Modulation of Lingo-1 and NMDA receptor expression by memantine and vitamin D3 co-therapy attenuates motor and non-motor symptoms in essential tremor.

ObjectivesTo compare non-motor symptoms (NMSs) among patients with essential tremor (ET), Parkinson’s disease (PD) subtypes (akinetic-rigid type (ART) and tremor-dominant type (TDT)), and healthy controls.Patients and methodsThis retrospective study included 129 participants, 72 PD (33 PD-ART, 33 PD-TDT, and 6 Mixed), 29 ET patients, and 28 controls. PD patients were assessed by the unified Parkinson’s disease rating scale (UPDRS), Hoehn, and Yahr scale (H&Y), while ET patients were evaluated by the Fahn Tolosa Marin Tremor Rating Scale. All subjects were evaluated by non-motor symptoms scale (NMSS) for NMSs and Beck depression inventory (BDI) for depression.ResultsPD subtypes groups, ET, and controls were age and gender-matched. Compared to controls, all PD, PD subtypes, and ET showed significantly worse most of NMSs (p<0.001) and depression. Compared to ET, all PD and PD-ART had significantly worse gastrointestinal (p = 0.002), urinary symptoms (p = 0.001, p = 0.003) and depression (p = 0.002) and PD-TDT worse depression, while ET patients showed worse memory/attention than PD subtypes. Total NMSS of ET is highly correlated to depression and moderately to tremor severity and age of onset, while total of NMSS is highly correlated to depression, disease severity, and disability.ConclusionThe current study demonstrated several comparable domains of NMSs of PD subtypes and ET, except worse gastrointestinal and urinary symptoms among PD-ART. Identifying different NMSs profiles is important for predicting, better assessing, and tailoring management of ET and PD subtypes.

Nonmotor Symptoms in Essential Tremor and Other Tremor Disorders.

In the last decade our perspective on essential tremor (ET) as a pure motor system disorder has begun to change. By virtue of recent studies of nonmotor symptoms (NMSs) that are used to characterize Parkinson's disease (PD), these symptoms have also been added to the definition of ET. There is increasing evidence to suggest that ET might not be as benign and monosymptomatic as we previously thought. The aim of this study was to evaluate nonmotor symptoms in ET, and to compare them with PD. We studied 37 ET and 23 PD patients. Tremor rate was evaluated using the Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) in ET patients. The patients with PD were scored for motor symptoms using the unified Parkinson's disease rating scale (UPDRS)-III and the Hoehn-Yahr scale. Cognitive functions were assessed with the Montreal Cognitive Assessment (MoCA) test. NMSs were evaluated with the nonmotor symptoms questionnaire (NMSQuest). In the ET group, the most common NMSs were forgetting things, feeling sad, nocturia, urgency, and difficulty concentrating. The mean NMSQuest score was 8.43 ± 4.14 in the ET group and 14.06 ± 5.44 in the PD group (p value <0.001). However, except for 12 items in NMSQuest, in comparing items one by one there was no statistical difference between them. The mean MoCA total score was 17.81 ± 4.56 in the ET group and 17.08 ± 4.08 in the PD group (p value 0.675). There were no significant differences in MoCA subgroup scores. Evaluation of nonmotor symptoms in ET may help us to understand this emerging definition of ET. This study contributes evidence toward this new concept.

Nonmotor symptoms in essential tremor: Comparison with Parkinson's disease and normal control

Essential tremor (ET) is primarily characterized by action tremor, but is also associated with various non-motor symptoms (NMS). However, the diagnostic relevance of NMS in ET remains unclear. This study aimed to compare NMS and motor symptoms of ET with those of Parkinson's disease-tremor dominant type (PD-TDT) and healthy controls (HCs) and to identify the presence and diagnostic relevance of NMS. Twenty-three ET patients, 23 PD-TDT patients, and 22 HCs were enrolled. Diagnoses of ET and PD were confirmed using Movement Disorder Society (MDS) criteria and Dopamine transporter single-photon emission computed tomography. Motor symptoms, NMS and quality of life (QOL) were evaluated using validated scales, including the Clinical Rating Scale for Tremor (CRST), MDS-Unified Parkinson's Disease Rating Scale (UPDRS), Non-Motor Symptoms Scale for Parkinson's Disease (NMSS), Odor Stick Identification Test for Japanese (OSIT-J), and Quality of Life in Essential Tremor Questionnaire (QUEST). ET patients had significantly higher NMSS total scores and MDS-UPDRS part IB scores than HCs, with more severe sleep disturbances, fatigue, and urinary problems. CRST scores were significantly correlated with QUEST scores. Logistic regression identified CRST Part B and OSIT-J as key factors distinguishing ET from PD-TDT, with 87% sensitivity and 90% specificity. ET patients showed more severe NMS than HCs. Differentiating ET from PD-TDT requires motor and sensory assessments, highlighting the diagnostic relevance of NMS. Comprehensive evaluation is essential for accurate diagnosis and management of ET.

Essential tremor (ET) is one of the most common movement disorders in human adults. It can be characterized as a progressive neurological disorder of which the most recognizable feature is a tremor of the arms or hands that is apparent during voluntary movements such as eating and writing. The pathology of ET remains unclear. Resting-state fMRI (RS-fMRI), as a non-invasive imaging technique, was employed to investigate abnormalities of functional connectivity in ET in the brain. Regional homogeneity (ReHo) was used as a metric of RS-fMRI to assess the local functional connectivity abnormality in ET with 20 ET patients and 20 age- and gender-matched healthy controls (HC). The ET group showed decreased ReHo in the anterior and posterior bilateral cerebellar lobes, the bilateral thalamus and the insular lobe, and increased ReHo in the bilateral prefrontal and parietal cortices, the left primary motor cortex and left supplementary motor area. The abnormal ReHo value of ET patients in the bilateral anterior cerebellar lobes and the right posterior cerebellar lobe were negatively correlated with the tremor severity score, while positively correlated with that in the left primary motor cortex. These findings suggest that the abnormality in cerebello-thalamo-cortical motor pathway is involved in tremor generation and propagation, which may be related to motor-related symptoms in ET patients. Meanwhile, the abnormality in the prefrontal and parietal regions may be associated with non-motor symptoms in ET. These findings suggest that the ReHo could be utilized for investigations of functional-pathological mechanism of ET.

To explore the incidence of depression in movement disorders and associated factors. A total of 121 Parkinson's disease (PD) patients from August 2010 to June 2011 and 62 ET patients from July 2009 to June 2010 were recruited. All of them were outpatients of our hospital. PD patients received the unified Parkinson's disease rating scale (UPDRS) -motor examination and a modified Hoehn and Yahr scale to stage the severity of their disorders while 62 essential tremor (ET) patients were evaluated with tremor rating scale for tremor-motor examination (items 1 - 15 of rating scale). All participants completed Hamilton depression rating scale (24 items) to measure the presence and degree of symptoms of depression. It was found that 56.2% of PD patients and 53.2% of ET patients were depressed (HAMD score of 8 or higher). Among them, the rates of mild depression were 38.9% and 35.5%, moderate depression 15.7% and 17.7% and severe depression 1.7% and 0% in PD and ET patients respectively. No significant differences existed between each group. The factor scores of cognitive impairment were 1.81 ± 1.86 and 1.04 ± 1.07 in PD and ET patients while those of sense of despair were 2.95 ± 1.97 and 4.09 ± 2.08 in each group. The differences had statistical significance in two factor scores of two groups (P < 0.05). No differences in anxiety/somatization, lose weight, day-and-night changes, block and sleep disorders between two groups. For PD patients, the motor score of UPDRS-III was positively correlated with total HAMD score (r = 0.511, P < 0.01). Similarly, for ET patients, tremor rating scale for tremor-motor subscale score and HAMD score were positively correlated (r = 0.828, P < 0.01). As two common movement disorders, PD and ET have a high incidence of depression. The severity of depression is similar in two groups. There is no significant intra-group difference in severity and frequency of depression. The most common symptoms are anxiety somatization, anhedonia, working difficulty, slowness and sleep disturbance. The depression and motor symptoms are positively correlated. Like the non-motor symptoms in PD, we should also pay attention to the non-motor symptoms in ET.

Voice Analysis in Patients with Essential Tremor

Essential tremor (ET) is a prevalent movement disorder, yet current therapeutic options remain limited. Emerging evidence implicates leucine-rich repeat and immunoglobulin-like domain-containing protein (Lingo-1) and neuroinflammation in the pathophysiology of ET. This study aimed to investigate whether agmatine, a biogenic amine neuromodulator attenuates tremors and modulates the expression of Lingo-1 and proinflammatory markers in a rodent model of ET. Tremor was induced in male Swiss Webster mice through intraperitoneal injections of harmaline (10mg/kg) on Days 1, 3, and 5 of the study. During the same period, agmatine (40mg/kg) was administered for 5 consecutive days. Behavioral assessments of tremor severity, gait, balance, muscular strength, locomotion, anxiety-like behavior, and memory were conducted. Moreover, Lingo-1 and interleukin (IL)-6 gene expression was examined in the cerebellum using real-time polymerase chain reaction (RT-PCR). Our findings demonstrated that agmatine administration significantly reduced tremors, ameliorated anxiety-like behaviors, and attenuated harmaline-induced locomotor deficits. At the molecular level, agmatine treatment significantly suppressed the overexpression of Lingo-1 elicited by harmaline. Moreover, IL-6 expression was attenuated to an extent comparable to control levels. Collectively, this study provides the first evidence that agmatine dampens tremor severity, improves behavioral outcomes, and modulates key pathways implicated in ET pathogenesis in a rodent model. The ability of agmatine to normalize Lingo-1 and IL-6 expression suggests regulation of these pathways could underlie its neuroprotective action. These results suggest promise for agmatine as a prospective therapeutic agent in ET.

Objective: To evaluate whether patients with Essential tremor (ET) have an increased prevalence of anosmia, depression, constipation and REM sleep behavior disorder (RBD). Background Cases of ET have been described with Lewy body inclusions, the hallmark of Parkinson disease (PD). Years before the appearance of their motor syndrome, patients with PD may suffer from anosmia, depression, constipation and RBD. Design/Methods: Patients with ET according to published criteria were enrolled. Telephone interviews were conducted to evaluate the presence or absence of anosmia, depression using the Geriatric Depression Scale - 15, constipation using Rome III diagnostic criteria and RBD using the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ). The Parkinson Disease Non-Motor Symptoms Questionnaire (PD NMS) was used to detect other non-motor symptoms. Results: 46 patients participated in the study. Their mean age was 57.17 ± 19.48 (13-86), the mean duration of ET was 24.67 ± 19.80 years and the mean age of onset of ET was 31.49 ± 22.57. Of these, 4.5% reported olfaction change or loss, 43.5% had a RBDSQ score suggesting the presence of RBD, 21.7% had constipation, 23.9% had depression, whereas 37% had had depression in the past. In contrast, in the general population, prevalence of hyposmia / anosmia is 1.60%, or RBD is 0.38 to 0.5%, of depression is 5-17%. The prevalence of constipation in the general population is similar at 27%. Conclusions: Patients with ET have more RBD and more depression than found in the general population. Patients with dystonia and ET do not appear to represent a distinct entity according to our results. Larger studies with normal control groups are needed. Disclosure: Dr. Lacerte has nothing to disclose. Dr. Chouinard has received personal compensation for activities with Teva Neuroscience, Novartis, Shires, and Prestwick. Dr. Chouinard has received personal compensation in an editorial capacity from Novartis. Dr. Chouinard has received research support from Novartis, Teva Neuroscience, Elan Corporation, Schering-Plough Corporation, Merck & Co., Inc., Kyowa, and Amarin. Dr. Jodoin has received personal compensation for activities with Teva Neuroscience, and EMD Serono. Dr. Jodoin has received research support from Abbott Laboratories, Inc. Dr. Bernard has received personal compensation for activities with Actelion Pharmaceuticals Canada Inc, Santhera, Venture in Research as a participant on advisory boards and research teams. Dr. Diab has nothing to disclose. Dr. Panisset has received personal compensation for activities with Teva Neuroscience, Novartis, Allergan, and Merz.Dr. Panisset has received research support from Teva Neuroscience, Novartis, and Allergan.

Background:Essential tremor (ET) is the most common adult movement disorder, characterized by several motor and increasingly well recognized non-motor symptoms. Sensory deficits, such as hearing impairment and olfactory dysfunction, are amongst them. This review analyzes the available evidence of these sensory deficits and their possible mechanistic basis in patients with ET.Method:A PubMed literature search on the topic was performed in the May 2019 database.Results:Nineteen articles on hearing impairment and olfactory dysfunction in ET patients were identified. The prevalence of hearing impairment is higher in ET patients than healthy controls or Parkinson disease. Cochlear pathologies are suggested as the underlying cause, but there is still a lack of information about retrocochlear pathologies and central auditory processing. Reports on olfactory dysfunction have conflicting results. The presence of mild olfactory dysfunction in ET was suggested. Conflicting results may be due to the lack of consideration of the disease’s heterogeneity, but according to recent data, most studies do not find prominent evidence of olfactory loss in ET.Conclusion:Although there is increasing interest in studies on non-motor symptoms in ET, there are few studies on sensory deficits, which are of particularly high prevalence. More studies are needed on to investigate the basis of non-motor symptoms, including sensory deficits.

Essential tremor (ET) is a prevalent movement disorder that also includes nonmotor symptoms such as anxiety, depression, and cognitive impairment. Deep brain stimulation (DBS) is an established treatment for ET, yet its impact on nonmotor symptoms remains unclear. This study aims to describe neuropsychological outcomes following ventral intermediate nucleus (VIM) DBS in a large cohort of patients with ET and identify factors associated with changes in depression and cognitive function. A retrospective cohort study of patients who had undergone VIM DBS was performed. Inclusion criteria were ET diagnosis, surgery between October 2007 and March 2020, and available pre- and post-DBS neuropsychological testing results. Neuropsychological measures included the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and cognitive measures assessing attention, executive function, language, memory, and visuospatial function. Post-DBS tremor improvement was graded, and active electrode coordinates and stimulation parameters were identified. Statistical analyses included descriptive statistics, t-tests to compare pre- and postoperative scores at the group level, and one-way analysis of variance to compare variables among patients who improved, were stable, or worsened in psychiatric and cognitive characteristics after DBS. One hundred thirty-nine patients met the study inclusion criteria. BDI-II scores significantly decreased postoperatively (9.82 ± 6.77 vs 8.29 ± 6.18, p < 0.001, Cohen's d = 0.176), whereas BAI scores remained unchanged. Both language (p = 0.003, Cohen's d = 0.259) and memory (p < 0.001, Cohen's d = 0.336) domains showed statistically significant small-magnitude declines following surgery, whereas attention, executive function, and visuospatial function were unchanged. Patients with improved depression (14.3%) following VIM DBS had significantly higher BDI-II scores preoperatively (p < 0.001, ω2 = 0.226). Patients with worsened language (18.7%) had higher preoperative language scores (p < 0.001, ω2 = 0.058). Patients with worsened memory (15.1%) had higher BAI scores preoperatively (p = 0.002, ω2 = 0.079). Preoperative scores were similar between patients with improved and worsened overall cognition postsurgery. Patients with improved overall cognition had improvements in attention, language, and visuospatial function. VIM DBS for ET did not result in large-magnitude neuropsychological changes. There were statistically significant, though likely not clinically meaningful, small-magnitude improvements in depression and worsening in language and memory scores. Associations were found between multiple preoperative mood and cognitive scores and post-DBS neuropsychological changes. These findings can help inform clinical decision-making and patient counseling for DBS.

Essential tremor (ET) is a common movement disorder characterized by persistent limb tremors. Currently, no effective treatment for ET exists. Natural plant-derived compounds, like the flavonoid, quercetin may provide therapeutic benefits, particularly when delivered in nanoemulsion formulations that enhance bioavailability and efficacy. This study evaluated the neuroprotective potential of quercetin nanoemulsion (Que-NE) in a harmaline-induced mouse model of ET. Thirty-two male Swiss mice were randomly divided into four groups (n = 8 each): Control, Harmaline (10mg/kg, i.p., on days 3, 5, and 7), Que-NE (20mg/kg, i.p., for 7 days), and Harmaline + Que-NE. Harmaline was used to reliably induce tremor via olivocerebellar hyperexcitability. Behavioral performance was assessed using the open field, elevated plus maze, tail suspension, wire grip, rotarod, and passive avoidance tests. Expression of NF-κB, TNF-α, IL-1β, IL-6, NMDA receptor, and Lingo-1 was determined by RT-PCR. Que-NE significantly reduced harmaline-induced tremor severity (p < 0.0001), decreased immobility time in the tail suspension test (p = 0.0003), and improved open field anxiety-like behaviors compared with harmaline alone (P = 0.0012). Que-NE downregulated pro-inflammatory mediators (P < 0.0001) and reduced Lingo-1 gene expression (P < 0.0001). However, Que-NE showed limited efficacy in severe motor coordination tasks (rotarod, wire grip) and passive avoidance memory. Que-NE exerts measurable anti-inflammatory, anxiolytic, and antidepressant-like effects in the harmaline model of ET. The impact of Que-NE on improving motor deficits, reducing inflammatory markers, and suppressing inhibitors of synaptic plasticity highlights the potential of Que-NE as a disease-modifying strategy. However, dose-response, protein-level, and long-term studies are needed to evaluate the therapeutic potential of Que-NE for ET management.

Non-motor symptoms in essential tremor: A review of the current data and state of the field

Essential tremor (ET) is one of the most common movement disorders. Over the last 10years, magnetic resonance imaging (MRI) has shed light on the structural and functional abnormalities possibly involved in ET pathophysiology. In this systematic review, we aimed to identify the cortical and subcortical structures involved and the role that different brain areas play in the pathophysiology of motor and non-motor ET features. We found that structural (grey and white matter) cerebellar damage and connectivity alterations between the cerebellum and various cortical areas play a role in both motor and non-motor symptoms of ET. In particular, many studies found an association between MRI findings and non-motor symptoms.