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Many clinical, neuroimaging, neuropathological, epidemiological, and genetic data suggest a relationship between essential tremor (ET) and Parkinson's disease (PD). Several hypothesis-based gene association studies attempted to find a genetic association between these diseases. Recent case-control association studies in Chinese and Spanish populations showed a marginal association between the CD4 rs1922452 and CD4 rs951818 single nucleotide variants (SNVs) and the risk of PD. The proteins encoded by the CD4 and LAG3 genes have an important role in modulating inflammatory responses, and some recent data associated inflammatory markers to ET. This study investigates a possible association between the most common SNVs in the LAG3/CD4 genes and the risk of ET in the Spanish Caucasian population. We genotyped 267 patients diagnosed with familial ET and 270 age- and sex-matched controls using specific TaqMan assays for CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 variants. We found a decreased risk for ET in carriers of the LAG3 rs870849 C/C genotype and the LAG3 rs870849C allelic variant exclusively in men. The mean age of onset of ET was not related to any of the variants studied. These data suggest no association of the gene variants studied with the overall risk for ET, except for a slight decrease in risk in male ET patients carrying the variant LAG3 rs870849C. However, such an association lost significance after correcting for multiple comparisons.

Introduction: Mutations in the teneurin transmembrane protein 4 (TENM4) gene, known to be involved in neuropsychiatric disorders, have been identified in three pedigree of essential tremor (ET) from Spain. ET has overlapping clinical manifestations and epidemiological symptoms with Parkinson's disease (PD), suggesting these two disorders may reflect common genetic risk factors. In this study, we investigated clinical and genetic manifestations in four unrelated pedigrees with both ET and PD in which TENM4 variants were identified. Methods: We subsequently explored whether TENM4 variants contributed to the risk of developing PD. The frequency of TENM4 variants was evaluated from four PD pedigrees and other 407 subjects. Results: The results revealed 12 different novel heterozygous variants, all at low frequency. A clear general enrichment of TENM4 variants was detected in early onset PD patients (p < 0.001, OR = 5.264, 95% CI = 1.957–14.158). Conclusion: The results indicate that rare TENM4 variants may be associated with an increased risk of PD. [ABSTRACT FROM AUTHOR]

Abstract: Background: Environmental correlates for essential tremor (ET) are largely unexplored. The search for such environmental factors has involved the study of a number of neurotoxins. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing toxin. In two prior case–control studies in New York, we demonstrated that blood harmane concentration was elevated in ET patients vs. controls, and especially in familial ET cases. These findings, however, have been derived from a study of cases ascertained through a single tertiary referral center in New York. Objective: Our objective was to determine whether blood harmane concentrations are elevated in familial and sporadic ET cases, ascertained from central Spain, compared to controls without ET. Methods: Blood harmane concentrations were quantified by a well-established high performance liquid chromatography method. Results: The median harmane concentrations were: 2.09g−10/ml (138 controls), 2.41g−10/ml (68 sporadic ET), and 2.90g−10/ml (62 familial ET). In an unadjusted logistic regression analysis, log blood harmane concentration was not significantly associated with diagnosis (familial ET vs. control): odds ratio=1.56, p =0.26. In a logistic regression analysis that adjusted for evaluation start time, which was an important confounding variable, the odds ratio increased to 2.35, p =0.049. Conclusions: Blood harmane levels were slightly elevated in a group of familial ET cases compared to a group of controls in Spain. These data seem to further extend our observations from New York to a second cohort of ET cases in Spain. This neurotoxin continues to be a source of interest for future confirmatory research. [Copyright &y& Elsevier]

Abstract: Background/objectives: Recently, a genome-wide association study revealed a significant statistical association between LINGO1 rs9652490 and rs11856808 polymorphisms and the risk of developing essential tremor (ET) in Icelandic people. Because the results of further association studies were controversial, we conducted a meta-analysis including all the studies published on the risk of ET related with these polymorphisms. Methods: The metaanalysis included 11 association studies between LINGO1 rs9652490 (3972 ET patients, 20,714 controls) and 7 association studies between LINGO1 rs11856808, and risk for ET (2076 ET patients, 18,792 controls), and was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramón y Cajal, Madrid, Spain). Heterogeneity between studies in terms of degree of association was tested using the Q-statistic. Results: Global diagnostic odds-ratios (ORs) and 95% confidence intervals (CI) for rs9652490 and rs11856808 of the total series were, respectively, 1.17 (1.00–1.36) (p=0.069) and 1.20 (1.05–1.36) (p=0.016). After excluding data on Icelandic people of the discovery series (that was responsible of a high degree of heterogeneity for rs9652490 polymorphism), the ORs and CI were 1.10 (0.97–1.26) (p=0.063) and 1.12 (0.99–1.27) (p=0.034). Global ORs and 95% CI for rs9652490 and rs11856808 of familial ET patients were, respectively, 1.27 (1.03–1.57) (p=0.014) and 1.21 (1.10–1.44) (p=0.031). Conclusions: The results of the meta-analysis suggest a relationship between LINGO1 rs11856808 polymorphism and the risk for ET and for familial ET, while rs9652490 polymorphism was only related with the risk for familial ET. [Copyright &y& Elsevier]

Background and purpose: Essential tremor (ET), one of the most prevalent neurological diseases, has been associated with a variety of comorbidities and, in some studies, a modest increase in risk of mortality. The mechanisms underlying this possible increased mortality have yet to be explored, although one possibility is increased frailty. Frailty has not been studied in ET, and our objective was to address this gap in knowledge. We hypothesized that frailty would be greater in ET cases than in controls. Methods: A 20-item frailty score assessed comorbid conditions, number of medications, and functional activity. The frailty score was compared in 237 non-demented elderly ET cases and 3903 non-demented age-matched controls from a population-based study in central Spain. Results: The frailty score was higher in ET cases than in controls (8.6 ± 5.2 vs. 6.8 ± 4.6, P < 0.001). Stratifying the frailty score into quartiles and tertiles similarly revealed case-control differences (both P < 0.001). The frailty score also increased with age ( r = 0.25, P < 0.001), was higher in women than men ( P = 0.02), was correlated with subjective rating of health status ( r = 0.42, P < 0.001), and was inversely correlated with body weight ( r = −0.06, P < 0.001) and hours/day that participants performed moderate or intensive physical activities ( r = −0.16, P < 0.001). Conclusion: Essential tremor cases had increased frailty compared to their counterparts without this disease. Whether this increased frailty is a contributor to the increased risk of mortality that has been observed in some studies is a question that deserves further scrutiny. [ABSTRACT FROM AUTHOR]

Background: Essential tremor (ET) is a frequent movement disorder with a substantial family aggregation. A genome-wide association study has recently shown that LINGO1 gene variants are associated with increased risk of ET. Methods: We intended to replicate these findings by genotyping rs9652490 and rs11856808 in a series of 226 familial ET subjects and 1117 healthy controls from referral movement disorder clinics in Spain. Results: We were unable to replicate the association between LINGO1 variants and familial ET. Conclusions: Our results indicate that the LINGO1 variants analyzed are not a major risk factor for developing familial ET in our population, which suggests the existence of other unknown genetic risk factors responsible for familial ET in the Spanish population. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) is often considered to be a transitional stage between normal aging and dementia. Frontal-executive dysfunction, memory impairments, and dementia have been associated with essential tremor (ET). Yet the association between MCI and ET has only been examined in one prior study. We determined whether ET is associated with MCI. We identified all persons with MCI and ET in a dementia-free, population-based study in central Spain (NEDICES). MCI was diagnosed using consensus criteria of the International Working Group on MCI. Forty-two (20.3%) of 207 ET cases had MCI versus 399 (16.1%) of 2,472 non-ET subjects (controls) (odds ratio [OR] = 1.32, 95% Confidence Interval [CI] = 0.93 to 1.89, p = 0.12). In a model that adjusted for age, gender, educational level, smoking, hearing impairment, depressive symptoms or antidepressant use, and use of a medication that could potentially affect cognitive function, the OR was 1.28, 95% CI = 0.88 to 1.84, p = 0.19. In an adjusted model, ET cases with tremor onset after age 65 were 57% more likely to have MCI than controls (OR = 1.57, 95% CI = 1.03 to 2.38, p = 0.03), whereas ET cases with tremor onset prior to age 65 and controls were equally likely to have MCI (OR = 0.73, 95% CI = 0.34 to 1.57, p = 0.43). In this study, older-onset ET was associated with MCI. This finding supports the hypothesis that cognitive disturbances are one of the core non-motor symptoms of ET. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive deficits have been reported in essential tremor (ET). However, these cognitive deficits have been assessed in cross-sectional rather than longitudinal analyses. Objective: To determine whether decline in cognitive test scores occurs at a faster rate in ET cases than controls. Methods: In a population-based study of older people (≥ 65 years) in central Spain (Neurological Disorders in Central Spain, NEDICES), non-demented ET cases and controls were followed prospectively. Participants with baseline or incident Parkinson’s disease or dementia were excluded as were participants who developed incident ET. At baseline (1994–1995) and at follow-up (1997–1998), a 37-item version of the mini-mental state examination (37-MMSE) was administered. Results: A total of 2319 participants (72.4 ± 5.8 years) included 135 prevalent ET cases and 2184 controls. At baseline, the mean 37-MMSE in cases was 28.8 ± 5.8 vs. 30.2 ± 4.8 in controls ( P = 0.02). During the 3-year follow-up period, the 37-MMSE declined by 0.70 ± 3.2 points in cases vs. 0.11 ± 3.8 points in controls ( P = 0.03). In analyses that adjusted for age, education, and other potential confounders, the case–control difference remained robust. Discussion: In this population-based, prospective study of non-demented elders, baseline cognitive test scores were lower in ET cases than controls; moreover, during the 3-year follow-up period, these scores declined at a rate that was seven-times faster in ET cases. This study provides evidence that cognitive deficits in ET are not static, and they appear to be progressing at a faster rate than in elders without this disease. [ABSTRACT FROM AUTHOR]

Introduction: Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET., Methods: This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency., Results: There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations., Conclusions: These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population., (Copyright © 2013 Elsevier Inc. All rights reserved.)