Brain structure comparison among Parkinson disease, essential tremor, and healthy controls using 7T MRI.

Both Parkinson disease (PD) and Essential tremor (ET) are movement disorders causing tremors in elderly individuals. Although PD and ET are different disease, they often present with similar initial symptoms, making their differentiation challenging with magnetic resonance imaging (MRI) techniques. This study aimed to identify structural brain differences among PD, ET, and health controls (HCs) using 7-Tesla (T) MRI. We assessed the whole-brain parcellation in gray matter volume, thickness, subcortical volume, and small regions of basal ganglia in PD (n = 18), ET (n = 15), and HCs (n = 18), who were matched for age and sex. Brain structure analysis was performed automatic segmentation through Freesurfer software. Small regions of basal ganglia were manually segmented by ITK-SNAP. Additionally, we examined the associations between clinical indicators (symptom duration, unified Parkinson diseases rating scale (UPDRS), and clinical rating scale for tremor (CRST)) and brain structure. PD showed a significant reduction in gray matter volume in the postcentral region compared to ET. ET showed a significant reduction in cerebellum volume compared to HCs. There was a negative correlation between CRST scores (B and C) and gray matter thickness in right superior frontal in ET. This study demonstrated potential of 7T MRI in differentiating brain structure differences among PD, ET, and HCs. Specific findings, such as parietal lobe atrophy in PD compared to ET and cerebellum atrophy in ET compared to HCs, the importance of advanced imaging techniques in accurately diagnosing and distinguishing between movement disorders that present with similar initial symptoms.

A Novel KCNN2 Variant in a Family with Essential Tremor Plus: Clinical Characteristics and In Silico Analysis.

BACKGROUND: Essential tremor (ET) is one of the more common movement disorders. Current diagnosis is solely based on clinical findings. ET appears to be inherited in an autosomal dominant pattern. Several loci on specific chromosomes have been studied by linkage analysis, but the causes of essential tremor are still unknown in many patients. Genetic studies described the association of several genes with familial ET. However, they were found only in distinct families, suggesting that some can be private pathogenic variants. AIM OF THE STUDY: to characterize the phenotype of an Italian family with ET and identify the genetic variant associated. METHODS: Clinical and genetic examinations were performed. Genetic testing was done with whole-exome sequencing (WES) using the Illumina platform. Bidirectional capillary Sanger sequencing was used to investigate the presence of variant in all affected members of the family. In silico prediction of pathogenicity was used to study the effect of gene variants on protein structure. RESULTS: The proband was a 15-year-old boy. The patient was the first of two children of a non-consanguineous couple. Family history was remarkable for tremor in the mother line. His mother suffered from bilateral upper extremity kinetic tremors (since she was 20 years old), anxiety, and depression. Other relatives referred bilateral upper extremity tremors. In the index case, WES analysis performed supposing a dominant mode of inheritance, identified a novel heterozygous missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) (NM_021614.3: c.1145G>A, p.Gly382Asp). In the pedigree investigation, all carriers of the gene variant had ET and showed variable expressivity, the elder symptomatic relative showing cognitive impairment and hallucinations in the last decade, in addition to tremor since a young age. The amino acid residue #382 is located in a transmembrane region and in silico analysis suggested a causative role for the variant. Modelling of the mutant protein structure showed that the variant causes a clash in the protein structure. Therefore, the variant could cause a conformational change that alters the ability of the protein in the modulation of ion channels Conclusions: The KCNN2 gene variant identified could be associated with ET. The variant could modify a voltage-independent potassium channel activated by intracellular calcium.

Reproducibility of cerebellar involvement as quantified by consensus structural MRI biomarkers in advanced essential tremor.

Essential tremor (ET) is the most prevalent movement disorder with poorly understood etiology. Some neuroimaging studies report cerebellar involvement whereas others do not. This discrepancy may stem from underpowered studies, differences in statistical modeling or variation in magnetic resonance imaging (MRI) acquisition and processing. To resolve this, we investigated the cerebellar structural differences using a local advanced ET dataset augmented by matched controls from PPMI and ADNI. We tested the hypothesis of cerebellar involvement using three neuroimaging biomarkers: VBM, gray/white matter volumetry and lobular volumetry. Furthermore, we assessed the impacts of statistical models and segmentation pipelines on results. Results indicate that the detected cerebellar structural changes vary with methodology. Significant reduction of right cerebellar gray matter and increase of the left cerebellar white matter were the only two biomarkers consistently identified by multiple methods. Results also show substantial volumetric overestimation from SUIT-based segmentation-partially explaining previous literature discrepancies. This study suggests that current estimation of cerebellar involvement in ET may be overemphasized in MRI studies and highlights the importance of methods sensitivity analysis on results interpretation. ET datasets with large sample size and replication studies are required to improve our understanding of regional specificity of cerebellum involvement in ET. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 21 March 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.6084/m9.figshare.19697776 .

Gene Expression Analysis of Laser-Captured Purkinje Cells in the Essential Tremor Cerebellum.

Essential tremor (ET) is a common, progressive neurological disease characterized by an 8-12-Hz kinetic tremor. Despite its high prevalence, the patho-mechanisms of tremor in ET are not fully known. Through comprehensive studies in postmortem brains, we identified major morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs), suggesting that PC damage is central to ET pathogenesis. We previously performed a transcriptome analysis in ET cerebellar cortex, identifying candidate genes and several dysregulated pathways. To directly target PCs, we purified RNA from PCs isolated by laser capture microdissection and performed the first ever PC-specific RNA-sequencing analysis in ET versus controls. Frozen postmortem cerebellar cortex from 24 ETs and 16 controls underwent laser capture microdissection, obtaining ≥2000 PCs per sample. RNA transcriptome was analyzed via differential gene expression, principal component analysis (PCA), and gene set enrichment analyses (GSEA). We identified 36 differentially expressed genes, encompassing multiple cellular processes. Some ET (13/24) had greater dysregulation of these genes and segregated from most controls and remaining ETs in PCA. Characterization of genes/pathways enriched in this PCA and GSEA identified multiple pathway dysregulations in ET, including RNA processing/splicing, synapse organization/ion transport, and oxidative stress/inflammation. Furthermore, a different set of pathways characterized marked heterogeneity among ET patients. Our data indicate a range of possible mechanisms for the pathogenesis of ET. Significant heterogeneity among ET combined with dysregulation of multiple cellular processes supports the notion that ET is a family of disorders rather than one disease entity.

Ability of Swept-source OCT and OCT-angiography to detect neuroretinal and vasculature changes in patients with Parkinson disease and essential tremor.

BACKGROUND/OBJECTIVES: To evaluate the ability of swept-source optical coherence tomography (SS-OCT) implemented with angiography analysis (SS-OCTA) to detect neuro-retinal and vasculature changes in patients with Parkinson's disease (PD) and essential tremor (ET), and to distinguish between both pathologies. SUBJECTS/METHODS: A total 42 PD and 26 ET patients and 146 controls underwent retinal evaluation using SS-OCT plus OCT-Angio™. The macular (m) and peripapillary (p) retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), and macular vasculature were assessed. A Linear discriminant function (LDF) was calculated to evaluate the diagnostic ability of SS-OCTA in both PD and ET. RESULTS: PD patients presented a reduction in mRNFL (p < 0.005), mGCL (all sectors, p < 0.05) and pRNFL (p < 0.005) vs healthy controls, and in mRNFL and pRNFL vs ET patients (p < 0.001). ET patients showed a significant reduction in mGCL vs controls (p < 0.001). No differences were observed in the macular vasculature between groups. Predictive diagnostic variables were significant only for PD and a LDF was obtained with an area under the ROC curve of 0.796. CONCLUSIONS: Neuro-retinal thinning is present in both diseases, being greater in PD. While SS-OCT could be useful in diagnosing ET and PD, the diagnostic potential for SS-OCTA based on an LDF applies only to PD, not ET.

Locus coeruleus degeneration and cerebellar gray matter changes in essential tremor.

BACKGROUND: The pathophysiology of essential tremor (ET) is not fully understood, and studies suggest pathological changes mainly occur in the cerebellum and locus coeruleus (LC). METHODS: Fifty-three ET patients, including 30 patients with head tremor (h-ET), 23 patients without head tremor (nh-ET), 71 age and education matched healthy controls (HCs) were enrolled. All participants underwent Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and T1 scans on a 3-Tesla MR system. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC) and the score of The Essential Tremor Rating Assessment Scale (TETRAS) and cerebellum gray matter (GM) volume. RESULTS: Significant difference of CNRLC was found between ET and HC groups. The CNRLC of ET groups is lower than the HC group (p = 0.031). Subgroup analysis showed that the CNRLC in nh-ET was significantly lower than HCs (p = 0.016). Compared to HCs, h-ETs showed marked atrophy in the cerebellum: the vermis IV-V and lobule VI (GRF corrected, p < 0.05). A significant negative correlation was found between CNRLC and the vermis lobule IV-V in h-ETs (r = - 0.651, p < 0.001). No significant correlation was found between CNRLC and TETRAS scores. CONCLUSION: The LC and the cerebellum might both involve in the pathophysiology of ET. LC evaluation using NM-MRI might be an effective tool for us to explore the pathophysiology of ET further.

Challenging functional connectivity data: machine learning application on essential tremor recognition.

BACKGROUND AND AIMS: This paper aimed to investigate the usefulness of applying machine learning on resting-state fMRI connectivity data to recognize the pattern of functional changes in essential tremor (ET), a disease characterized by slight brain abnormalities, often difficult to detect using univariate analysis. METHODS: We trained a support vector machine with a radial kernel on the mean signals extracted by 14 brain networks obtained from resting-state fMRI scans of 18 ET and 19 healthy control (CTRL) subjects. Classification performance between pathological and control subjects was evaluated using a tenfold cross-validation. Recursive feature elimination was performed to rank the importance of the extracted features. Moreover, univariate analysis using Mann-Whitney U test was also performed. RESULTS: The machine learning algorithm achieved an AUC of 0.75, with four networks (language, primary visual, cerebellum, and attention), which have an essential role in ET pathophysiology, being selected as the most important features for classification. By contrast, the univariate analysis was not able to find significant results among these two conditions. CONCLUSION: The machine learning approach identifies the changes in functional connectivity of ET patients, representing a promising instrument to discriminate specific pathological conditions and find novel functional biomarkers in resting-state fMRI studies.

Characterizing Lewy Pathology in 231 Essential Tremor Brains From the Essential Tremor Centralized Brain Repository.

The Essential Tremor Centralized Brain Repository is the largest repository of prospectively collected essential tremor (ET) brains (n = 231). Hence, we are uniquely poised to address several questions: What proportion of ET cases has Lewy pathology (LP)? What is the nature of that pathology and how does it relate to other comorbidities? Each brain had a complete neuropathological assessment, including α-synuclein immunostaining. We created a 10-category classification scheme to fully encapsulate the patterns of LP observed. Four metrics of cerebellar pathology were also quantified. Mean age at death = 89.0 ± 6.4 years. Fifty-eight (25.1%) had LP and 46 (19.9%) had early to late stages of Parkinson disease (PD). LP was very heterogeneous. Of 58 cases with LP, 14 (24.1%) clinically developed possible PD or PD after a latency of 5 or more years. There was a similar degree of cerebellar pathology in ET cases both with and without LP. In summary, 1 in 4 ET cases had LP-a proportion that seems higher than expected based on studies among control populations. Heterogeneous LP likely reflects clinical associations between ET and PD, and ET with Alzheimer disease-type neuropathology. These data further our understanding of ET and its relatedness to other degenerative diseases.

Essential tremor plus rest tremor: current concepts and controversies.

Since the initial description of Essential Tremor (ET), the entity of ET with rest tremor has proven to be a controversial concept. Some authors argued it could be a late manifestation of ET, others suggested it could be a variant of ET, yet others suggested it could represent a transitional state between ET and Parkinson's disease. The novel tremor classification has proposed the construct of ET-plus to differentiate patients with rest tremor from pure ET. However, there is no clarity of what ET-plus rest tremor represents. With the aim of shedding light on this controversial entity, we have, therefore, systematically reviewed all clinical, electrophysiological, imaging and anatomopathological studies indexed in the Medline database published both before and after the new tremor classification and involving patients with ET-plus rest tremor. Forty-four studies involving 4028 patients were included in this review and analyzed in detail by means of descriptive statistics. The results of the current review suggest that ET-plus rest tremor is a heterogenous group of conditions: thus, rest tremor might represent a late feature of ET, might reflect a different disorder with higher age at onset and lower dependance on genetic susceptibility than ET, might suggest the development of Parkinson's disease or might indicate a misdiagnosis of ET. The reviewed lines of evidence refuse recent claims arguing against the construct of ET-plus, which should be viewed as a syndrome with different possible underpinnings, and highlights methodological issues to be solved in future research.

Cognitive functioning in essential tremor without dementia: a clinical and imaging study.

BACKGROUND AND AIMS: To explore the cognitive functioning of ET patients without dementia and delineate its imaging counterpart. METHODS: We enrolled 99 subjects (49 non-demented ET patients and 50 education-matched healthy controls) that underwent neuropsychological and MRI evaluation. In order to identify the cognitive parameters that better reflect the profile of ET patients, we used a double statistical approach: (i) direct comparison between groups and (ii) machine learning approach with feature selection. Then, to evaluate the correlation between cognitive performances and the degree of brain atrophy in the ET group, we included the results derived from the uni- and multivariate analysis in whole-brain voxel-based morphometry (VBM) model. RESULTS: In ET patients, the univariate analysis showed differences in cognitive tests evaluating executive functions (FAB, MCST-CA), verbal memory-delayed recall (RAVLT-DR), and working memory (Digit Span B). The relative scores were significantly worse compared to controls, although within the normal range (subclinical dysfunctions). The machine learning approach also provided similar findings: tests exploring the executive functions, verbal memory, and language (RAVLT-DR, FAB, COWAT, RAVLT-IR, TOKEN) showed the highest importance rank in classification's task. Regardless of the explored test, the MRI analysis revealed a correlation (p < 0.005 uncorrected, whole brain) between test scores and widespread areas including cerebellum, inferior and middle frontal cortices, cingulate cortices, and temporal cortex. CONCLUSION: This study improves the knowledge on cognitive impairment in ET, as our findings demonstrate a heterogeneous pattern of cognitive dysfunction involving memory, executive function, and language domains in the ET group. This clinical profile relates with the deep involvement of the cerebellum and its connections with large-scale brain structures, suggesting that changes spreading in wide-ranging brain pathways may contribute to the physiopathology of cognitive dysfunction in ET.

Essential tremor and cognitive impairment: who, how, and why.

BACKGROUND AND AIMS: Recent years have witnessed the switch from considering essential tremor (ET) a monosymptomatic disorder to consider it as part of a spectrum, including other neurological signs, such as mild cognitive impairment and dementia, thus defining it as "ET plus." There are few data on cognitive impairment in ET patients. The aim of this review is to analyze the clinical characteristics of ET patients developing cognitive impairment, their neuropsychological profile, the underpinning mechanisms, and the possible biomarkers. METHODS: The authors performed a narrative review on cognitive decline in essential tremor, including articles written in English since the year 2000. DISCUSSION: The most recent pathogenetic theories of cognitive impairment in ET rely on the cerebellar dysfunction, being part of the Cerebellar Cognitive Affective Syndrome spectrum. Cognitive impairment in ET patients could be assessed through many tests that demonstrate the involvement of different domains, such as attention, executive functions, and language. There are some clinical characteristics of ET that may indicate a greater risk of developing cognitive impairment, namely, cerebellar symptoms, falls, age at onset, and family history. However, there are no established clinical, neurophysiological, neuropathological, and fluid biomarkers of cognitive impairment in ET. CONCLUSIONS: Increasing data are showing in ET the presence of cerebellar symptoms and cognitive impairment. Further studies are needed to better understand cognition in ET patients, and to define the boundary between ET and ET plus, since deeper phenotyping might have important clinical and therapeutic implications.

Chronic Encapsulated Expanding Hematoma After Gamma Knife Thalamotomy for Essential Tremor.

There have been no previous reports of chronic encapsulated expanding hematoma after Gamma Knife thalamotomy. The present case underwent Gamma Knife thalamotomy for essential tremor at the age of 78 years. Three- and 12-month posttreatment magnetic resonance imaging (MRI) showed small T2 high-intensity lesions on the target and along with the internal capsule. Hemiparesis developed 17 months after the treatment. Twenty months post treatment, T2-MRI showed a hypointense mass across the target and internal capsule. Gradual expansion of the mass was confirmed on MRI at 26-38 months. A 54-month posttreatment MRI showed marked expansion of the mass with multiple cysts surrounded by a T2-hypointense rim. Gadolinium-enhanced T1-MRI showed partial enhancement of the mass. MRI findings suggested a radiation-induced cavernoma. Hemiparesis, dysesthesia, and pain on the right side of the body persisted even after steroid therapy for several months. Long-term careful observation is necessary after Gamma Knife thalamotomy.

The Contribution of Neuroimaging to the Understanding of Essential Tremor Pathophysiology: a Systematic Review.

Essential tremor (ET) is one of the most common movement disorders. Over the last 10 years, 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.

Lesions of the cerebello-thalamic tract rather than the ventral intermediate nucleus determine the outcome of focused ultrasound therapy in essential tremor: A 3T and 7T MRI-study.

INTRODUCTION: The ventral intermediate nucleus of the thalamus (VIM) is an important relay station receiving cerebellar and pallidal fiber tracts. Data on structural visualization of the VIM however is limited and uncertainty prevails to what extent lesional approaches to treat tremor affect the VIM itself or passing tracts. The aim of the study was to analyze the localization of individual lesions with respect to the VIM and the cerebello-thalamic tract (CTT). METHODS: We employed ultrahigh resolution (7 Tesla) MRI to delineate the VIM and performed 3 T-DTI-imaging pre- and post-interventional in seven ET patients undergoing transcranial magnetic resonance guided focused ultrasound (tcMRgFUS). Tremor improvement was measured using a modified subscore of the Clinical Rating Scale for Tremor. RESULTS: All subjects showed substantial tremor improvement (88.5%, range 80.7%-94,8%) after tcMRgFUS. We found only a minor overlap of the lesions with the VIM (4%, range 1%-7%) but a larger overlap with the CTT (43%, range 23%-60%) in all subjects. CONCLUSIONS: Lesions within the CTT rather than the VIM seem to drive the tremorlytic response and clinical improvement in tcMRgFUS.

Clinical-Instrumental patterns of neurodegeneration in Essential Tremor: A data-driven approach.

INTRODUCTION: Essential Tremor (ET) is increasingly recognized as a complex disorder with additional clinical signs other than tremor. It is still unknown whether a unique pathophysiologic or neurodegenerative process underlies progression and prognosis of the disease. The aim of the study was to identify ET phenotypes through a clinical-instrumental data-driven approach and to characterize possible patterns of neurodegeneration. METHODS: ET patients were categorized using spatio-temporal and kinematic variables related to mobility and dynamic stability processed by motion transducers. Differences between the identified groups in clinical-demographic variables, neuropsychological performances and retinal parameters by Optical Coherence Tomography (OCT) segmentation analysis were tested. RESULTS: Twenty-five ET patients were studied. Based on clustering of kinematic and spatio-temporal gait parameters, two independent groups were identified: cluster "A" (N = 15) and cluster "B" (N = 10). Compared to group A, group B had overall worse performance in mobility, especially on turning tasks. Identified clusters did not differ in terms of age, age at onset and disease duration. Patients in group B had more head tremor and more severe action tremor in the upper limbs as compared to group A, demonstrating also worse performances on cognitive assessments. Based on OCT analysis, group B presented a reduced thickness of the retinal inner layer as compared to group A, suggesting underlying neurodegenerative processes. CONCLUSIONS: The presence of gait and mobility impairment, associated with midline tremor, cognitive decline and retinal degeneration suggests a subtype of ET associated with neurodegeneration.

Essential Tremor versus "ET-plus": A Detailed Postmortem Study of Cerebellar Pathology.

Essential tremor (ET) is among the most prevalent movement disorders, and by some accounts, the most common form of cerebellar degeneration. Over the past 15 years, we have carefully documented a large number of postmortem changes within the cerebellum; these cerebellar changes differ significantly between ET and controls. A recent Consensus Classification of tremor proposed that ET patients with other neurological signs aside from action tremor (e.g., parkinsonism, ataxia, cognitive changes, dystonia) should be segregated off as "ET-plus". This diagnostic concept has raised considerable controversy and its validity is not yet established. Indeed, "ET-plus" has not been distinguished from ET based on differences in genetics, pathology or prognosis. Here we determine whether ET cases differ from "ET-plus" cases in underlying pathological changes in the postmortem brain. We examined postmortem brains from 50 ET cases (24 ET and 26 ET-plus), using a set of 14 quantitative metrics of cerebellar pathology determined by histologic and immunohistochemical methods. These metrics reflect changes across the Purkinje cell (PC) body (PC counts, empty baskets, heterotopias), PC dendrites (swellings), PC axon (torpedoes and associated axonal changes), basket cell axonal hypertrophy and climbing fiber-PC dendrite synaptic changes. ET and ET-plus were similar with respect to 13 of 14 cerebellar pathologic metrics (p > 0.05). Only one metric, the linear density of thickened PC axon profiles, differed between these groups (ET = 0.529 ± 0.397, ET-plus = 0.777 ± 0.477, p = 0.013), although after correcting for multiple comparisons, there were no differences. If ET-plus were indeed a different entity, then the underlying pathological basis should be distinct from that of ET. This study demonstrated there were no pathological differences in cerebellar cortex between ET versus ET-plus cases. These data do not support the notion that ET and ET-plus represent distinct clinical-pathological entities.

Anatomical texture patterns identify cerebellar distinctions between essential tremor and Parkinson's disease.

Voxel-based morphometry is an established technique to study focal structural brain differences in neurologic disease. More recently, texture-based analysis methods have enabled a pattern-based assessment of group differences, at the patch level rather than at the voxel level, allowing a more sensitive localization of structural differences between patient populations. In this study, we propose a texture-based approach to identify structural differences between the cerebellum of patients with Parkinson's disease (n = 280) and essential tremor (n = 109). We analyzed anatomical differences of the cerebellum among patients using two features: T1-weighted MRI intensity, and a texture-based similarity feature. Our results show anatomical differences between groups that are localized to the inferior part of the cerebellar cortex. Both the T1-weighted intensity and texture showed differences in lobules VIII and IX, vermis VIII and IX, and middle peduncle, but the texture analysis revealed additional differences in the dentate nucleus, lobules VI and VII, vermis VI and VII. This comparison emphasizes how T1-weighted intensity and texture-based methods can provide a complementary anatomical structure analysis. While texture-based similarity shows high sensitivity for gray matter differences, T1-weighted intensity shows sensitivity for the detection of white matter differences.

Relative increase in cerebellar gray matter in young onset essential tremor: Evidence from voxel-based morphometry analysis.

This study is to investigate the presence of brain gray matter abnormalities in young onset essential tremor (ET) patients with arm tremor. Thirty ET patients together with 30 healthy volunteers were taken as candidates. Magnetic resonance imaging (MRI) was performed and voxel-based morphometry was used to compare gray matter density between the patients and volunteers. Washington Heights-Inwood Genetic Study of Essential Tremor (WHIGET) rating scale was applied to assess tremor severity in the patients. Eventually Twenty-Seven ET patients and Twenty-Seven volunteers were enrolled in the study. Voxel-based morphometry showed significant expansion of the bilateral cerebellum, occipital fusiform cortices, right inferior temporal gyrus, and precentral lobes (P < 0.05, TFCE corrected). Decrease in gray matter was detected only in the left parietal lobe. Region of interest analysis showed volume enlargement in thalamus, midbrain, and precuneus (P < 0.05, TFCE corrected). Importantly, significant negative correlation was found between the lateralized index of cerebellum and the tremor score which might implicate that the altered rightward lateralization in the cerebellum is possibly a response of the tremor effects in ET patients. Cerebellar gray matter expansion in young onset ET patients with arm tremor might be the result of compensation towards decline of cerebellar function.