Integrative Multi-Omics Analysis Prioritizes Candidate Genes for Essential Tremor and Reveals a Gap Between Computational Prediction and Experimental Validation.

The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown. The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches. Case-control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome-wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome-wide association study (TWAS) was done to identify novel risk genes for ET. We identified several novel dysregulated genes, including CACNA1A and SHF. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, SHF, is associated with a blood pressure medication (P = 9.3E-08), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in SHF when treated, suggesting it may rescue the underexpression. We found that calcium-related pathways were enriched across the GWGAS, TWAS, and transcriptome. SHF was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of SHF. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes. © 2020 International Parkinson and Movement Disorder Society.

Linking LINGO1 to essential tremor

Experimental and clinical data indicate that the cerebellum is involved in the pathophysiology of advanced stages of essential tremor (ET). The aim of this study was to determine whether a dysfunction also affects cerebellar structures involved in eye movement control. Eye movements of 14 patients with ET and 11 age-matched control subjects were recorded using the scleral search-coil technique. Vestibular function was assessed by electro-oculography. Eight ET patients had clinical evidence of intention tremor (ET(IT)); six had a predominantly postural tremor (ET(PT)) without intention tremor. ET patients showed two major deficits that may indicate cerebellar dysfunction: (i) an impaired smooth pursuit initiation; and (ii) pathological suppression of the vestibulo-ocular reflex (VOR) time constant by head tilts ('otolith dumping'). In the step ramp smooth pursuit paradigm, the initial eye acceleration in the first 60 ms of pursuit generation was significantly reduced in ET patients, particularly in ET(IT) patients, by approximately 44% (mean 23.4 degrees/s(2)) compared with that of control subjects (mean 41.3 degrees/s(2)). Subsequent steady-state pursuit velocity and sinusoidal pursuit gain (e.g. 0.4 Hz: 0.90 versus 0.78) were also significantly decreased in ET patients, whereas pursuit latency was unaffected. The intention tremor score correlated with the pursuit deficit, e.g. ET(IT) patients were significantly more affected than ET(PT) patients. Gain and time constant (tau) of horizontal VOR were normal, but suppression of the VOR time constant by head tilt ('otolith dumping') was pathological in 41% of ET patients, particularly in ET(IT) patients. Saccades and gaze-holding function were not impaired. The deficit of pursuit initiation, its correlation with the intensity of intention tremor, and the pathological VOR dumping provide additional evidence of a cerebellar dysfunction in the advanced stage of ET, when intention tremor becomes part of the clinical symptoms, and point to a common pathomechanism. The oculomotor deficits may indicate an impairment of the caudal vermis in ET.

Prior studies suggest that patients with essential tremor (ET) have increased rates of healthcare utilization, but the reason for this increased use is unknown. The objective of this study was to evaluate the reasons for healthcare use among ET patients. This was a retrospective cross-sectional study of ET patients with an admission or emergency department (ED) visit at a tertiary health system from 2018-2023. Patients were matched on an encounter level with control patients based on propensity scores incorporating age, sex, race, and co-morbid conditions. The primary outcome was the odds of an encounter for each diagnostic category comparing ET patients with matched controls. Only inpatient admissions for neurologic diagnoses were more likely for ET compared to control patients (odds ratio (OR) 3.73, 95% confidence interval (CI) 2.54 - 5.49, p < 0.001). Once admissions related to the surgical treatment of tremor were excluded, admissions for neurologic diagnoses were equally likely among ET and control patients (OR 0.96, 95% CI 0.59 - 1.57, p = 0.88). Surgical treatment of tremor appears to be a key driver of healthcare use among ET patients. Future investigations should examine the pattern of healthcare use of ET patients before and after surgery. Prior studies have shown increased healthcare use among essential tremor (ET) patients. The objective of this study was to evaluate the reasons for healthcare use among ET patients compared to matched control patients. Surgical treatment of tremor was found to be a key driver of healthcare use among ET patients.

Essential tremor (ET) is the most common movement disorder among adults. Cerebellar dysfunction is thought to be involved in the pathogenesis of ET; however, imaging, electrophysiological studies, and clinical observations have suggested that the cerebral cortex also may participate. We sought to investigate the possible motor cortical contribution to ET by assessing response to continuous theta-burst stimulation (cTBS), a recognized tool that can produce transient plastic changes, in the primary motor and premotor cortex of patients with ET. We compared parameters, including motor-evoked potential amplitude, cortical silent period, and short-interval intracortical inhibition, before and after applying cTBS in healthy controls and patients with ET. We found that, although cTBS applied to either the motor or premotor cortex was capable of producing a suppressive effect on motor cortical excitability in ET patients, the effects lasted for a significantly shorter time compared with the effect produced in healthy individuals. The change seen in measures of intracortical inhibition after motor cortical or premotor cTBS in healthy controls was reduced or absent in the ET patients. Tremor amplitude was decreased significantly after applying cTBS over either the motor or premotor cortex, but the tremor frequency remained unchanged. These findings suggest that inhibitory circuits within the motor cortex are aberrant and less modifiable in ET patients. The reduced plasticity in response to motor and premotor TBS supports the theory of abnormal gamma-aminobutyric acid (GABA) modulation in ET.

To explore the incidence of cognitive dysfunction and associated factors in 62 essential tremor (ET) cases, 60 normal controls and 61 Parkinson's disease (PD) cases. A total of 62 ET and 61 PD patients from September 2009 to September 2013 were recruited from our outpatient clinic. ET patients received the Tremor Rating Scale for Tremor-motor examination (items 1-15 of rating scale) while 61 PD patients were examined with the Unified Parkinson's Disease Rating Scale (UPDRS)-motor examination and a modified Hoehn and Yahr scale for staging disorder severity. All participants completed Montreal Cognitive Assessment (MoCA) Beijing version for measuring cognitive functions. And depression was evaluated by the Hamilton Depression Scale (HAMD). The serum levels of uric acid were tested. A MoCA score <26 (at least mildly cognitive) was observed in 14 (23.3%) normal controls, compared to 24 (38.7%) ET cases and 27 (44.3%) PD cases (P = 0.045 when comparing all 3 groups, and P = 0.532 when comparing ET and PD). The factor scores of visual space/execution were 4.1 ± 1.0, 3.8 ± 1.1 and 3.2 ± 1.6 in normal controls, ET and PD patients, the factor scores of naming 2.9 ± 0.4, 2.8 ± 0.6 and 2.3 ± 0.8 in control, ET and PD patients, the factor scores of delay memory 3.9 ± 0.9, 2.7 ± 1.3 and 2.5 ± 1.7 in control, ET and PD patients. Statistical differences existed in visual space/execution, naming and delay memory (P < 0.05) among 3 groups. Yet there were no statistical differences in attention, language, abstract and directional among 3 groups. Statistical differences existed in visual space/execution and naming between ET and PD patients (P < 0.05). PD cases had the lowest visual space/execution score, followed by ET (intermediate) and highest scores in controls (P < 0.05). In ET patients, cognitive scores were correlated with serum levels of uric acid, education, tremor Rating Scale for Tremor-motor subscale score and depression levels (r = 0.589, P = 0.000; r = 0.449, P = 0.010; r = 0.452, P = 0.009; r = 0.466, P = 0.025). In PD patients, cognitive scores correlated with serum levels of uric acid, education, score of UPDRS-III and depression levels (r = 0.694, P = 0.000; r = 0.614, P = 0.000; r = 0.604, P = 0.000; r = 0.376, P = 0.000). The incidence of cognition is higher in ET and PD. There were no significant inter-group differences for cognition frequency. The most frequently endorsed symptoms were poor visual spatial ability, execution disturbance and delayed recall disorders. Some connition scores in ET were intermediate between those of PD cases and normal controls. Thus a mild form of connition dysregulation may be present in ET. The degree of cognition symptoms is correlated with serum levels of uric acid, education and serious motor.

Imaging studies investigating cerebellar gray matter (GM) in essential tremor (ET) showed conflicting results. Moreover, no large study explored the cerebellum in ET patients with resting tremor (rET), a syndrome showing enhanced blink reflex recovery cycle (BRrc). To investigate cerebellar GM in ET and rET patients using voxel-based morphometry (VBM) analysis. Seventy ET patients with or without resting tremor and 39 healthy controls were enrolled. All subjects underwent brain 3T-MRI and BRrc recording. We compared the cerebellar GM volumes between ET (n = 40) and rET (n = 30) patients and controls through a VBM analysis. Moreover, we investigated possible correlations between cerebellar GM volume and R2 component ofBRrc. rET and ET patients had similar disease duration. All rET patients and none of ET patients had enhanced BRrc. No differences in the cerebellar volume were found when ET and rET patients were compared to each other or with controls. By considering together the two tremor syndromes in a large patient group, the VBM analysis showed bilateral clusters of reduced GM volumes in Crus II in comparison with controls. The linear regression analysis in rET patients revealed a cluster in the left Crus II where the decrease in GM volume correlated with the R2BRrc increase. Our study suggests that ET and rET are different tremor syndromes with similar mild cerebellar gray matter involvement. In rET patients, the left Crus II may play a role in modulating the brainstem excitability, encouraging further studies on the role of cerebellum in these patients.

Background:There are few medications for the treatment of essential tremor (ET). One of these, primidone, which is one of only two front-line agents, is associated with considerable adverse drug reactions (ADRs). It is unclear why some primidone-treated ET patients develop ADRs whereas others do not, and why these ADRs seem to be more prevalent in ET patients than primidone-treated patients with epilepsy.Objective:To review several possible explanations underlying the above-referenced differences.Methods:A literature search was conducted in PubMed in October 2021. Studies reporting the ADRs of primidone in different neurological conditions were comprehensively reviewed.Discussion:Although there were no head-to-head data, a review of the previous studies on ET and epilepsy patients indicates that the former is relatively more intolerant to primidone. Moreover, not all ET patients develop ADR of similar nature or severity. We discuss several potential mechanisms for this variability in the intolerance to primidone. These include: (i) older age (ET vs. epilepsy patients), (ii) cross-tolerance to primidone in patients with epilepsy, (iii) neurobiological (GABA-related) abnormalities associated with ET.Conclusion:We speculate that there are several possible explanations for primidone intolerance in ET. These possibilities should be tested in future studies, and we propose the roadmap for designing these studies. It is of value to obtain detailed insight into these complex issues because primidone remains one of the few frontline anti-tremor medications in ET. Answers to issues we have raised in this article could facilitate more customized formulation of primidone in ET patients.

Objective: Essential tremor (ET) is a common movement disorder that has a high heritability. A number of genetic studies have associated different genes and loci with ET, but few have investigated the biology of any of these genes. STK32B was significantly associated with ET in a large genome-wide association study (GWAS) and was found to be overexpressed in ET cerebellar tissue. The objective of this study is to determine the effects of overexpressed STK32B in cerebellar DAOY cells.Methods: Here, we overexpressed STK32B RNA in human cerebellar DAOY cells and used an RNA-Seq approach to identify differentially expressed genes (DEGs) by comparing the transcriptome profile of these cells to one of the control DAOY cells.Results: Pathway and gene ontology enrichment identified axon guidance, olfactory signaling, and calcium-voltage channels as significant. Additionally, we show that overexpressing STK32B affects transcript levels of previously implicated ET genes such as FUS.Conclusion: Our results investigate the effects of overexpressed STK32B and suggest that it may be involved in relevant ET pathways and genes.

Eye movements in essential tremor patients with parkinsonian and cerebellar signs

BackgroundThe search for essential tremor (ET) genes is active, and it is only a matter of time before genetic tests become available. Genetic testing preferences in families have been studied in numerous other neurological disorders but there are no published data about ET.MethodsWe surveyed 34 ET probands and their relatives (43 affected, 28 unaffected) enrolled in our Family Study of Essential Tremor to assess their interest in genetic testing. We examined whether clinical factors influenced their interest in testing. Clinical utility (“Your physician will be able to use the information obtained to improve your care”) and penetrance (“How likely an individual who carries an ET gene is to develop ET”) were defined for participants.ResultsInterest in genetic testing was high in ET families (90/105 [85.7%]). There was a significant difference between affected (including probands and affected relatives) and unaffected relatives in terms of their interest in genetic testing, with the former being more interested (70/77 [90.9%] vs. 20/28 [71.4%] p = 0.04). Participants were more likely to want testing in the scenarios with high clinical utility; disease penetrance was not a determining factor (all p < 0.05). Sixteen hypothetical factors were identified that might influence a participant’s decision to undergo genetic testing for ET.DiscussionInterest in genetic testing was high in ET families. While genetic testing is not currently available for ET, the hunt for ET genes is ongoing, and this is a highly familial disorder. Understanding genetic testing preferences will greatly aid clinicians once a genetic test becomes available.

Essential tremor (ET) is one of the most prevalent movement disorders. However, the complete understanding of ET pathophysiology remains elusive. To explore the pathophysiological role of primary motor cortex (M1) in ET, specifically exploring its neurophysiological changes and their correlation with voluntary motor abnormalities. We recruited 30 ET patients and 18 healthy controls (HC). Evaluations were conducted on patients using clinical scales. Transcranial magnetic stimulation (TMS) was used to assess M1 excitability, including motor thresholds and motor evoked potentials (MEPs) input/output curve, together with intracortical excitability measures. Long-term potentiation (LTP)-like plasticity of M1 was tested using intermittent theta-burst stimulation (iTBS). Objective assessments of tremor and voluntary movement execution during finger-tapping were conducted through kinematic analysis. Finally, we explored the potential relationship between TMS, clinical, and kinematic data. Compared with HC, ET patients had lower excitability, intracortical inhibition, and lower LTP-like plasticity of M1. ET patients also exhibited slower finger-tapping performance compared with HC. Among ET patients, the degree of movement slowing during finger-tapping correlated with alterations in corticospinal excitability. Specifically, reduced M1 excitability was associated with lower finger-tapping velocity. No other correlations were found. The study findings reveal neurophysiological alterations of M1 in ET and demonstrate correlations between excitability measures and voluntary motor performance. These results provide novel insight into the pathophysiology of ET, emphasizing the role of M1 changes in this condition. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The clinical benefits of targeting the ventral intermediate nucleus (VIM) for the treatment of tremors in essential tremor (ET) patients suggest that the VIM is a key hub in the network of tremor generation and propagation and that the VIM can be considered as a seed region to study the tremor network. However, little is known about the central tremor network in ET patients. Twenty-six ET patients and 26 matched healthy controls (HCs) were included in this study. After considering structural and head-motion factors and establishing the accuracy of our seed region, a VIM seed-based functional connectivity (FC) analysis of resting-state functional magnetic resonance imaging (RS-fMRI) data was performed to characterize the VIM FC network in ET patients. We found that ET patients and HCs shared a similar VIM FC network that was generally consistent with the VIM anatomical connectivity network inferred from normal nonhuman primates and healthy humans. Compared with HCs, ET patients displayed VIM-related FC changes, primarily within the VIM-motor cortex (MC)-cerebellum (CBLM) circuit, which included decreased FC in the CBLM and increased FC in the MC. Importantly, tremor severity correlated with these FC changes. These findings provide the first evidence that the pathological tremors observed in ET patients might be based on a physiologically pre-existing VIM - MC - CBLM network and that disruption of FC in this physiological network is associated with ET. Further, these findings demonstrate a potential approach for elucidating the neural network mechanisms underlying this disease.

This study examined differences in selected phonatory characteristics of essential tremor (ET) patients and normal, matched controls. All patients exhibited limb tremor of 4–10 Hz and minimal to severe audible vocal tremor. Tape-recorded speech sample for 14 ET and normal speakers from our subject pool were analyzed acoustically to determine individual and group mean fundamental frequency (f0) measures. Both the female and male ET groups had a significantly lower mean f0 (20–40 Hz) than that of their matched controls during sustained vowel productions. As well, the performance patterns of the ET and control groups were markedly different across repeated trials of vowel production. In connected speech, the male ET speakers' average f0 and phonation range were significantly reduced relative to that of their matched controls. Although there was no statistical difference, female ET speakers also tended to have a reduced mean f0 and phonation range in connected speech compared to their matched controls. These preliminary findings suggest that an abnormally low f0 may be a critical factor contributing to the perception of voice tremor in ET patients. [Work supported by Center on Aging, KUMC.]

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.