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001) and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25%) and I (45%) patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

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.

Weight Change Is a Characteristic Non-Motor Symptom in Drug-Naïve Parkinson’s Disease Patients with Non-Tremor Dominant Subtype: A Nation-Wide Observational Study

Despite the clinical impact of non-motor symptoms (NMS) in Parkinson’s disease (PD), the characteristic NMS in relation to the motor subtypes of PD is not well elucidated. In this study, we enrolled drug-naïve PD patients and compared NMS between PD subtypes. We enrolled 136 drug-naïve, early PD patients and 50 normal controls. All the enrolled PD patients were divided into tremor dominant (TD) and non-tremor dominant (NTD) subtypes. The Non-Motor Symptom Scale and scales for each NMS were completed. We compared NMS and the relationship of NMS with quality of life between normal controls and PD patients, and between the PD subtypes. Comparing with normal controls, PD patients complained of more NMS, especially mood/cognitive symptoms, gastrointestinal symptoms, unexplained pain, weight change, and change in taste or smell. Between the PD subtypes, the NTD subtype showed higher total NMS scale score and sub-score about weight change. Weight change was the characteristic NMS related to NTD subtype even after controlled other variables with logistic regression analysis. Even from the early stage, PD patients suffer from various NMS regardless of dopaminergic medication. Among the various NMS, weight change is the characteristic NMS associated with NTD subtype in PD patients.

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.

Structural Brain Alterations in Motor Subtypes of Parkinson's Disease: Evidence from Probabilistic Tractography and Shape Analysis.

Background and ObjectivesThe postural instability and gait disorder (PIGD) and tremor dominant (TD) subtypes of Parkinson’s disease (PD) show different patterns of alterations in functional connectivity (FC) between specific brain regions. This study aimed to investigate the relation between symptomatic heterogeneity in PD and structural alterations underlying these FC changes.Methods68 PD patients classified as PIGD (n = 41) or TD (n = 19) and 19 age-matched controls underwent Magnetic Resonance Imaging (MRI). Diffusion-weighted images were used to assess fractional anisotropy (FA) and mean diffusivity (MD) at the whole-brain level using tract-based spatial statistics (TBSS). In addition, structural connectivity was assessed between regions that previously showed altered FC using probabilistic tractography. Anatomical images were used to determine shape and volume of the putamen, caudate and pallidum.ResultsTBSS revealed widespread FA reductions in PIGD compared to controls involving the superior longitudinal fasciculi and corpus callosum. No such differences were found in TD. Both PD subgroups had increased MD compared to controls in tracts connecting the left caudate with the bilateral ventral putamen. TD patients additionally showed increased MD compared to PIGD and controls in tracts connecting the right inferior parietal lobule with the right premotor and primary motor cortex, which previously showed altered FC. We also found grey matter atrophy in the rostrodorsal head of the caudate in PIGD compared to controls.ConclusionMicrostructural changes in white matter tracts, particularly in those connecting striatal sub-areas, partly underlie FC alterations in PD subtypes. Caudate shape alterations further implicate the striatum in PIGD pathophysiology.

Postural instability and gait are associated with severity and prognosis of Parkinson disease.

Differences in disease progression in Parkinson disease (PD) have variously been attributed to 2 motor subtypes: tremor-dominant (TD) and postural instability and gait difficulty (PIGD)-dominant (PG). We evaluated the role of these phenotypic variants in severity and progression of nondopaminergic manifestations of PD and motor complications. Linear mixed models were applied to data from the Profiling Parkinson's disease (PROPARK) cohort (n = 396) to evaluate the effect of motor subtype on severity and progression of cognitive impairment (Scales for Outcomes in Parkinson's disease [SCOPA]-Cognition [SCOPA-COG]), depression (Hospital Anxiety and Depression Scale [HADS]), autonomic dysfunction (SCOPA-Autonomic [SCOPA-AUT]), excessive daytime sleepiness, psychotic symptoms (SCOPA-Psychiatric Complications [SCOPA-PC]), and motor complications. In first analyses, subtype as determined by the commonly used ratio of tremor over PIGD score was entered as a factor, whereas in second analyses separate tremor and PIGD scores were used. Results were verified in an independent cohort (Estudio Longitudinal de Pacientes con Enfermedad de Parkinson [ELEP]; n = 365). The first analyses showed that PG subtype patients had worse SCOPA-COG, HADS, SCOPA-AUT, SCOPA-PC, and motor complications scores, and exhibited faster progression on the SCOPA-COG. The second analyses showed that only higher PIGD scores were associated with worse scores for these variables; tremor score was not associated with severity or progression of any symptom. Analyses in the independent cohort yielded similar results. In contrast to PIGD, which consistently was associated with greater severity of nondopaminergic symptoms, there was no evidence of a benign effect of tremor. Our findings do not support the use of the TD subtype as a prognostic trait in PD. The results showed that severity of PIGD is a useful indicator of severity and prognosis in PD by itself.

Clinical findings and genetic screening for copy number variation mutations in a cohort of South African patients with Parkinson's disease.

Parkinson's disease (PD), with a prevalence of up to 4% in Western countries, appears to be less common in Africa, possibly in part because of genetic factors. African studies investigating the genetic causation of PD are limited. To describe the clinical and genetic findings in a group of black South African patients with PD. All black African patients with PD from a tertiary hospital neurology clinic were examined. Symptoms were scored according to the Unified Parkinson's Disease Rating Scale (UPDRS), and patients were classified according to motor features. Genomic DNA was extracted and multiplex ligation-dependent probe amplification was used for detection of copy number variation (CNV) mutations in the known PD-causing genes. Sixteen patients were identified (ages 56 - 82 years). Three had a family history of PD. Classification into motor subtypes showed 44% mixed, 31% akinetic-rigid, and 25% tremor-dominant subtypes. UPDRS scores ranged from 7 to 88, with dementia in 20%. No patient had G2019SLRRK2and A30PSNCAmutations, and all except one had no CNV mutations in the known PD-causing genes. A female patient (age of onset 50 years, no family history) had aparkingene heterozygous deletion of exon 4. She had hyperreflexia, bilateral Hoffmann's reflexes, normal plantar responses and no dystonia. This group of black African patients showed similar characteristics to patients in Western studies, possibly with a higher proportion having tremor-dominant disease. Genetic analysis showed oneparkingene mutation. The limited knowledge on PD-causing genes and mutations in black populations warrants further studies involving next-generation sequencing approaches.

How stable are Parkinson's disease subtypes in de novo patients: Analysis of the PPMI cohort?

ObjectiveTo determine the frequency and stability over time of the subgroup characterization of the tremor dominant (TD) versus postural instability gait disorder dominant (PIGD) Parkinson's disease (PD) in de novo patients. BackgroundThere is a substantial body of literature on the clinical sub classification of PD into TD versus PIGD subtype. However, there are limited data on the stability of this classification especially in early disease. MethodsParkinson's Progression Markers Initiative (PPMI) is a longitudinal case control study of de novo, untreated PD participants at enrollment. Participants undergo a number of assessments including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). TD versus PIGD subtype was defined based on the previously published formula. We report one-year analysis data. Results320 of 423 PD recruited subjects had data on subtype classification at year 1 and were included in the analysis. 228 (71%) were classified as TD, 56 (18%) as PIGD and 36 (11%) as indeterminate at baseline. At 12 months, 39% PIGD and 18% TD shifted subtypes: 29% PIGD shifted to TD and 11% to Indeterminate; 10% TD shifted to PIGD and 8% to Indeterminate. The classification was not affected by the dopaminergic treatment (p = 0.59). ConclusionsTD versus PIGD subtype classification has substantial variability over first year in PD de novo cohort specifically for PIGD subtype. Dopaminergic therapy does not impact the change of the PD subtype. This instability has to be taken into consideration specifically when establishing correlations with the biomarkers and for long term prognostication.

Motor Subtype as a Predictor of Future Working Memory Performance in Idiopathic Parkinson's Disease.

Parkinson’s disease is a progressive neurodegenerative disorder associated with reduced spatial and verbal working memory ability. There are two established motor subtypes of PD, tremor dominant (TD) and postural instability and gait difficulty (PIGD). This study used structural equation modelling to explore the longitudinal relationship between the two subtypes and working memory assessed at a 2-year follow-up. The study comprised 84 males and 30 females (N = 114), aged between 39 and 85 (M = 64.82, SD = 9.23) with confirmed PD. There was no significant relationship between motor subtype at Time 1 and working memory at Time 2. Postural symptom severity at Time 1 predicted Time 2 spatial working memory for the PIGD subtype (p = .011) but not the TD subtype. Tremor symptoms were not associated with Time 2 working memory in either subtype. Predictive significance of Time 1 postural symptoms only in the PIGD subtype suggests an interaction between symptom dominance (subtype) and symptom severity that future subtyping should consider. This study demonstrates a predictive relationship between postural difficulties and working memory performance assessed at a 2-year follow-up. Establishing physical symptoms as predictors of cognitive change could have significant clinical importance.

How Do I Examine for Re-Emergent Tremor?

Although rest tremor is the typical form of tremor associated with Parkinson's disease (PD), particularly the tremor-dominant subtype,1 parkinsonian patients may also exhibit postural tremor. In many parkinsonian patients, this postural tremor emerges after a latency of a few seconds or even minutes. In our original description, we coined the term "re-emergent tremor" to differentiate this postural tremor from essential tremor, which occurs without any latency, and to link it to PD rest tremor that is "reset" after some latency when a new holding posture is assumed.2 The relationship of this re-emergent tremor to the typical rest tremor is supported by the observation that this tremor shares many characteristics with the typical rest tremor, such as the same, 3 to 5-Hz frequency, occasional supinating-pronating component, and relatively good response to dopaminergic therapy. Rarely, postural tremor, occurring after a brief (2-4 seconds) latency can be seen even without observable rest tremor.3 In most patients with PD, it is the postural (re-emergent) tremor that is more troublesome for them than the typical rest tremor, because this re-emergent tremor interferes with their ability to hold objects, such as newspapers, against gravity and results in spilling of liquids. Postural tremor of PD is often misdiagnosed as essential tremor, and this diagnostic challenge can be further confounded when both conditions coexist.4 When that occurs, the postural tremor is present without latency, although the amplitude may gradually increase as the underlying re-emergent tremor becomes more evident.

Functional connectivity alterations in the motor and fronto-parietal network relate to behavioral heterogeneity in Parkinson's disease

BackgroundInsight into the neural mechanisms of postural instability and gait disorder (PIGD) and tremor dominant (TD) subtypes in Parkinson's disease (PD) is indispensable for generating pathophysiology hypotheses underlying this phenotyping. This cross-sectional study aimed to gain insight in specific and brain-wide functional connectivity (FC) and its correlation with motor deterioration and preservation in PD subtypes. Methods68 PD patients classified as PIGD (n = 41), TD (n = 19) or indeterminate (n = 8) and 19 age-matched controls underwent resting-state fMRI while ‘off’ medication to assess FC between regions of interest (ROIs) in the motor and fronto-parietal network and on a whole-brain level using a parcellated template. FC alterations were correlated with quantitative behavioral measures. ResultsROI-analyses showed decreased FC between the caudate and putamen in PIGD compared to TD. This hypo-connectivity was correlated with behavioral impairment. In contrast, TD-specific hyper-connectivity between motor cortical areas and the inferior parietal lobule correlated with less behavioral impairment, suggesting compensatory mechanisms. Both subgroups showed hyper-connectivity between the left supplementary motor area and pedunculopontine nucleus, whereas PIGD-specific right lateralized hyper-connectivity was shown between this nucleus and the premotor cortex. Whole-brain analyses revealed 65% hypo-connectivity and 35% hyper-connectivity in PIGD compared to TD. TD also revealed primarily hypo-connectivity compared to controls, but had more pronounced hyper-connectivity involving temporo-occipital areas. ConclusionThis multilevel analysis showed differential connectivity alterations in large scale neural networks and between motor and cognitive control areas that related to behavioral heterogeneity in PD, underscoring the classic TD-PIGD phenotypical classification.

A comparative study of oxidative stress markers between the tremor dominant and akinetic-rigid subtypes of patients with Parkinson's disease

A comparative study of oxidative stress markers between the tremor dominant and akinetic-rigid subtypes of patients with Parkinson's disease

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.

Heart rate variability shows different cardiovascular modulation in Parkinson's disease patients with tremor dominant subtype compared to those with akinetic rigid dominant subtype.

Parkinson's disease (PD) can present with different motor subtypes depending on the predominant symptoms (tremor or rigidity/bradykinesia). Slower disease progression and less cognitive decline are observed in tremor-dominant patients compared to those with akinetic-rigid subtype. Autonomic cardiovascular disorders have been described in parkinsonian patients, although the definite correlations with different subtypes of PD are not clear. In this context, heart rate variability (HRV) analysis represents a non-invasive and established tool in assessing cardiovascular autonomic modulation. We investigate cardiovascular autonomic modulation in PD patients with tremor dominant subtype in comparison to akinetic rigid dominant subtype subjects using HRV analysis. Twenty-eight PD patients (17 with tremor dominant subtype and 11 with akinetic rigid dominant subtype) were enrolled and compared to 17 age and sex-matched healthy controls. HRV was analyzed in time- and frequency-domains. Low-frequency (LF) values were significantly lower in the akinetic rigid dominant subtype than in the tremor dominant group [LF 41.4 ± 13.6 vs 55.5 ± 11.6 (p < 0.007)] indicating that the disease led to a more evident impairment of the baroreflex modulation of the autonomic outflow mediated by both sympathetic and parasympathetic systems in the first class of patients. These findings support the biological relevance of clinical subtypes supporting the idea of a different pathophysiological process between these subtypes. These differences also suggest that different subtypes may also result in different responses to therapy or in the possible development of cardiovascular side effects of dopaminergic drugs in these different populations.

Distal motor deficit contributions to postural instability and gait disorder in Parkinson's disease

Clinical subtypes in Parkinson's disease (PD) are often based on the presence of clustered motor symptoms. In contrast to the tremor dominant (TD) subtype, the postural instability and gait disorder (PIGD) subtype is characterized by predominantly axial motor involvement and increased cognitive impairment. It is, however, unclear if subtypes represent distinct underlying neuropathological mechanisms or reflect more severe disease progression. We aimed to clarify the validity of PD subtypes by investigating behavioral outcomes at multiple levels. Therefore, spatiotemporal kinematics of gait, upper and lower limb repetitive movements in combination with a balance and cognitive assessment were recorded in 73 patients with PD. We classified patients as PIGD (n=43), TD (n=22) or indeterminate (n=8) while ‘off’ medication and recruited 20 age-matched controls. Surprisingly, differences between PIGD and TD were more prominent during repetitive distal motor tasks than during gait. Gait impairment in PIGD was only shown by reduced step length and gait speed. However, motor scaling and coordination of distal movements were more affected in PIGD than in TD patients. PIGD patients also had impaired postural control compared to TD patients as shown by lower mini-BESTest scores. There were no cognitive differences between patient subgroups. Distal movement was not significantly different in TD patients from controls, except for greater movement asymmetry. The results indicate a widespread impairment within PIGD with more pronounced distal than axial motor deficits. This suggests involvement of different neurotransmitter systems in the neuropathology of PD subtypes, which are at least partially independent of disease progression.

Morphologic changes in the mesolimbic pathway in Parkinson's disease motor subtypes.

Parkinson's disease (PD) is a common neurodegenerative disorder associated with gray matter atrophy. Cortical atrophy patterns may further help distinguish between PD motor subtypes. Comparable differences in subcortical volumes have not been found. Twenty-one cognitively intact and treated PD patients, including 12 tremor dominant (TD) subtype, Nine postural instability gait dominant (PIGD) subtype, and 20 matched healthy control subjects underwent 3.0T high-resolution structural MRI scanning. Subcortical volumetric analysis was performed using FreeSurfer and shape analysis was performed with FIRST to assess for differences between PD patients and controls and between PD subtypes. No significant differences in subcortical volumes were found between motor PD subtypes, but comparing grouped PD patients with controls revealed a significant increase in hippocampal volume in PD patients (p=0.03). A significant shape difference was detected in the right nucleus accumbens (NAcc) between PD and controls and between motor subtypes. Shape differences were driven by positive deviations in the TD subtype. Correlation analysis revealed a trend between hippocampal volume and decreasing MDS-UPDRS (p=0.06). While no significant differences in subcortical volumes between PD motor subtypes were found, increased hippocampal volumes were observed in PD patients compared to controls. Right NAcc shape differences in PD patients were driven by changes in the TD subtype. These unexpected findings may be related to the effects of chronic dopaminergic replacement on the mesolimbic pathway. Further studies are needed to replicate and determine the clinical significance of such morphologic changes.