Quantitative Assessment of Pathological Tau Burden in Essential Tremor: A Postmortem Study.
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ABSTRACT:
SUBMITTER: Farrell K
PROVIDER: S-EPMC6289218 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
Publications
Quantitative Assessment of Pathological Tau Burden in Essential Tremor: A Postmortem Study.
Farrell Kurt K Cosentino Stephanie S Iida Megan A MA Chapman Silvia S Bennett David A DA Faust Phyllis L PL Louis Elan D ED Crary John F JF
Journal of neuropathology and experimental neurology 20190101 1
Essential tremor (ET) patients develop more cognitive impairment and dementia than controls, although there are surprisingly few data on the neuropathological basis for cognitive changes in ET. In this postmortem study, we assessed tau and other pathologies in 26 ET cases and 73 controls (non-ET) (1:3 matching). The mean age = 88.6 years; 55% were cognitively normal, 24% had mild cognitive impairment (MCI), and 20% had dementia. We found similar burdens of pathology using Braak, β-amyloid and Le ...[more]
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Project description:BackgroundEssential tremor involves the cerebellum, yet quantitative analysis of dentate nucleus neurons has not been conducted.ObjectivesTo quantitatively compare neuronal density or neuronal number in the dentate nucleus of essential tremor versus age-matched controls.MethodsUsing a 7-μm thick Luxol fast blue hematoxylin and eosin-stained paraffin section, dentate nucleus neuronal density (neurons/mm2 ) was determined in 25 essential tremor cases and 25 controls. We also applied a stereological approach in a subset of four essential tremor cases and four controls to estimate total dentate nucleus neuronal number.ResultsDentate nucleus neuronal density did not differ between essential tremor cases and controls (P = 0.44). Total dentate nucleus neuronal number correlated with neuronal density (P = 0.007) and did not differ between essential tremor cases and controls (P = 0.95).ConclusionsNeuronal loss, observed in the Purkinje cell population in essential tremor, did not seem to similarly involve the dentate nucleus in essential tremor. © 2020 International Parkinson and Movement Disorder Society.
| S-EPMC8046734 | biostudies-literature
Project description:Background Essential tremor (ET) is among the most common movement disorders in adults. While ET is diagnosed and primarily characterized by the presence of tremor, it also can impact cognition, sleep, mood, and motor functioning more broadly. The manifestations of ET can have various consequences, including difficulty with activities of daily living (ADL), embarrassment, and overall decline in health-related quality of life, which have not been fully explored in prior studies. Objective We performed a systematic literature review to comprehensively characterize the burden experienced by patients with ET from the clinical and humanistic perspectives, focusing on outcomes beyond tremor. Methods This systematic literature review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches in PubMed, Embase, and Cochrane Library identified original, observational studies of the clinical and humanistic burden in adult patients with ET published in English between 2010 and 2020. Studies assessing epidemiology, treatment patterns, or disease management were excluded. Search results were screened according to pre-determined eligibility criteria. Data from included studies were collected, independently verified, and qualitatively synthesized. Results Following the screening of 2,303 records and 145 full-text articles, 39 studies were identified. There was significant heterogeneity in study designs, statistical approaches, and patient cohorts across the included studies. Patients with ET in these studies exhibited more severe disabilities and reduced independence compared to healthy individuals, and they often struggled to perform ADL and relied on caregivers for physical and emotional support. Patients also experienced various issues with movement and balance, increased risk of falls, depression, anxiety, poor sleep quality, and psychosocial consequences including embarrassment, apathy, and enfeeblement. Conclusion A systematic literature review of non-tremor manifestations and/or consequences of ET identified far-reaching negative impacts on patients' ability to function independently and revealed accompanying psychosocial effects, including social fear and embarrassment. The reduced function and psychosocial deficits observed in patients with ET result in significant clinical and humanistic burdens, decreasing quality of life. Future studies should evaluate this condition beyond the tremor itself to provide an improved understanding of the multi-dimensional burden of the disease, thereby highlighting the need to diagnose and appropriately manage patients with ET.
| S-EPMC9354397 | biostudies-literature
Project description:BackgroundGenome-wide association studies have revealed a link between essential tremor (ET) and the gene SLC1A2, which encodes excitatory amino acid transporter type 2 (EAAT2). We explored EAAT biology in ET by quantifying EAAT2 and EAAT1 levels in the cerebellar dentate nucleus, and expanded our prior analysis of EAAT2 levels in the cerebellar cortex.ObjectiveTo quantify EAAT2 and EAAT1 levels in the cerebellar dentate nucleus and cerebellar cortex of ET cases vs.ControlsMethodsWe used immunohistochemistry to quantify EAAT2 and EAAT1 levels in the dentate nucleus of a discovery cohort of 16 ET cases and 16 controls. Furthermore, we quantified EAAT2 levels in the dentate nucleus in a replicate cohort (61 ET cases, 25 controls). Cortical EAAT2 levels in all 77 ET cases and 41 controls were quantified.ResultsIn the discovery cohort, dentate EAAT2 levels were 1.5-fold higher in 16 ET cases vs. 16 controls (p = 0.007), but EAAT1 levels did not differ significantly (p = 0.279). Dentate EAAT2 levels were 1.3-fold higher in 61 ET cases vs. 25 controls in the replicate cohort (p = 0.022). Cerebellar cortical EAAT2 levels were 20% and 40% lower in ET cases vs. controls in the discovery and the replicate cohorts (respective p values = 0.045 and < 0.001).ConclusionEAAT2 expression is enhanced in the ET dentate nucleus, in contrast to differentially reduced EAAT2 levels in the ET cerebellar cortex, which might reflect a compensatory mechanism to maintain excitation-inhibition balance in cerebellar nuclei.
| S-EPMC5501729 | biostudies-literature
Project description:Essential tremor (ET) is among the most common neurological diseases and it often runs in families. How knowledgeable ET patients and their families are about their disease has been the subject of surprisingly little scholarship.To fill this gap in knowledge, we administered a comprehensive 32-item survey (i.e., questions about etiology, pathophysiology, symptoms and signs, natural history, and treatments) to 427 participants, including 76 ET probands, 74 affected relatives (AFRs), 238 unaffected relatives, and 39 spouses of unaffected relatives, all of whom were participating in two ET family studies. We hypothesized that there would be gaps in knowledge about ET and furthermore, that probands and AFRs would be the most knowledgeable, followed by unaffected relatives and then spouses of unaffected relatives, who would be the least knowledgeable.Overall, ET patients lacked knowledge about their disease. Nearly one-third of probands answered "yes" or "do not know" to the question, "is ET the same or different from the type of tremor that many normal people can get when they become old and frail?" A similar proportion did not know whether children could get ET or they responded "no." Nearly one-fourth of affecteds (i.e., probands and AFRs) did not know whether or to what degree (e.g., very well, moderately well, not well) the symptoms of ET could be medically controlled, and 38.0% either reported that there was no brain surgery for ET or reported that they did not know. Nearly 17% of affecteds did not endorse genes as a cause for ET, which was surprising given the fact that this was a family study of ET. Probands and AFRs were the most knowledgeable, followed by unaffected relatives. Spouses of unaffected relatives were the least knowledgeable.We targeted a large group of ET patients and their families, as this group is perhaps most likely to be informed about the disease. ET patients and their AFRs were more knowledgeable about the features of ET than their family members without ET. Overall, however, knowledge of ET was very limited and this lack of knowledge encompassed all aspects of the disease including its underlying causes, the nature of the symptoms and signs, its natural history and its treatment. Further ET awareness education and programs targeting both families of ET patients and the public would help alleviate this gap in knowledge.
| S-EPMC5790790 | biostudies-literature
Project description:BackgroundPatients with upper limb action tremor frequently exhibit additional neurological signs of uncertain significance. Clinicians vary in their interpretation, and interrater agreement on the final diagnosis is poor.ObjectivesA new clinical tool for assessing the presence or absence of clinical signs that are important in axis-1 classification of tremor patients is introduced: the Standardized Tremor Elements Assessment (STEA). Interrater agreement is determined, and signs leading to disagreement in the final diagnosis are identified.MethodsThree tremor-focussed and one dystonia-focussed movement disorder specialists rated 59 videos of patients with upper limb action tremor syndromes using STEA. Interrater agreements for final diagnosis and STEA items were calculated.ResultsInterrater agreement regarding the final diagnosis was higher within the group of tremor specialists and poor between dystonia and tremor specialists. Greater agreement was found for items characterizing tremor than for signs of dystonia.ConclusionsClinical signs leading to diagnostic disagreement were identified with STEA, and STEA should therefore be useful in future studies of diagnostic disagreement. The thresholds for considering neurological signs as soft versus significant for ataxia, parkinsonism, dystonia, etc. are critically important in tremor classification and must be studied across movement disorder subspecialties, not simply within a pool of tremor specialists.
| S-EPMC8015892 | biostudies-literature
Project description:Essential tremor (ET) is a progressive neurological disease associated with functional disability, diminished quality of life and, in some individuals, poorer balance, cognitive impairment, depression and sleep dysregulation. Individuals with ET may rely on family members and friends to act as informal caregivers to assist with daily activities and provide emotional support. There is a high prevalence of embarrassment among individuals with ET, which may be a result of the outwardly visible nature of tremor. Studies in populations with outwardly visible disability have shown that perception by caregivers of a care-recipient's social distress can contribute to caregiver burden. We hypothesize that in ET, perception by caregivers of ET participant embarrassment is a predictor for caregiver burden. Data were collected from 57 ET participants and their caregivers. We measured ET participant embarrassment using the Essential Tremor Embarrassment Assessment (ETEA), and measured perception by caregivers of ET participant embarrassment using a modified version of the ETEA. The Zarit Burden Interview was used to measure caregiver burden. Perceived embarrassment was associated with ET participant embarrassment. In linear regression models, perceived embarrassment was a stronger predictor for caregiver burden than measures of ET participant cognitive and physical impairment. The results indicate that perception of ET participant embarrassment can be burdensome for caregivers. Clinicians may wish to address patient embarrassment and perceived embarrassment to better support caregivers and ET patients.
| S-EPMC5739080 | biostudies-other
Project description:Essential tremor (ET) is among the most common neurological diseases. Postmortem studies have noted a series of pathological changes in the ET cerebellum. Heterotopic Purkinje cells (PCs) are those whose cell body is mis-localized in the molecular layer. In neurodegenerative settings, these are viewed as a marker of the progression of neuronal degeneration. We (1) quantify heterotopias in ET cases vs. controls, (2) compare ET cases to other cerebellar degenerative conditions (spinocerebellar ataxias (SCAs) 1, 2, 3, and 6), (3) compare these SCAs to one another, and (4) assess heterotopia within the context of associated PC loss in each disease. Heterotopic PCs were quantified using a standard LH&E-stained section of the neocerebellum. Counts were normalized to PC layer length (n-heterotopia count). It is also valuable to consider PC counts when assessing heterotopia, as loss of PCs extends both to normally located as well as heterotopic PCs. Therefore, we divided n-heterotopias by PC counts. There were 96 brains (43 ET, 31 SCA [12 SCA1, 7 SCA2, 7 SCA3, 5 SCA6], and 22 controls). The median number of n-heterotopias in ET cases was two times higher than that of the controls (2.6 vs. 1.2, p < 0.05). The median number of n-heterotopias in the various SCAs formed a spectrum, with counts being highest in SCA3 and SCA1. In analyses that factored in PC counts, ET had a median n-heterotopia/Purkinje cell count that was three times higher than the controls (0.35 vs. 0.13, p < 0.01), and SCA1 and SCA2 had counts that were 5.5 and 11 times higher than the controls (respective p < 0.001). The median n-heterotopia/PC count in ET was between that of the controls and the SCAs. Similarly, the median PC count in ET was between that of the controls and the SCAs; the one exception was SCA3, in which the PC population is well known to be preserved. Heterotopia is a disease-associated feature of ET. In comparison, several of the SCAs evidenced even more marked heterotopia, although a spectrum existed across the SCAs. The median n-heterotopia/PC count and median PC in ET was between that of the controls and the SCAs; hence, in this regard, ET could represent an intermediate state or a less advanced state of spinocerebellar atrophy.
| S-EPMC5803474 | biostudies-other
Project description:Two recent studies investigated the association of the microtubule associated protein tau (MAPT) H1 haplotype, a known risk factor for neurodegenerative disease including progressive supranuclear palsy and Parkinson's disease (PD), with essential tremor (ET).To confirm this association in a different population the distribution of allele and genotype frequencies for the MAPT H1/H2 tagging single-nucleotide polymorphism (SNP) rs1052553 in ET cases and controls enrolled in a clinical-epidemiological study of ET at Columbia University was analyzed.Overall, no association was observed between ET and the MAPT H1 haplotype. The analysis was also restricted to clinical subtypes including early-onset (?40 years of age), Ashkenazi Jewish ancestry, white non-Ashkenazi, or ET cases with a 'definite' or 'probable/possible' diagnosis; none of these stratified analyses showed evidence of association with ET. A meta-analysis of the H1/H2 tagging SNP rs1052553 in published data sets and the H1 haplotype with risk for ET in the current study was also performed and did not find evidence for association.The inconsistent reports of association of MAPT H1 in three emerging studies (our own and two published studies) may reflect sampling issues and/or clinical heterogeneity in these populations.
| S-EPMC4057305 | biostudies-literature
Project description:BackgroundPatients with essential tremor (ET) have an increased risk of cognitive impairment, yet little is known about the predictors of cognitive decline in these patients. Exposures to infectious agents throughout the lifespan may impact the later development of cognitive impairment. For example, high Infection exposure has been associated with lower cognitive performance in Alzheimer's and Parkinson's disease. However, this predictor has not been examined in ET.ObjectivesTo determine whether a higher baseline infection burden is associated with worse cognitive performance at baseline and greater cognitive decline over time in an ET cohort.Method/design160 elderly non-demented ET participants (80.0 ± 9.5 years) underwent an extensive cognitive evaluation at three time points. At baseline, participants completed an infection burden questionnaire (t-IBQ) that elicited information on previous exposure to infectious agents and number of episodes per disease. Analysis of covariance and generalized estimated equations (GEEs) were used.ResultsOverall, infection burden was not associated baseline cognitive performance. Adjusted GEE models for repeated measures yielded a significant time interaction between moderate infection burden at baseline and better performance in the attention domain over time (p = 0.013). Previous history of rubella was associated with faster rate of decline in visuospatial performance (p = 0.046).ConclusionThe data were mixed. Moderate self-reported infection burden was associated with better attention performance over time. Self-reported history of rubella infection was related to lower visuospatial performance over time in this cohort. Follow-up studies with additional design elements would be of value.
| S-EPMC8121006 | biostudies-literature
Project description:Essential tremor (ET) is associated with physical and cognitive impairments, as well as embarrassment, avoidance of social settings, and related difficulties that negatively impact the lives of patients. In similar disease contexts, burden on friends and relatives acting as caregivers has been noted and has well-documented implications. There has been no study examining caregiver burden related to ET.Data were gathered from 55 ET participants enrolled in a clinical study and their caregivers. The Zarit Burden Interview was used to assess caregiver burden. To assess clinical features that may be associated with burden, we collected several variables including the Montreal Cognitive Assessment, self-reported tremor disability, a videotaped neurological examination, questionnaires assessing ET participants' suffering, caregivers' perceptions of that suffering, and both caregiver and ET participant depressive symptoms. Spearman's correlations were performed between caregiver burden and clinical features, and we created a multivariate linear regression model predicting caregiver burden.Many ET caregivers provide little to no care and experience little to no burden. However, some caregivers (11%) provide over 25 h of care/week, and 13% experience high levels of burden. Caregivers most commonly provided assistance with writing and cooking. Increased burden was associated with the ET participants' decreased cognition, more caregiving tasks, more hours/week of caregiving activities, a longer duration of care, more ET participant falls/year, more medications taken by the ET participant, and more depressive symptoms in both the ET participant and the caregiver (all p < 0.05). ET participants' suffering and their caregivers' perceptions of suffering were both associated with increased burden. Neither tremor severity score nor self-reported tremor disability score was associated with increased caregiver burden. Using a multivariate linear regression model, we found that caregivers' increased perception of their partners' suffering was the best predictor of caregiver burden.While not all relatives and friends of ET patients provide extensive care or experience high burden, there is a group reporting high levels of caregiver burden that requires the attention and counseling of clinicians. This burden is associated with primarily non-tremor symptoms of ET and with caregivers' perception that their partners are suffering.
| S-EPMC5557742 | biostudies-other