Tremor Dominant Group Research Articles

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.

Resting-state functional connectivity of subthalamic nucleus in different Parkinson's disease phenotypes

Previous studies showed that the subthalamic nucleus (STN) plays a crucial role in Parkinson's disease (PD) pathophysiology. During rest, PD phenotypes exhibit different STN functional connectivity. STN functional connectivity was examined in 31 PD patients [12 tremor-dominant (TD) and 19 posture instability gait difficulty (PIGD)] and 22 healthy controls (HC). Compared with controls and PIGD patients, the TD patients exhibited higher functional connectivity between the bilateral STN and the left cerebellar anterior lobe. Compared with the TD and HC groups, in the PIGD subgroup functional connectivity was lower between the left putamen and the STN, as well as between the pons and the STN. In the PIGD subgroup, functional connectivity was greater between the STN and bilateral occipital lobe, which positively correlated with PIGD scores in PD patients. Additionally, STN-cerebellum connectivity positively correlated with the tremor score, and STN-putamen connectivity negatively correlated with the PIGD score in PD patients. PD subtypes with distinguished STN functional connectivity might explain the various pathophysiological mechanisms in tremor and gait disorders. Increased coupling between the STN and cerebellum might underlie the neural substrate of PD tremors. Lower functional connectivity between the STN and putamen might underpin PD gait and posture disturbances, while higher functional connectivity between the STN and visual cortex might play a compensatory role.

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.

Local brain activity in different motor subtypes of Parkinson's disease with fMRI

To explore the changes of local brain activity in motor subtypes of Parkinson's disease (PD) with functional magnetic resonance imaging (fMRI). A total of 60 idiopathic PD and 30 age- and gender-matched normal controls were examined with resting-state fMRI from January 2013 to March 2014. All subjects gave their written informed consent for the study. The amplitude of low-frequency fluctuation (ALFF) was calculated to measure local brain activity. The PD patients were divided into two groups of tremor dominant (TD) and postural instability/gait difficulty (PIGD) (n = 30 each). All subjects gave their written in formed consent for the study.One-way ANOVA and post-hoc t-test were performed to detect the differences of local brain activity between PD and normal subjects. And the correlations were examined between ALFF, scores and levodopa dose. Compared with normal subjects, the TD group showed increased activity in bilateral cerebellums (-37, -47, -38), thalamus (-18, -17,0), pons (-3, -23, -37) and left precentral gyrus (-41, -30, 46) versus decreased activity in bilateral frontal lobes (-13, 69, 6), temporal lobes (-42, 18, -21), left insula (-32, 22, 2) and left anterior cingulated (-7, 32, -5). The PIGD group showed increased activity in right postcentral gyrus (63, -18, 39) and decreased activity in bilateral putamens (-24, 12, 3), pre-supplementary motor area (10, 10, 58), frontal lobes (15, -15, 57), temporal lobes (-39, 18, -3) and left insula (-29, 20, 11). Compared with PIGD, the TD group showed increased activity in temporal lobes, but decreased activity in frontal lobes. Additionally, ALFF in bilateral cerebellums and frontal lobes was positively correlated with TD scores while ALFF in left precentral gyrus, bilateral putamens and temporal lobes negatively correlated with TD scores. ALFF in bilateral frontal lobes and left temporal lobe was positively correlated with PIGD scores.However, in right postcentral gyrus and bilateral putamens, ALFF was negatively correlated with PIGD scores. The levodopa dose was positively correlated with frontal lobes and temporal lobe in TD and cerebellums and inferior parietal lobule in PIGD. A specific pattern of intrinsic activity in TD and PIGD may provide insights into neurophysiological mechanisms of PD motor subtypes. The changes of brain activity in TD are caused by the interaction between cerebello-thalamo-cortical circuit and basal ganglia loop while the changes in PIGD result largely from damaged basal ganglia loop.

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.

Evolution of mild cognitive impairment in Parkinson disease.

Editors' Note: In the study by Broeders et al. concerning cognitive impairment in Parkinson disease (PD), 2 different groups report their own experiences. Kano et al. propose that patients with rigidity-dominant PD may be more susceptible to developing cognitive impairment than those in the tremor-dominant group. The need to provide more specific inclusion and exclusion criteria and the need to use specific tests are Dr. Dyck's main concerns regarding the Dutch survey on small-fiber neuropathy. —Chafic Karam, MD, and Robert C. Griggs, MD Broeders et al.1 reported on the evolution of …

Selective use of low frequency stimulation in Parkinson's disease based on absence of tremor

High frequency stimulation (HFS) of the subthalamic nucleus is one of the most effective treatments for advanced Parkinson's disease (PD). HFS has provided beneficial improvements in the cardinal features of PD, but has not been proven as effective for addressing the axial predominant levodopa resistant symptoms, such as speech disturbances, gait disturbances, and postural instability. Recent studies have suggested that changes in stimulation parameters may influence differing PD symptoms. The purpose of this study was to compare the effects of low frequency stimulation (LFS) versus HFS on the Unified Parkinson's Disease Rating Scale (UPDRS), gait, balance, and verbal fluency. Eight tremor dominant and nine non-tremor dominant participants with bilateral deep brain stimulation of the subthalamic nucleus were tested off stimulation, during LFS, and during HFS. Results revealed that HFS significantly reduced UPDRS tremor score in the tremor dominant group; however no differences emerged within the non-tremor dominant group. No differences between groups or stimulation conditions were found for gait, balance, and verbal fluency measures. These results may suggest that HFS is better than LFS for reducing tremor in tremor dominant patients. However, patients with mild or no tremor show no acute differences in benefit from LFS as compared to HFS.

CLINICAL PHENOTYPE–SPECIFIC DIFFERENCES IN CEREBRAL HAEMODYNAMICS IN IDIOPATHIC PARKINSON'S DISEASE

IntroductionIdiopathic Parkinson's disease (IPD) exhibits significant heterogeneity in respect of both motor and non motor clinical features. The ‘neurovascular model’ implicates neurovascular mechanisms as key players in the neurodegenerative process.1...

Gray matter atrophy distinguishes between Parkinson disease motor subtypes

To assess differences in gray matter (GM) atrophy between 2 Parkinson disease (PD) subtypes: the tremor dominant (TD) subtype and the postural instability gait difficulty (PIGD) subtype. Patients were classified as belonging to the predominately PIGD (n = 30) or predominately TD (n = 29) subtype. Voxel-based morphometry was used to compare GM in these 2 subtypes and to evaluate correlations between predefined regions of interest and the degree of symptoms. In the regions where GM atrophy was associated with symptoms, the relationship between GM volumes and functional connectivity was examined. GM was reduced in the predominately PIGD group, compared with the predominately TD group, in areas that involve motor, cognitive, limbic, and associative functions (p < 0.05, false discovery rate corrected). Lower GM volumes in the pre-supplementary motor area (SMA) and in the primary motor area were associated with increased severity of PIGD symptoms (r = -0.42, p < 0.001; r = -0.38, p < 0.003, respectively). Higher GM volumes within the pre-SMA were associated with stronger functional connectivity between the pre-SMA and the putamen (r = 0.415, p < 0.025) in the patients with predominately PIGD. In patients with PD, PIGD symptoms are apparently associated with GM atrophy in motor-related regions and decreased functional connectivity. GM degeneration and a related decrease in spontaneous coactivation between cortical and subcortical motor-planning areas may partially account for the unique clinical characteristics of a subset of patients with PD.

Retinal nerve changes in patients with tremor dominant and akinetic rigid Parkinson’s disease

Parkinson disease is a multisystem neurodegenerative disease which involves not only basal ganglia and extrapyramidal system but also many other neurologic systems such as retinal ganglion cells. Optical coherence tomography (OCT) is a non-invasive method for assessment of retinal nerve fiber layer (RNFL) thickness and its changes in different diseases. To evaluate the RNFL thickness in patients with Parkinson disease (PD), we performed OCT in patients with PD and compared it with a control group. From October 2010 to July 2011, 27 PD patients (54 eyes) and 25 healthy persons (50 eyes) were entered to this analytical cross-sectional study according to the defined criteria. PD patients were categorized into two groups "akinetic rigid (AR) and tremor dominant (TD)". RNFL was divided into four quadrants and was assessed by OCT. Afterwards; the data were analyzed by bivariate and multivariate models. The RNFL thickness in PD was significantly lower than the control group. Also, the thicknesses of inferior and nasal quadrants of RNFL in TD group were significantly more than AR group. According to these findings, OCT can be used as a sensitive and objective marker for assessment of early neurodegenerative changes of PD and early initiation of neuroprotective treatments. Future studies with adequate sample sizes are recommended to investigate interactions between age, distribution of the disease and type of PD as well as the effects of individual factors.

Prevalence of depression in Parkinson's disease: Effects of disease stage, motor subtype and gender

Depression is one of the most common non-motor symptoms of Parkinson's disease (PD) with a large negative impact on the quality of life. Factors such as disease stage, subtype of PD and gender might play an important role in the prevalence of depression, but a large study investigating all these factors in a within-subject design is lacking. Therefore we studied a homogeneous group of 256 Dutch PD patients (60% men, mean age=65.12 (±9.6) years). In total, 36.3% of the subjects had a BDI-score indicative for a minor depression, while 12.9% had a major depression. Notably, only 8.6% of the minor depressed patients and 30.3% of the major depressed patients were taking antidepressants. A higher prevalence of depression was observed in the later stages of the disease. However, this finding was absent in a smaller subsample after correction for cognitive impairment. Our data did not show a difference in the prevalence of depression between the motor subtypes and showed a trend towards higher prevalence of depression in the tremor dominant group. There was no significant difference in the prevalence of depression between men and women. We will discuss the relevance of these results in relation to the findings of other studies.

A clinico-pathological study of subtypes in Parkinson's disease

We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25%), tremor dominant (31%), non-tremor dominant (36%) and rapid disease progression without dementia (8%) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70% of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.

Gait Analysis in Patients With Parkinson’s Disease: Relationship to Clinical Features and Freezing

Background: The purpose of our study was to investigate gait dynamics and kinematics in patients with Parkinson 's disease (PD) and to correlate these features with the predominant clinical features and with the presence of the freezing of gait (FOG). W e m easured the tempor ospatial and kinemat ic paramet ers of gait in 30 patients with PD (M:F=12:18, age=68.43±7.54) using a computerized video motion analysis system. Me thods: W e divided the subjects into subgroups: (1) tremor-dominant (TD) group and postural instability and gait disturbance (PIGD) group and (2) FOG group and non-FOG group. We compared the gait parameters between the subgroups. Results: The walking velocity and stride length were reduced significantly in the PIGD group compared to the TD group. The PIGD group showed a significantly reduced range of motion in the pelvic and lower extremity joints by kinematics. Stride time variability was significantly increased and the pelvic oblique range was significantly reduced in the freezing gait disorder group. Conclusion: Our findings suggest that there are differences in the perturbation of the basal ganglia-cortical circuits based on major clinical features. The reduction of the pelvic oblique range of motion may be a compensatory mechanism for postural instability and contributes to stride time variability in patients with FOG. Journal of Movement

Brain SPECT analysis by 3D-SSP and phenotype of Parkinson's disease

Objectives We hypothesize that the regional pattern of blood flow reduction in the brain is different between tremor-dominant Parkinson's disease (PD) and postural instability gait difficulty (PIGD)-dominant PD. We therefore investigated the association of phenotypes in untreated PD with brain perfusion on SPECT using three-dimensional stereotactic surface projection (3D-SSP) technique. Patients and methods Thirty-three patients who had PD without dementia (12 men and 21 women with a mean age of 67.1 ± 6.4 years) were included in this study. Their symptoms were rated using the Unified Parkinson's Disease Rating Scale (UPDRS). Patients were grouped in two phenotypes: tremor and PIGD-dominant groups based on UPDRS components. Around the same time, all patients were examined by N-isopropyl- p[ 123I] iodoamphetamine single photon emission computed tomography ( 123I-IMP SPECT), and obtained images were analyzed with 3D-SSP using an image-analysis software, NEUROSTAT. Data on brain surface perfusion extracted by 3D-SSP analysis were compared between the PD patients and the normal control group. The same comparisons were made for subgroups of PD patients. Results Cerebral perfusion was decreased at the anterior cingulate cortex and primary visual cortex of the PD patients, and especially by the pixel-by-pixel comparison, perfusion was significantly decreased at the right anterior cingulate cortex compared with the normal controls. In the PIGD-dominant group, more severe hypoperfusion was seen at the same regions. In the tremor-dominant group, significant hypoperfusion was not seen compared with the normal controls. Conclusions The regional pattern of blood flow reduction in the brain was found to be different between tremor-dominant PD and PIGD-dominant PD. These regional differences were considered to suggest different and disease-specific combinations of underlying pathophysiological and neurochemical processes.

Olfaction testing in patients with tremor‐dominant Parkinson's disease: Is this a distinct condition?

There is considerable controversy regarding the relationship between essential tremor (ET) and Parkinson's disease (PD), especially when tremor is the dominant feature of PD or there is a family history of tremor. Reduced olfaction function is one of the initial signs of PD. In contrast, ET has relatively preserved olfaction. To infer whether the tremor-dominant subgroup of PD is intrinsically different from mainstream PD, we tested olfaction using the University of Pennsylvania Smell Identification Test-40 (UPSIT) in this group and compared the findings with those of patients with non-tremor-dominant "regular" PD. We then evaluated predictors of reduced UPSIT scores within the tremor-dominant group. Overall, olfaction did not differ between tremor-dominant PD and regular PD; however, the subgroup of tremor-dominant PD with a family history of tremor had less olfaction loss than those without a family history (P = 0.0007) or those with regular PD (P = 0.0350). Other clinical features of this tremor-dominant PD with a family history of tremor group mostly resembled those without a family history. This finding suggests that patients with a family history of tremor may represent a different disease process even though, aside from differences in olfaction, they are clinically similar to other patients with tremor-dominant parkinsonism. It additionally suggests phenotypic overlap between PD and ET.

Cardiac 123I-MIBG scintigraphy can assess the disease severity and phenotype of PD

Objective: Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy studies of patients with idiopathic Parkinson's disease (PD) found decreased uptake. Whether this decrease is associated with clinical severity as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) and the phenotypes of PD has not been determined. Methods: Cardiac MIBG scintigraphy was performed on 34 patients with PD, 7 with multiple system atrophy (MSA), 4 with dementia with Lewy bodies (DLB), and 11 normal controls (NCs). Early and delayed MIBG heart/mediastinum (H/M) ratios were evaluated. PD severity was assessed by the Hoehn and Yahr (H–Y) stage and UPDRS. Patients were grouped in two phenotypes, tremor and postural instability gait difficulty (PIGD)-dominant groups based on UPDRS components. Associations between MIBG uptake and age at onset, UPDRS, and disease phenotype were analyzed in each group. Results: The early H/M ratio was significantly lower in patients with PD (1.45±0.207) than in the NCs (2.08±0.231), and in those with MSA (1.99±0.284), but not in those with DLB (1.29±0.0435). The delayed H/M ratio for PD (1.33±0.276) also was significantly decreased as compared to the ratios for NCs (2.17±0.286) and MSA (2.16±0.414) but not DLB (1.16±0.0949). The early H/M ratio was significantly correlated with both UPDRS score and age at onset, whereas the delayed H/M ratio only was significantly correlated with age at onset. The PIGD-dominant group had significantly higher UPDRS scores and lower H/M ratios than the tremor-dominant group. Conclusion: Cardiac MIBG scintigraphy can be used to differentiate PD from MSA and NC, and to determine the disease severity and phenotypes of PD.

Parkinson's disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis.

The current study presents preliminary data regarding the development and validation of a rating system designed to classify PD patients into clinical subgroups. Using portions of the Unified Parkinson's Disease Rating Scale, a ratio value was derived, yielding three patient subtypes: a tremor-dominant group (T), an akinetic-rigid group (AR), and a mixed group (MX). Validation of the schema was conducted by grouping PD surgical candidates into specific disease subtypes and evaluating differences in neurotransmitter profiles among disease subtypes and non-PD neurological controls. High pressure liquid chromatography analysis of ventricular cerebrospinal fluid indicated 5-hydroxyindoleacetic acid was significantly lower in the AR and MX groups compared to non-PD controls; whereas, glycine was significantly higher in the AR group compared to the T, MX, and control groups. The results suggest that an operational approach can be utilized to differentiate between PD subtypes with distinct neurochemical profiles.