Essential tremor (ET) is one of the most common neurological disorders among adults, and is the most common tremor disorder. ET has classically been viewed as a benign monosymptomatic condition. Yet over the past 10 years, a growing body of evidence indicates that this is a progressive condition that is clinically heterogeneous, and may be associated with a variety of different features such as gait abnormalities, parkinsonism, cognitive impairment, dementia, personality disturbances, depressive symptoms, and sensory abnormalities (e.g., mild olfactory dysfunction and hearing impairment). In addition, postmortem studies are showing a pathologically heterogeneous neurodegenerative disease. The emerging view is that ET might be a family of diseases, unified by the presence of kinetic tremor, but further characterized by etiological, clinical and pathological heterogeneity. The diagnosis of ET is clinical and made by history and physical examination. Effective pharmacological treatments for the disorder currently remain limited. Drugs are generally initiated when the tremor begins to interfere with the patient's ability to perform daily activities or when the tremor becomes embarrassing. For severe, medically refractory ET, thalamic ventralis intermedius nucleus deep brain stimulation may lessen tremor and improve function.

Essential tremor (ET), among the most common movement disorders, is characterized by 8–12 Hz action tremor of the upper extremities. Cognitive dysfunction is increasingly recognized. Postmortem studies of anterior cerebellar cortex, which plays a major role in motor function, have systematically identified morphologic changes centered on Purkinje cells (PCs) and adjacent neuronal connections, distinguishing ET from controls. However, the cerebellar cortex is compartmentalized into distinct functional anatomic regions, including control of cognition in posterior lobe. No systematic study of this posterior region has been undertaken in ET. Leveraging resources of the Essential Tremor Centralized Brain Repository, we compared the pathology across anterior and posterior hemispheric cerebellar cortices in each brain in a postmortem series of 123 brains in ET (n = 80) and controls (n = 43). We used 11 quantitative morphologic metrics that reflected PC loss, heterotopic PCs, PC dendritic changes, PC axonal changes (torpedoes, torpedo-associated and non-torpedo related), basket cell axonal hypertrophy, and climbing fiber-PC puncta changes. These metrics distinguished ET cases from controls in both anterior (11/11 metrics) and posterior regions (10/11 metrics) (p values 0.045 to < 0.0001), and 10/11 metrics demonstrated a greater burden of pathology in the ET anterior versus ET posterior cerebellar region (p values 0.045 to < 0.0001). Regional differences among controls were present to a lesser extent than in ET (6/11 metrics; p values 0.035 to < 0.0001). In a principal component analysis, these combined metrics segregated control and ET cases according to both diagnosis and cerebellar region. This is the first study to carefully document that pathology in the ET cerebellum extends beyond the anterior cerebellar region to also involve a posterior cerebellar region. In line with the prominent motor features of ET, the burden of cerebellar pathology was greater in the anterior region. These results advance our nascent understanding of the underlying neuropathological substrate of this highly prevalent disease.

INTRODUCTION:Elders with essential tremor (ET) are at a heightened risk for incident dementia. Although the consequences of this diagnosis are formidable, we know little about what factors elevate the risk of ET-dementia. We analyzed data from a large, prospective, longitudinal study of cognitive status in an ET cohort to examine whether a range of demographic, lifestyle, and clinical variables contribute to dementia risk. METHODS:The cognitive status (normal cognition [NC], mild cognitive impairment [MCI], or dementia) of a baseline sample of 350 ET cases (M age = 79.5 years) was tracked for up to 7.5 years (M follow-up = 4.7 years). Cox proportional hazards regressions identified baseline characteristics that predicted the development of dementia. RESULTS:Older age and greater cognitive impairment at baseline (MCI versus NC) each predicted incident dementia, HR > 1.10, p < 0.0001. Diminished functional abilities (HR = 0.39), greater gait impairment (HR = 1.30), lower confidence in one's balance skills (HR = 0.98), and more depressive symptoms at baseline (HR = 1.08) further predicted conversion to dementia, all p < 0.006. Neither continuous nor categorical measures of ET onset age predicted incident ET-dementia. CONCLUSIONS:These data represent the most comprehensive assessment to date of risk factors for ET-dementia in terms of number of factors studied and cohort size. At least one of these risk factors - depression - is modifiable and may offer intervention points to reduce risk of dementia. Older age of ET onset, previously viewed as a risk factor, did not predict incident ET-dementia.

INTRODUCTION:Efforts to characterize the semiology of tremor have considerable value. Despite this, available data on the extent and clinical correlates of tremor asymmetry in essential tremor (ET) are surprisingly scarce. Furthermore, there are no longitudinal data. OBJECTIVE:To enhance our understanding of tremor asymmetry in ET. METHODS:ET cases were enrolled in a prospective, longitudinal study of older adults with ET and examined at baseline and every 18 months using a reliable and valid clinical rating scale for action tremor (range = 0 - 23 in each arm). RESULTS:In most cases (263 of 306, 85.9%), there was some degree of tremor asymmetry. The range of tremor asymmetry (side-side difference in tremor scores) was 0 to 13.5. In 108 cases (35.3%, i.e., one in three cases) tremor asymmetry was ≥3 points (equivalent to at least a 1-point difference between sides on three tasks). In cross-sectional analyses, degree of tremor asymmetry was weakly inversely associated with tremor duration (Spearman's rho = -0.154, p = 0.007). In longitudinal analyses of 89 cases with up to 4.5 years of follow-up, degree of asymmetry was consistent across time (intraclass correlation coefficients = 0.799 - 0.840, p < 0.001). CONCLUSIONS:Most ET cases evidenced tremor asymmetry. In one third of cases, tremor asymmetry was ≥3 points (equivalent to at least a 1-point difference between sides on three tasks). In cross-sectional analyses, there was a weak inverse association between tremor asymmetry and tremor duration. During longitudinal follow-up, tremor asymmetry remained consistent, although length of follow-up was limited.

BACKGROUND AND OBJECTIVES:It is increasingly recognized that cognitive decline is a feature of essential tremor (ET). However, studies of the prevalence, incidence, and annual conversion proportions to mild cognitive impairment (MCI) and dementia are based on limited data, and results are heterogeneous. METHODS:Older individuals with ET were enrolled in a prospective longitudinal study of cognitive function. Recruitment was national, and participants resided in 43 states. Extensive neuropsychological testing was conducted during home visits at baseline and again during follow-up visits at 18, 36, 56, 72, and 90 months (M years of observation = 4.7 years, maximum = 7.5 years). Participants were assigned a cognitive diagnosis of normal cognition (NC), MCI, or dementia by expert consensus based on the detailed assessments conducted during each visit. Prevalence, incidence, and annual conversion proportions to MCI and dementia were calculated. We also performed a systematic review of the relevant literature followed by a meta-analysis to derive pooled estimates of prevalence, incidence, and annual conversion proportions for comparison purposes. RESULTS:There were 350 participants, M baseline age = 79.6 years, 60.6% female. Cumulative prevalences of MCI and dementia were 22.0% (95% confidence interval [CI] = 18.0-26.6) and 14.6% (95% CI = 11.3-18.7), cumulative incidences were 12.9% (95% CI = 9.3-17.6) and 10.2% (95% CI = 7.2-14.2), respectively, and the average annual proportion of conversions from MCI to dementia was 13.8%. Pooled estimates of these values were derived from meta-analyses of our data and existing studies of ET cohorts, general population cohorts, and Parkinson disease (PD) cohorts. The burden of MCI and dementia in ET was overall substantially higher than that observed in the general population yet lower than that seen in PD. DISCUSSION:The data document the longitudinal trajectory of cognitive impairment in ET in the largest available sample to date. Whether considered as stand-alone results, or when combined with data from the extant literature, the occurrence of MCI and dementia in ET is higher than observed in same age members of the general population, but is less pronounced than observed in same aged individuals with PD.

Background:Motor features aside from tremor are increasingly recognized in essential tremor (ET) patients. The relationship between these features and tremor has received sparse attention. We examined whether the severity of action tremor in the arms was correlated with the severity of tandem gait difficulty and balance confidence. Methods:212 ET cases enrolled in a prospective clinical study, from which baseline data on the following variables were analyzed: severity of action tremor (total tremor score [TTS] from the Washington Heights-Inwood Genetic Study of Essential Tremor rating scale, range = 0-36 [severe tremor]), tandem gait mis-steps (range = 0-10), and Activities of Balance Confidence (ABC-6) Scale (range = 0 [least confident] - 100). Results:Higher TTS was associated with a greater number of tandem gait mis-steps (Spearman's rho = 0.216, p = 0.002) and higher tertile of number of tandem gait mis-steps (Spearman's rho = 0.237, p < 0.001). Higher TTS was associated with reduced balance confidence (i.e., lower ABC-6 score) (Spearman's rho = -0.196, p = 0.004) and lower tertile of balance confidence (Spearman's rho = -0.175, p = 0.01). Discussion:We report an association between the severity of upper limb action tremor in ET and both a self-reported measure of balance confidence and a performance-based measure of balance. These data support the model that upper limb action tremor and tandem gait difficulty are associated in some way, with one possible interpretation being that they are both related to a common underlying element, cerebellar dysfunction.

Essential tremor (ET) is among the most prevalent neurological diseases. Postmortem studies have demonstrated Purkinje cell (PC) loss in ET. In addition, PCs and their micro-circuitry in the cerebellar cortex—including basket cells and climbing fibers—display several characteristic pathological features in these studies. While several studies in ET have focused on the interactions between PCs and climbing fibers, less has been written about basket cells and their interactions with PCs (i.e., formation of empty baskets and hypertrophy of basket cell axonal processes around the PC soma). These changes are not unique to ET, yet scarcely anything has been written about basket cells and their interactions with PCs more broadly across disorders of cerebellar degeneration. We examined the relationship between three metrics (PC linear density, percentage of empty baskets, basket plexus rating [a measure of basket cell axonal process hypertrophy]) in 332 brains: 178 ET, 56 with a range of spinocerebellar ataxias, 13 Friedreich’s ataxia, and 85 controls. We hypothesized that there would be overlapping but not uniform findings across these disorders. In all groups, PC linear density significantly negatively correlated with percentage of empty baskets, although to differing degrees. Basket plexus ratings were significantly associated with PC linear density and percentage of empty baskets only in some diseases. In summary, PC linear density, percentage of empty baskets and basket plexus rating were associated metrics across a range of cerebellar degenerative conditions and even in control brains. However, their relationships with one another were variable.

Introduction:Patients with essential tremor (ET) may exhibit intention tremor (IT), a sign of cerebellar dysfunction. The prevalence of this sign has been established in cross-sectional studies. To date, however, there have been no cohort studies, re-assessing ET cases prospectively, to determine whether the severity of IT increases over time. The fundamental question is whether IT is progressive in ET. Methods:90 cases enrolled in a prospective, longitudinal study of elders with ET. IT was assessed in each arm during the finger-nose-finger maneuver (10 repetitions per arm) and scored by a movement disorders neurologist on a 3-item scale - 0 (absent), 0.5 (probable), or 1 (definite), with the IT score (sum of IT in both arms) ranging from 0 - 2. Data from four evaluations every 18 months (T1 - T4) over a 4.5-year period were analyzed. Results:A one-way repeated measures analysis of variance revealed a time effect for IT, indicating significant variance across time in this variable. Paired sample t-tests indicated that the mean IT score at T4 was greater than those at T1, T2 and T3. There was heterogeneity in the sample, with the T4 score being greater than the T1 score in 46 (51.1%) of 90, but not all individuals. Conclusion:The cerebellar sign, IT, progressively worsened over time in ET. To our knowledge, this is the first demonstration that any canonical cerebellar sign gets progressively worse during prospective follow-up of ET. This clinical observation serves to further the links between ET and progressive cerebellar decline.

Background: Clinical, neuroimaging and postmortem studies indicate cerebellar dysfunction in essential tremor (ET). Clinically this is reflected in intention tremor, gait ataxia, and impaired motor timing. However, the effect of cerebellar dysfunction on speech in ET remains unclear, and research on dysarthria in ET is limited. This study aimed to 1) identify the perceptual features of dysarthria in ET, 2) verify the prominent perceptual features using acoustical analyses, and 3) determine the percentage of participants exhibiting hyperkinetic, ataxic or mixed hyperkinetic-ataxic dysarthria. Methods: Speech samples from fifteen participants with ET were analyzed. An expert rater completed auditory-perceptual ratings, and acoustical analyses were completed that corresponded to perceptual features detected in participants' speech, including speech timing, prosody, and voice quality measures. Results: Perceptual analyses revealed slow and variable speech rate, prolonged interword intervals and phonemes, imprecise consonants, distorted vowels, hypernasality, vocal tremor, harshness, breathiness, hoarseness, reduced loudness, and excess loudness variation in more than 50% of the participants. Acoustical analyses confirmed the presence of vocal tremor as well as numerically lower articulation rate, longer and more variable syllable duration, and lower smoothed cepstral peak prominence in more than 50% of participants compared to normative data from prior studies. Acoustical analyses classified one participant as ataxic and 14 participants as mixed hyperkinetic-ataxic. Discussion: This study revealed the presence of cerebellar signs of dysarthria in speakers with ET, primarily supporting a mixed hyperkinetic-ataxic dysarthria profile in ET. The data indicate that cerebellar dysfunction in ET does not spare speech and voice.

BACKGROUND:Population-based data on mild parkinsonian signs (MPS) and parkinsonism in nonagenarians are scarce. OBJECTIVES:To estimate the prevalence of MPS, definite parkinsonism, and broader parkinsonian motor phenotypes; assess MPS after excluding idiopathic Parkinson disease and definite parkinsonism; and examine associations with sex and dementia in a cohort of nonagenarians. METHODS:This cross-sectional analysis included 144 participants from the Neurological Disorders in Central Spain (NEDICES) cohort aged ≥90 years on May 1, 1999; 97 were examined, and 47 had reliable indirect information. Unified Parkinson's Disease Rating Scale (UPDRS) motor data were evaluable in 96 of the examined participants. MPS were classified using established UPDRS-based operational criteria. Definite parkinsonism was defined primarily by a bradykinesia score ≥2 plus rigidity ≥1 or rest tremor ≥1; participants with an established Parkinson's disease diagnosis receiving antiparkinsonian treatment were also retained as definite cases when supported by prior clinical documentation. Bradykinesia ≥2 plus postural instability ≥2 in the absence of rest tremor and rigidity defined an instability-defined phenotype. Wilson's 95% confidence intervals (CIs) and two-sided Fisher's exact tests were used. RESULTS:MPS were present in 90/96 participants (93.8%; 95% CI, 87.0-97.1%). Prevalence remained 93.4% (85/91; 95% CI, 86.4-96.9%) after excluding idiopathic Parkinson's disease and 92.6% (75/81; 95% CI, 84.8-96.6%) after excluding all 15 examined definite cases. Definite parkinsonism affected 16/144 participants (11.1%; 95% CI, 7.0-17.3%), including 5 with idiopathic Parkinson's disease (3.5%; 95% CI, 1.5-7.9%). Among the 96 UPDRS-evaluable participants, 15 had definite parkinsonism, 7 additional participants had instability-defined parkinsonism, and inclusion of uncertain phenotypes expanded the broader parkinsonian motor spectrum to 63/96 (65.6%; 95% CI, 55.7%-74.4%). Dementia was more frequent with definite parkinsonism (13/16 vs 28/128; P < .001). Definite parkinsonism did not differ by sex; rest tremor was more frequent in men (P = .006). CONCLUSIONS:Parkinsonian motor features were frequent and phenotypically diverse among nonagenarians with evaluable UPDRS motor assessments. Definite parkinsonism represented only part of the broad parkinsonian motor spectrum, and idiopathic Parkinson's disease comprised only a small proportion of definite cases. These findings should not be interpreted either as synonymous with Parkinson's disease or as merely reflecting normal aging.

Introduction: The prevalence of essential tremor (ET) demonstrates substantial differences across study populations and has been assessed in more than 40 population-based studies, but never in Greece. We directly estimated the prevalence of ET in community-dwelling adults aged 65 years and older, which was the age group expected to have the highest prevalence. METHODS:Participants in a population-representative cohort aged ≥65 years underwent a neurological evaluation. ET was operationally defined as a Bain and Findley scale score ≥4 on the Archimedes' spirals drawn with the more affected arm, excluding alternative causes of tremor. In a subset of participants, we validated this against diagnoses of ET assigned based on videotaped neurological examination. Logistic regression models were performed to assess independent effects of age and sex on prevalence. RESULTS:A total of 172 of 1,926 participants were classified as having ET, corresponding to a crude prevalence of 8.9% (95% confidence interval [CI] = 7.7%, 10.2%). The prevalence of ET increased with increasing age (65-69: 6.4%; 70-74: 6.6%; 75-79: 12.1%; ≥80: 14.1%, X2 test, p < 0.001) and was higher in male than female participants (11.7% vs. 7.0%, X2 test, p < 0.001). Both age and sex were significant predictors of ET, when assessed simultaneously using logistic regression - odds ratio (95% CIs) = 1.07 (1.04, 1.10) and 1.54 (1.11, 2.12), respectively. DISCUSSION:Our study provides the first estimate of ET prevalence in Greece and shows that ET is highly prevalent as it affects 8.9% of Greeks aged ≥65. .

Recent years have witnessed an evolution of our understanding of the underlying neuropathological features of essential tremor (ET). Studies have revealed a cascade of neurodegenerative changes in the cerebellar cortex, centered on the Purkinje cell (PC) population and its surrounding neuronal populations and connections. A fundamental question is whether there is heterogeneity across ET cases with respect to the expression of this cerebellar pathology. We examined postmortem tissue from 155 ET brains using a set of 15 quantitative metrics of cerebellar cortical pathology determined by histologic and immunohistochemical methods. These metrics reflect changes across the PC body (PC counts, empty baskets, heterotopias), PC dendrites (swellings), PC axon (torpedoes), basket cell axonal hypertrophy and climbing fiber-PC dendrite synaptic changes. Principal component analysis (PCA) was used to identify the major data dimensions. Outlier cases were then identified, followed by k-means clustering to identify subgroups of ET cases. The first 5 principal components explained 78.6% of the variance. Twenty-two (14.2%) cases were outliers. k-means clustering indicated that these 22 cases were distributed in 4 clusters. In each cluster, specific quantitative metrics of cerebellar pathology showed greater severity of change than observed in the main group of 133 ET cases. A small number of clinical features distinguished clusters from one another, although these analyses were limited by sample size. Cerebellar cortical pathology in ET was not homogeneously expressed across every case. It was possible to identify clusters of cases that differed with respect to the expression of postmortem features.

Pathological tremor affects over 40 million people worldwide, significantly impairing daily activities and quality of life. Pharmacological treatments show limited efficacy, with up to 30% discontinuation rates, while surgical interventions like deep brain stimulation achieve significant tremor reduction but are often unsuitable due to age, comorbidities, or personal preference. Recently, the need for safe and effective alternatives has led to the development of innovative, noninvasive, and patient-friendly technologies for tremor management. This clinical application review analyzed 134 studies (1969-2025), categorizing them into three major modalities, focusing on their underlying neurophysiological mechanisms, with a special emphasis on the clinical perspective. The three considered modalities were force-controlling (orthoses and functional electrical stimulation), central neuromodulation (transcranial magnetic stimulation, transcranial electrical stimulation, low-intensity focused ultrasound, and transcutaneous spinal cord stimulation), and peripheral neuromodulation (afferent stimulation and vibration). Force-controlling strategies showed promising acute effects, though clinical translation remains limited by poor wearability and the development of muscle fatigue. Central neuromodulation produced moderate effects, while peripheral neuromodulation has gained clinical traction, with several devices now being commercially available. However, heterogeneity in study design, patient populations, and technology maturity remain the main obstacles for the direct comparison of techniques. Future research should prioritize larger multicenter trials, standardized outcome measures, and accessibility considerations to enable personalized, evidence-based treatment selection for diverse tremor populations.

In postmortem studies, we have identified morphologic changes centered in and around Purkinje cells (PCs) in essential tremor (ET); these are indicative of cerebellar degeneration. Recent analyses of 100 ET and 50 control cerebella demonstrated that using a combination of these cerebellar morphologic metrics, which individually measure degenerative changes, correctly predicted a diagnosis of ET or control with sensitivity and specificity 95

Foundation models have transformed computational pathology by providing generalizable representations from large-scale histology datasets. However, existing models are predominantly trained on surgical pathology data, which is enriched for non-nervous tissue and overrepresents neoplastic, inflammatory, metabolic, and other non-neurological diseases. Neuropathology represents a markedly different domain of histopathology, characterized by unique cell types (neurons, glia, etc.), distinct cytoarchitecture, and disease-specific pathological features including neurofibrillary tangles, amyloid plaques, Lewy bodies, and pattern-specific neurodegeneration. This domain mismatch may limit the ability of general-purpose foundation models to capture the morphological patterns critical for interpreting neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and cerebellar ataxias. To address this gap, we developed NeuroFM, a foundation model trained specifically on whole-slide images of brain tissue spanning diverse neurodegenerative pathologies. NeuroFM demonstrates superior performance compared to general-purpose models across multiple neuropathology-specific downstream tasks, including mixed dementia disease classification, hippocampal region segmentation, and neurodegenerative ataxia identification encompassing cerebellar essential tremor and spinocerebellar ataxia subtypes. This work establishes that domain-specialized foundation models trained on brain tissue can better capture neuropathology-specific features than models trained on general surgical pathology datasets. By tailoring foundation models to the unique morphological landscape of neurodegenerative diseases, NeuroFM enables more accurate and reliable AI-based analysis for brain disease diagnosis and research, setting a precedent for domain-specific model development in specialized areas of digital pathology.

Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell-specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.

Terminology in the field of movement disorders has evolved multiple times over the years. Traditionally, classification schema have utilized a two-category approach, with a hyper- and hypokinetic branchpoint as the first step towards describing movement disorders and elucidating phenomenological diagnoses. However, this terminology falls short, as it does not adequately capture the complexity of several abnormalities of movement- including ataxia and rigidity- at the electrophysiologic and phenotypic levels. Rather, these movement disorders are characterized by mixed hyper- and hypokinetic phenomena. We propose a third category, "mixed", which would optimally classify the full range of movements.

Background: Prospective data show an increased risk of mortality in essential tremor (ET). Understanding the contributors to this increased mortality is of value. Methods: 347 cases enrolled in a prospective study of cognition in elders with ET (M baseline age = 79.6 years, M follow-up length = 2.7 years). At each visit, cases completed clinical assessments, a cognitive test battery and were assigned a Clinical Dementia Rating (CDR). Cox proportional hazards regression equations identified predictors of cases’ relative risk of mortality. Results: 41 (11.8%) of 347 cases died during follow-up. Deceased cases were older at baseline, had fewer years of education, used more medication, had more severe tremor, had more gait impairment, and reported more falls, less physical activity, and more depressive symptoms than did living cases. In univariate analyses, a CDR score of 1 or 2 (dementia) was associated with a six-fold increased the risk of mortality (Hazards ratio, HR = 6.33). Moderate rather than milder levels of dementia (CDR 2 rather than 1) were driving this effect, with multivariate models demonstrating HRs in excess of 7.5 (p <0.001). Gait impairment and falls were also associated with significant increased risk of mortality in multivariate models. Conclusion: We identified several factors that may be used to risk-stratify ET patients with respect to mortality. The information from these analyses can be of value in identifying subgroups of ET patients who demonstrate risk for early death; such subgroups can then be targeted for interventions as well as preventive measures.