Tremor-dominant Parkinson's Disease Research Articles

Magnetic Resonance-Guided Focused Ultrasound without Anesthesiologist Support

Introduction: Magnetic resonance-guided focused ultrasound (MRgFUS) is an effective treatment option for essential tremor (ET) and tremor dominant Parkinson’s disease (TDPD), which is often performed with sedation or in the presence of an anesthesiologist in an effort to minimize adverse events and maximize patient comfort. This study explores the safety, feasibility, and tolerability of performing MRgFUS without an anesthesiologist. Methods: This is a single academic center, retrospective review of 180 ET and TDPD patients who underwent MRgFUS treatment without anesthesiologist support. Patient demographics, intra-procedural treatment parameters, peri-procedural adverse events, and 3-month Clinical Rating Scale for Tremor Part B (CRST-B) scores were compared to MRgFUS studies that utilized varying degrees of anesthesia. Results: There were no anesthesia related adverse events or unsuccessful treatments. There were no early treatment terminations due to patient discomfort, regardless of skull density ratio. 94.6% of patients would repeat the procedure again. The most common side effects during treatment were facial/tongue paresthesia (26.3%), followed by nausea (22.3%), dysarthria (8.6%), and scalp pain (8.0%). No anxiolytic, pain, or antihypertensive medications were administered. The most common early adverse event after MRgFUS procedure was gait imbalance (58.3%). There was a significant reduction of 83.1% (83.4% ET and 80.5% TDPD) of the mean CRST-B scores of the treated hand when comparing 3-month and baseline scores (1.8 vs. 10.9, n = 109, p Conclusion: MRgFUS without intra-procedural anesthesiologist support is a safe, feasible, and well-tolerated option, without an increase in peri-procedural adverse events.

Cortico-cortical connectivity is influenced by levodopa in tremor-dominant Parkinson's disease

Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the basal-ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor. This study investigated SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor. Dual-site transcranial magnetic stimulation was used to measure SMA-M1 connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry. Stimulating SMA inhibited M1 excitability OFF levodopa, and facilitated M1 excitability ON levodopa. ON medication, SMA-M1 facilitation was significantly associated with smaller tremor than SMA-M1 inhibition. The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.

Evaluation of Cardiovascular Autonomic Nervous System in Essential Tremor and Tremor Dominant Parkinson's Disease.

(1) Background: The differential diagnosis of essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD) can be challenging. Only a few studies have investigated the autonomic nervous system (ANS) in ET. However, some of these suggested that heart rate variability (HRV) might be useful in the differential diagnosis. (2) Methods: Demographic and clinical data, including medications and comorbidities, were collected from 15 TDPD patients, 19 ET patients, and 20 healthy controls. Assessment with the SCOPA-AUT questionnaire, 5 min HRV analysis in time and frequency domains, and evaluation of orthostatic hypotension (OH) with tilt test were performed. (3) Results: There were no significant differences between all groups on the SCOPA-AUT questionnaire. PD patients had OH more frequently and a larger drop in systolic blood pressure (SBP) during the tilt test than ET patients and controls. HRV was affected in PD, but not in ET and controls. Power in the low frequency band, the standard deviation of all normal RR intervals and SBP drop were potentially useful in differential diagnosis with AUCs of 0.83, 0.78, and 0.83, respectively. (4) Conclusions: Cardiovascular ANS dysfunction was present in TDPD, but not in ET and controls. HRV analysis and assessment of SBP drop may be potentially useful in the differential diagnosis of ET and TDPD.

Combined brain topological metrics with machine learning to distinguish essential tremor and tremor-dominant Parkinson's disease.

Essential tremor (ET) and Parkinson's disease (PD) are the two most prevalent movement disorders, sharing several overlapping tremor clinical features. Although growing evidence pointed out that changes in similar brain network nodes are associated with these two diseases, the brain network topological properties are still not very clear. The combination of graph theory analysis with machine learning (ML) algorithms provides a promising way to reveal the topological pathogenesis in ET and tremor-dominant PD (tPD). Topological metrics were extracted from Resting-state functional images of 86 ET patients, 86 tPD patients, and 86 age- and sex-matched healthy controls (HCs). Three steps were conducted to feature dimensionality reduction and four frequently used classifiers were adopted to discriminate ET, tPD, and HCs. A support vector machine classifier achieved the best classification performance of four classifiers for discriminating ET, tPD, and HCs with 89.0% mean accuracy (mACC) and was used for binary classification. Particularly, the binary classification performances among ET vs. tPD, ET vs. HCs, and tPD vs. HCs were with 94.2% mACC, 86.0% mACC, and 86.3% mACC, respectively. The most power discriminative features were mainly located in the default, frontal-parietal, cingulo-opercular, sensorimotor, and cerebellum networks. Correlation analysis results showed that 2 topological features negatively and 1 positively correlated with clinical characteristics. These results demonstrated that combining topological metrics with ML algorithms could not only achieve high classification accuracy for discrimination ET, tPD, and HCs but also help to reveal the potential brain topological network pathogenesis in ET and tPD.

Differential patterns of functional connectivity in tremor dominant Parkinson's disease and essential tremor plus.

Tremor dominant Parkinson's disease (TDPD) and essential tremor plus (ETP) syndrome are commonly encountered tremor dominant neurological disorders. Although the basal ganglia thalamocortical (BGTC) and cerebello thalamocortical (CTC) networks are implicated in tremorogenesis, the extent of functional connectivity alterations across disorders is uncertain. This study aims to evaluate functional connectivity of the BGTC and CTC in TDPD and ETP. Resting state functional MRI was acquired for 25 patients with TDPD, ETP and 22 healthy controls (HC). Following pre-processing and denoising, seed-to-voxel based connectivity was carried out at FDR < 0.05 using ROIs belonging to the BGTC and CTC. Fahn-Tolosa-Marin tremor rating scale (FTMRS) was correlated with the average connectivity values at FDR < 0.05. Compared to HC, TDPD showed decreased connectivity between cerebellum and pre, post central gyrus. While, ETP showed decreased connectivity between pallidum and occipital cortex, precuneus, cuneus compared to HC. In comparison to ETP, TDPD showed increased connectivity between precentral gyrus, pallidum, SNc with the default mode network (DMN), and decreased connectivity between cerebellum with superior, middle frontal gyrus was observed. Tremor severity positively correlated with connectivity between SNc and DMN in TDPD, and negatively correlated with pallidal connectivity in ETP. Pattern of BGTC, CTC involvement is differential i.e., higher connectivity of the BGTC nodes in TDPD, and higher connectivity of cerebellar nodes in ETP. The interesting observation of pallidal involvement in ETP suggests the role of BGTC in the pathogenesis of ETP, and indicated similarities in concepts of tremor genesis in TDPD and ETP.

One-pass deep brain stimulation of subthalamic nucleus and ventral intermediate nucleus for levodopa-resistant tremor-dominant Parkinson's disease.

Tremor-dominant Parkinson's disease (TD-PD) can be further separated into levodopa-responsive and levodopa-resistant types, the latter being considered to have a different pathogenesis. Previous studies indicated that deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus internus (GPi) individually was not sufficient for tremor control, especially for the levodopa-resistant TD-PD (LRTD-PD). The thalamic ventral intermediate nucleus (VIM) has been regarded as a potent DBS target for different kinds of tremors. Therefore, we focused on the LRTD-PD subgroup and performed one-pass combined DBSs of STN and VIM to treat refractory tremors, aiming to investigate the safety and effectiveness of this one-trajectory dual-target DBS scheme. We retrospectively collected five LRTD-PD patients who underwent a one-pass combined DBS of STN and VIM via a trans-frontal approach. The targeting of VIM was achieved by probabilistic tractography. Changes in severity of symptoms (measured by the Unified Parkinson Disease Rating Scale part III, UPDRS-III), levodopa equivalent daily doses (LEDD), and disease-specific quality of life (measured by the 39-item Parkinson's Disease Questionnaire, PDQ-39) were evaluated. Three-dimensional reconstruction of electrodes illustrated that all leads were successfully implanted into predefined positions. The mean improvement rates (%) were 53 ± 6.2 (UPDRS-III), 82.6 ± 11.4 (tremor-related items of UPDRS), and 52.1 ± 11.4 (PDQ-39), respectively, with a mean follow-up of 11.4 months. One-pass combined DBS of STN and VIM via the trans-frontal approach is an effective and safe strategy to alleviate symptoms for LRTD-PD patients.

Amelioration of Parkinsonian tremor evoked by DBS: which role play cerebello-(sub)thalamic fiber tracts?

BackgroundCurrent pathophysiological models of Parkinson’s disease (PD) assume a malfunctioning network being adjusted by the DBS signal. As various authors showed a main involvement of the cerebellum within this network, cerebello-cerebral fiber tracts are gaining special interest regarding the mediation of DBS effects.ObjectivesThe crossing and non-decussating fibers of the dentato-rubro-thalamic tract (c-DRTT/nd-DRTT) and the subthalamo-ponto-cerebellar tract (SPCT) are thought to build up an integrated network enabling a bidimensional communication between the cerebellum and the basal ganglia. The aim of this study was to investigate the influence of these tracts on clinical control of Parkinsonian tremor evoked by DBS.MethodsWe analyzed 120 electrode contacts from a cohort of 14 patients with tremor-dominant or equivalence-type PD having received bilateral STN-DBS. Probabilistic tractography was performed to depict the c-DRTT, nd-DRTT, and SPCT. Distance maps were calculated for the tracts and correlated to clinical tremor control for each electrode pole.ResultsA significant difference between “effective” and “less-effective” contacts was only found for the c-DRTT (p = 0.039), but not for the SPCT, nor the nd-DRTT. In logistic and linear regressions, significant results were also found for the c-DRTT only (pmodel logistic = 0.035, ptract logistic = 0,044; plinear = 0.027).ConclusionsWe found a significant correlation between the distance of the DBS electrode pole to the c-DRTT and the clinical efficacy regarding tremor reduction. The c-DRTT might therefore play a major role in the mechanisms of alleviation of Parkinsonian tremor and could eventually serve as a possible DBS target for tremor-dominant PD in future.

Long-Term Follow-Up of Unilateral Deep Brain Stimulation Targeting the Caudal Zona Incerta in 13 Patients with Parkinsonian Tremor

Introduction: Deep brain stimulation (DBS) is an established treatment for Parkinson’s disease (PD) and other movement disorders. The ventral intermediate nucleus of the thalamus is considered as the target of choice for tremor disorders, including tremor-dominant PD not suitable for DBS in the subthalamic nucleus (STN). In the last decade, several studies have shown promising results on tremor from DBS in the posterior subthalamic area (PSA), including the caudal zona incerta (cZi) located posteromedial to the STN. The aim of this study was to evaluate the long-term effect of unilateral cZi/PSA-DBS in patients with tremor-dominant PD. Methods: Thirteen patients with PD with medically refractory tremor were included. The patients were evaluated using the motor part of the Unified Parkinson Disease Rating Scale (UPDRS) off/on medication before surgery and off/on medication and stimulation 1–2 years (short-term) after surgery and at a minimum of 3 years after surgery (long-term). Results: At short-term follow-up, DBS improved contralateral tremor by 88% in the off-medication state. This improvement persisted after a mean of 62 months. Contralateral bradykinesia was improved by 40% at short-term and 20% at long-term follow-up, and the total UPDRS-III by 33% at short-term and by 22% at long-term follow-up with stimulation alone. Conclusions: Unilateral cZi/PSA-DBS seems to remain an effective treatment for patients with severe Parkinsonian tremor several years after surgery. There was also a modest improvement on bradykinesia.

Artificial-intelligence-based MRI brain volumetry in patients with essential tremor and tremor-dominant Parkinson's disease.

Essential tremor and Parkinson's disease patients may present with various tremor types. Overlapping tremor features can be challenging to diagnosis and misdiagnosis is common. Although underlying neurodegenerative mechanisms are suggested, neuroimaging studies arrived at controversial results and often the different tremor types were not considered. We investigated whether different tremor types displayed distinct structural brain features. Structural MRI of 61 patients with essential tremor and 29 with tremor-dominant Parkinson's disease was analysed using a fully automated artificial-intelligence-based brain volumetry to compare volumes of several cortical and subcortical regions. Furthermore, essential tremor subgroups with and without rest tremor or more pronounced postural and kinetic tremor were investigated. Deviations from an internal reference collective of age- and sex-adjusted healthy controls and volumetric differences between groups were examined; regression analysis was used to determine the contribution of disease-related factors on volumetric measurements. Compared with healthy controls, essential tremor and tremor-dominant Parkinson's disease patients displayed deviations in the occipital lobes, hippocampus, putamen, pallidum and mesencephalon while essential tremor patients exhibited decreased volumes within the nucleus caudatus and thalamus. Analysis of covariance revealed similar volumetric patterns in both diseases. Essential tremor patients without rest tremor showed a significant atrophy within the thalamus compared to tremor-dominant Parkinson's disease and atrophy of the mesencephalon and putamen were found in both subgroups compared to essential tremor with rest tremor. Disease-related factors contribute to volumes of occipital lobes in both diseases and to volumes of temporal lobes in essential tremor and the putamen in Parkinson's disease. Fully automated artificial-intelligence-based volumetry provides a fast and rater-independent method to investigate brain volumes in different neurological disorders and allows comparisons with an internal reference collective. Our results indicate that essential tremor and tremor-dominant Parkinson's disease share structural changes, indicative of neurodegenerative mechanisms, particularly of the basal-ganglia-thalamocortical circuitry. A discriminating, possibly disease-specific involvement of the thalamus was found in essential tremor patients without rest tremor and the mesencephalon and putamen in tremor-dominant Parkinson's disease and essential tremor without rest tremor.

[Alterations in erythrocytic oligomeric alpha-synuclein in patients with Parkinson's disease and multiple system atrophy].

Objective: To analyze the content of α-synuclein oligomer(O-α-Syn) in erythrocytes in patients with Parkinson's disease (PD) and multiple system atrophy (MSA) and the correlation with clinical symptoms. Methods: Two hundred and ninety-six PD patients and 85 MSA patients were recruited from the Department of Functional Neurosurgery and Neurology of Xuanwu Hospital, Capital Medical University from July 2020 to October 2021. Four hundred and three healthy controls (HC) were recruited from the Beijing Longitudinal Study of Aging community cohort during the same period. The levels of RBC-O-α-Syn were measured by enzyme-linked immunosorbent assay (ELISA). Univariate linear regression model was used to analyze the correlation between the content of RBD-O-α-Syn and various motor and non-motor functional scores, such as Unified Parkinson Disease Rating Scale (UPDRS) Ⅲ, Unified Multiple System Atrophy Rating Scale (UMSARS) Ⅲ, Mini-Mental State Examination (MMSE), rapid eye movement sleep disorder questionnaire-HongKong(RBDQ-HK) and Montreal Cognitive Assessment (MoCA). Receiver operating characteristic (ROC) curves was used to evaluate the specificity, sensitivity, and the area under the curve (AUC) of RBC-O-α-Syn in distinguishing PD and MSA patients from HC subjects. Results: The average age of HC subjects was (70±8) years old, the average age of PD patients was (64±9) years old, including 115 (38.9%) cases with tremor dominant PD (TD-PD), 132 cases (44.6%) of postural instability disorder predominant PD (PIGD-PD), and 142 cases (48.0%) of patients with H-Y stage 2. UPDRS Ⅲ score was 31.2±17.8. The mean age of MSA patients was (64±9) years, with the mean UMSARS Ⅱ score of 18.9±10.3. The non-motor symptoms of PD and MSA patients were significantly different from those of HC subjects (P<0.001). The levels of RBC-O-α-Syn in PD [(50±17) ng/mg] and MSA [(52±19) ng/mg] were significantly higher than those in HC subjects [(21±10) ng/mg] (P<0.001). The sensitivity and specificity of RBC-O-α-Syn in distinguishing PD patients and HC subjects were 87.16% (95%CI: 82.87%-90.50%) and 86.10% (95%CI: 82.38%-89.14%), with an AUC of 0.933 (95%CI: 0.914-0.951), and the sensitivity and specificity in distinguishing MSA patients and HC subjects were 85.88% (95%CI: 76.93%-91.74%) and 81.39% (95%CI: 77.30%-84.89%), with an AUC of 0.921 (95%CI: 0.884-0.957). The levels of RBC-O-α-Syn in PD patients with rapid eye movement sleep behavior disorder (RBD) were higher than that in PD patients without RBD [(53±16) ng/mg vs (48±17) ng/mg, P=0.029].The content of RBC-O-α-Syn in female PD patients and HC subjects was higher than that in male, but there was no significant difference between subjects of different ages and disease duration (P>0.05). In addition, RBC-O-α-Syn content was positively correlated with UPDRS Ⅲ (r=0.18, P=0.002) and the score of rapid eye movement sleep behavior disorder questionnaire(Hong Kong) (RBDQ-HK)(r=0.19, P<0.001). But there was no correlation with H-Y stage, non-motor symptoms scale (NMSS), MMSE, Moca, Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA) scores (all P>0.05). There was no correlation between RBC-O-α-Syn content and UMSARS Ⅱ, NMSS, MMSE, MoCA, HAMD, HAMA in patients with MSA (all P>0.05). Conclusions: Levels of RBC-O-α-Syn are significantly increased in PD and MSA patients. There are positive correlations between levels of RBC-O-α-Syn and scores of UPDRS Ⅲ and RBDQ-HK.

Magnetic resonance imaging-guided focused ultrasound thalamotomy launch with remote telemedicine international proctorship.

COVID-19 limitations have hindered the implementation of new technologies by preventing proctors from coming to the site. We share our first experience of magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) treatment with an international remote online proctorship, and develop and evaluate the methodology of remote MRgFUS proctorship. This single-center, nonrandomized controlled prospective study included 94 patients: 27 with essential tremor (ET) and 67 with tremor-dominant Parkinson's disease (PD). The coming of proctors was impossible, so we arranged for the remote participation of proctors from the United Kingdom, Spain, and Israel. A total of 38 patients (40.4%) received telemedicine-proctored treatment (proctor group) and 56 received their treatment independently (solo group). We used the Clinical Rating Scale for Tremor (CRST) for ET patients and the Unified Parkinson's Disease Rating Scale (UPDRS) Part III for PD patients. In patients with ET, success rates were 81.8% (proctor group) and 100% (solo group) (p = 0.22). CRST reduction on the treated side was 71.43% [65.83%; 80.56%] (proctor group) versus 60.87% [53.99; 79.58] (solo group) (p = 0.19). None of the patients showed worsening of tremors within 1 year. In patients with PD, the success rates were 92.6% (proctor group) and 100% (solo group) (p = 0.08). The UPDRS Part III improvement was 30.1% (proctor group) versus 39.9% (solo group) (p = 0.003). The 1-year recurrence rate was 40% (proctor group) and 17.5% (solo group) (p = 0.04). No complications were observed at 6 months. We developed a feasible and safe methodology for telemedicine remote online-proctored MRgFUS treatment. No significant difference was observed between the solo and developed remote proctor protocols in terms of complication rate, effect, and long-term results; however, UPDRS Part III improvement was better in the PD solo group. This study demonstrated that the MRgFUS international proctorship can be performed successfully remotely.

Jumping to conclusions bias, psychosis and impulsivity in early stages of Parkinson’s disease

ObjectivesThe aim was to explore the correlations between Jumping to Conclusions (JtC) tendency and neuropsychiatric features in patients with early Parkinson’s disease (PD).BackgroundAccording to few reports, PD patients with impulsive–compulsive behaviors (ICBs) are prone to working memory difficulties including JtC bias. The correlation of psychotic features and JtC tendency remains still unclear.MethodsHealthy controls and patients within 3 years of PD onset were recruited. Participants were examined for psychotic symptoms using a 10 question PD-specific psychosis severity scale. JtC was measured by a probalistic reasoning scenario (beads task). In PD group, medication use, motor and non-motor symptoms were documented. Impulsivity was evaluated using the Questionnaire for Impulsive–Compulsive Disorders in PD (QUIP).ResultsThe prevalence of JtC bias was 9% (6/70) in healthy individuals, compared to 32% (22/68) of PD group [p = 0.001]. No association was detected between the presence of JtC tendency and PD-associated psychosis (p = 0.216). Patients with JtC had shorter duration of PD, more tremor-dominant PD subtype and higher QUIP scores, regardless of the dopaminergic therapy (p = 0.043, p = 0.015, p = 0.007, respectively). A trend towards attention and inhibition control deficit was noticed in JtC patients.ConclusionsWe found a high prevalence of JtC bias in early, cognitively intact PD population and a potential link between subthreshold ICBs and poor performance on beads task. Additional studies are needed to confirm our results and elaborate on the mechanisms that correlate impulsivity with JtC tendency, which are likely to be different from those mediating psychotic features in early PD.

Focused Ultrasound Thalamotomy for Tremor in Parkinson's Disease: Outcomes in a Large, Prospective Cohort.

Magnetic resonance guided focused ultrasound (MRgFUS) is United States Food and Drug Administration approved for the treatment of tremor-dominant Parkinson's disease (TdPD), but only limited studies have been described in practice. To report the largest prospective experience of unilateral MRgFUS thalamotomy for the treatment of medically refractory TdPD. Clinical outcomes of 48 patients with medically refractory TdPD who underwent MRgFUS thalamotomy were evaluated. Tremor outcomes were assessed using the Fahn-Tolosa-Marin scale and adverse effects were categorized using a structured questionnaire and clinical exam at 1 month (n = 44), 3 months (n = 34), 1 year (n = 22), 2 years (n = 5), and 3 years (n = 2). Patients underwent magnetic resonance imaging <24 hours post-procedure. Significant tremor control persisted at all follow-ups (P < 0.001). All side effects were mild. At 3 months, these included gait imbalance (38.24%), sensory deficits (26.47%), motor weakness (17.65%), dysgeusia (5.88%), and dysarthria (5.88%), with some persisting at 1 year. MRgFUS thalamotomy is an effective treatment for sustained tremor control in patients with TdPD. © 2023 International Parkinson and Movement Disorder Society.

Gray matter alterations in tremor-dominant Parkinson's disease after MRgFUS thalamotomy are correlated with tremor improvement: a pilot study.

Regional differences in gray matter volume (GMV) have been reported to be a reliable marker for diagnosing Parkinson's disease (PD). This study aimed to explore the clinical value of GMV to assess magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy as a treatment for tremor-dominant PD (TDPD). Nine TDPD patients with MRgFUS thalamotomy were recruited for structural magnetic resonance image (MRI) scanning and clinical score evaluation. GMV was calculated. To investigate changes after treatment, voxel- and region of interest (ROI)-wise GMV analyses were performed. Then, GMV with significant differences was extracted from patients to investigate its dynamic alterations by one-way repeated-measures analysis of variance (ANOVA). The nonparametric Spearman rank correlation analysis was used to evaluate the relationship between GMV alterations and tremor improvement after thalamotomy. Tremors were significantly relieved after MRgFUS thalamotomy in nine patients (P<0.05). The treated hand tremor scores improved 74.82% on average in patients from pre-operation to 12 months post-operation. Voxel-wise analysis at the cluster level showed a significant decrease in GMV in the left middle occipital gyrus (MOG) [t=11.81, voxel-level P<0.001, cluster-level Pfamily-wise error (FWE) <0.05] and an increase in GMV in the left precentral gyrus (PreCG) (t=7.99, voxel-level P<0.001, cluster-level PFWE <0.05) in TDPD patients from preoperative to 12 months post-operation, which was significantly correlated with tremor scores (rho =0.346-0.439, P<0.05). ROI-wise analysis showed that GMV related to MRgFUS thalamotomy was associated with long-term structural alterations (P<0.05 with Bonferroni correction), including specific basal ganglia and related nuclei and cerebellum subregions. GMV can be used to reflect tremor improvement after MRgFUS thalamotomy and be helpful to better understand the distant effect of MRgFUS thalamotomy and the involvement of GMV in tremor control in TDPD. ClinicalTrials.gov identifier: NCT04570046.

Integrative Brain States Facilitate the Expression of Parkinson's Tremor.

Parkinson's disease (PD) rest tremor emerges from pathological activity in the basal ganglia and cerebello-thalamo-cortical circuits. A well-known clinical feature is the waxing and waning of PD tremor amplitude, but the mechanisms that drive this variability are unclear. Previous work has shown that arousal amplifies PD tremor by increasing between-network connectivity. Furthermore, brain states in PD are biased toward integration rather than segregation, a pattern that is also associated with increased arousal. The aim was to test the hypothesis that fluctuations in integrative brain states and/or arousal drive spontaneous fluctuations in PD rest tremor. We compared the temporal relationship between cerebral integration, the ascending arousal system, and tremor, both during cognitive load and in the resting state. In 40 tremor-dominant PD patients, we performed functional magnetic resonance imaging using concurrent tremor recordings and proxy measures of the ascending arousal system (pupil diameter, heart rate). We calculated whole-brain dynamic functional connectivity and used graph theory to determine a scan-by-scan measure of cerebral integration, which we related to the onset of tremor episodes. Fluctuations in cerebral integration were time locked to spontaneous changes in tremor amplitude: cerebral integration increased 13 seconds before tremor onset and predicted the amplitude of subsequent increases in tremor amplitude. During but not before tremor episodes, pupil diameter and heart rate increased and correlated with tremor amplitude. Integrative brain states are an important cerebral environment in which tremor-related activity emerges, which is then amplified by the ascending arousal system. New treatments focused on attenuating enhanced cerebral integration in PD may reduce tremor. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

IgA-Biome Profiles Correlate with Clinical Parkinson's Disease Subtypes.

Parkinson's disease is a heterogeneous neurodegenerative disorder with distinctive gut microbiome patterns suggesting that interventions targeting the gut microbiota may prevent, slow, or reverse disease progression and severity. Because secretory IgA (SIgA) plays a key role in shaping the gut microbiota, characterization of the IgA-Biome of individuals classified into either the akinetic rigid (AR) or tremor dominant (TD) Parkinson's disease clinical subtypes was used to further define taxa unique to these distinct clinical phenotypes. Flow cytometry was used to separate IgA-coated and -uncoated bacteria from stool samples obtained from AR and TD patients followed by amplification and sequencing of the V4 region of the 16 S rDNA gene on the MiSeq platform (Illumina). IgA-Biome analyses identified significant alpha and beta diversity differences between the Parkinson's disease phenotypes and the Firmicutes/Bacteroides ratio was significantly higher in those with TD compared to those with AR. In addition, discriminant taxa analyses identified a more pro-inflammatory bacterial profile in the IgA+ fraction of those with the AR clinical subclass compared to IgA-Biome analyses of those with the TD subclass and with the taxa identified in the unsorted control samples. IgA-Biome analyses underscores the importance of the host immune response in shaping the gut microbiome potentially affecting disease progression and presentation. In the present study, IgA-Biome analysis identified unique proinflammatory microbial signature in the IgA+ fraction of those with AR that would have otherwise been undetected using conventional microbiome analysis approaches.

Clinical Symptoms Influencing Parkinson's Patients' Quality of Life in Latvia: A Single-Center Cohort Study.

Background and Objectives: Parkinson's disease (PD) is a chronic, progressive illness with a profound impact on health-related quality of life, and it is crucial to know what factors influence the quality of life throughout the course of the disease. This study aimed to evaluate PD patients' motor and non-motor symptoms to compare symptom severity between PD clinical phenotypes and to assess the impact of disease symptoms on quality of life in a cohort of Latvian patients. Materials and Methods: We evaluated 43 patients with Parkinson's disease. Fourteen patients had tremor dominant (TD) PD, twenty-five patients had postural instability/gait difficulty (PIGD), and four patients had a mixed phenotype. Results: The patients' mean age was 65.21 years, and the disease's mean duration was 7 years. The most common non-motor symptoms were fatigue (95.3%), sleep disturbance (83.7%), daytime sleepiness (83.7%), and pain and other sensations (81.4%). PIGD patients had a higher prevalence of depressed mood, daytime sleepiness, constipation, lightheadedness on standing, cognitive impairment, and severe gastrointestinal and urinary disturbances (as assessed using the SCOPA-AUT domains) compared with TD patients. A high prevalence of fatigue was assessed in both disease subtypes. Health-related quality of life significantly statistically correlated with MDS-UPDRS parts III and IV (r = 0.704), the Hoehn and Yahr scale (r = 0.723), as well as the SCOPA-AUT scale's gastrointestinal (r = 0.639), cardiovascular (r = 0.586), thermoregulatory (r = 0.566) and pupillomotor domains (r = 0.597). Conclusions: The severity of motor symptoms, as well as non-motor symptoms, such as fatigue, apathy, sleep problems and daytime sleepiness, pain, and disturbances in gastrointestinal and cardiovascular function, negatively affect PD patients' health-related quality of life. Thermoregulatory and pupillomotor symptoms also significantly affect PD patients' well-being.

Introversion and Neuroticism in Akinetic-Rigid Parkinson's Disease: Association With Frontal-Executive Dysfunction.

Personality changes have often been reported among people with Parkinson's disease (PD); however, no studies have investigated the associations between personality traits, cognitive function, and specific motor symptoms. In this study, the investigators assessed whether particular personality traits were associated with specific motor subtypes of PD (e.g., tremor-dominant and akinetic-rigid phenotypes) and whether frontal-executive functions were associated with personality traits among patients with a specific motor phenotype. Forty-one people with PD and 40 healthy control participants were enrolled in the study. All participants underwent assessments of cognitive and psychological function and personality traits. The study was conducted in Italy. Tremor-dominant symptoms occurred among 20 (48.8%) people with PD, whereas 21 (51.2%) patients exhibited akinetic-rigid symptoms. Multivariate analyses of variance revealed that participants with akinetic-rigid PD demonstrated significantly poorer performance on frontal-executive tests compared with those with tremor-dominant PD. Moreover, those with akinetic-rigid PD exhibited more psychopathological symptoms and higher neuroticism and introversion compared with those with tremor-dominant PD. Correlations revealed that among participants with akinetic-rigid PD, psychopathological symptoms and neuroticism and introversion personality traits were associated with frontal-executive dysfunction, whereas among those with tremor-dominant PD, no significant associations were found between personality traits and cognitive abilities. These findings suggest that specific personality and frontal-executive profiles are associated with the akinetic-rigid motor subtype of PD, thus helping to refine the different clinical manifestations of PD. A better understanding of the psychological, personality, and cognitive mechanisms in PD could also help to develop more targeted treatments.

Cerebrospinal fluid alpha-synuclein, amyloid beta, total tau, and phosphorylated tau in tremor-dominant Parkinson's disease.

Protein misfolding within specific brain regions is a common characteristic of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease (PD). Therefore, a common term often used for these disorders is "proteinopathy". Currently, there has been increasing attention toward the overlap of pathogenesis between proteinopathies. We aimed to explore the cross-sectional and longitudinal level of the CSF α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in PD subjects with tremor dominant (TD) and a non-tremor dominant (nonTD) subtype from the Parkinson Progression Markers Initiative (PPMI). We enrolled 411 early-stage PD patients and 187 healthy controls (HCs) from the PPMI. We compared the level of CSF biomarkers at four time points including baseline, 6months, 1year, and 2years. To investigate longitudinal changes in CSF proteins within each group, we used linear mixed models. The level of CSF biomarkers was significantly lower in PD patients compared to HCs at any visit. Moreover, there was no statistically significant difference in the level of CSF α-syn, Aβ1-42, t-tau, and p-tau between PD-TD and PD-nonTD. Longitudinal analysis showed significant CSF α-syn reduction after one year from baseline in PD-TD patients (P = 0.047). Also, there was a significant reduction in the level of CSF Aβ1-42 after two years in PD-nonTD patients but not HCs and PD-TD (P = 0.033). Our results indicate that different patterns in longitudinal changes of CSF biomarkers could be due to different pathophysiological mechanisms involved in each PD motor subtype.

Cavitation with low-energy sonication during focused ultrasound thalamotomy for a patient with tremor-dominant Parkinson's disease: a potential risk.

We report a patient with tremor-dominant Parkinson's disease who had a mild cavitation bioeffect during magnetic resonance-guided focused ultrasound thalamotomy. During the aligning phase with low-energy sonication, cavitation caused mild dysarthria and paresthesia, prompting treatment cessation. At the same time, tremor and rigidity improved. MRI revealed extensive high-intensity lesions in the thalamus 1day after the procedure followed by steroid infusion, which resulted in resolution of adverse events. Tremor and rigidity improved 1.5years after the procedure. Although cavitation can relieve tremors and rigidity, it should be carefully monitored due to potential permanent adverse events by unpredictable and unknown behaviors.