Brain microstructural changes and cognitive function in non-demented essential tremor patients: a diffusion tensor imaging study.

BACKGROUND: Essential tremor (ET) is disease with both motor and non-motor features. Notable among the non-motor features is cognitive impairment. While this impairment has been attributed to cortico-thalamo-cerebellar pathway pathology, it is likely that a more complicated involvement of brain structures underlies cognitive function in ET. OBJECTIVE: To evaluate the brain microstructural changes of both white matter and grey matter in ET using region of interest based diffusion tensor imaging (DTI), and to correlate these changes with cognitive function assessed during detailed neuropsychological testing. METHOD: Thirty-five non-demented ET patients with a range of cognitive function (Clinical Dementia Rating = 0-0.5, mean age = 57.5 ± 16.7 years, age range = 23-76 years) underwent a comprehensive neuropsychological evaluation and brain magnetic resonance imaging, including DTI. DTI findings were reported as fractional anisotropy, average diffusion coefficient, these values were evaluated for 32 ROIs. Cognitive domains included attention, visuospatial functions, executive function, verbal memory, visual memory, and language. Domain Z-scores were calculated each cognitive domain and compared for each brain region. RESULTS: Microstructural changes in prefrontal cortical areas (dorsolateral, ventrolateral), paralimbic and limbic structures (posterior cingulate cortex, precuneus, hippocampus), basal ganglia (substantia nigra, putamen, caudate nucleus) and white matter bundles (corpus callosum, anterior thalamic radiation, longitudinal fasciculus, frontooccipital fasciculus, etc.) correlated with specific domains of cognitive function in ET patients. CONCLUSION: These data suggest that not only the cerebello thalamocortical pathway, but numerous other brain structures are related to level of cognitive performance and possibly underlie cognitive dysfunction in ET.

Cognition in non-demented Parkinson's disease vs essential tremor: A population-based study.

OBJECTIVES: Patients with Parkinson's disease (PD) and essential tremor (ET) have a higher risk of cognitive impairment than age-matched controls. Only a few small studies (11-18 subjects per group) have directly compared the cognitive profile of these conditions. Our aim was to compare the cognitive profile of patients with these two conditions to each other and to healthy individuals in a population-based study of non-demented participants. MATERIALS AND METHODS: This investigation was part of the NEDICES study, a survey of the elderly in which 2438 dementia-free participants underwent a short neuropsychological battery. We used nonparametric techniques to evaluate whether there are differences and/or a gradient of impairment across the groups (PD, ET, and controls). Also, we performed a head-to-head comparison of ET and PD, adjusting for age and education. RESULTS: Patients with PD (N=46) and ET (N=180) had poorer cognition than controls (N=2212). An impaired gradient of performance was evident. PD scored lower than ET, and then each of these lower than controls, in memory (P<.05) and verbal fluency (P<.001) tasks. When we compared PD and ET, the former had lower scores in verbal fluency (P<.05), whereas the later had a poorer cognitive processing speed (P<.05). CONCLUSIONS: This large population-based study demonstrates that both conditions influence cognitive performance, that a continuum exists from normal controls to ET to PD (most severe), and that although deficits are in many of the same cognitive domains, the affected cognitive domains do not overlap completely.

Reduced body mass index in essential tremor: a study of 382 cases and 392 matched controls.

BACKGROUND AND PURPOSE: There is mounting evidence that essential tremor (ET) is a neurodegenerative disease. Reduced body mass index (BMI) is a clinical feature of many neurodegenerative diseases, yet there has been little documentation of BMI in patients with ET. METHODS: Essential tremor cases and controls were enrolled in a study of the environmental epidemiology of ET at Columbia University Medical Center. Weight and height were measured using a standard protocol; BMI was weight (kg) divided by height (m(2)). Daily calorie count (kcal) was calculated using the Willett Semi-Quantitative Food Frequency Questionnaire. Tremor severity was assessed with a clinical rating scale (total tremor score, range 0-36). RESULTS: The 382 ET cases and 392 controls were similar with respect to age, gender and other demographic variables. BMI was lower in ET cases than controls [26.7 ± 5.0 (median = 26.2) vs. 27.7 ± 5.6 (median = 26.7), P = 0.03] despite the fact that the daily caloric intake was marginally higher in ET cases than controls (P = 0.09). In ET cases, BMI was not associated with tremor severity (Spearman's r = -0.02, P = 0.66) but, among younger onset ET cases, longer tremor duration was associated with lower BMI (Spearman's r = -0.14, P = 0.049). CONCLUSIONS: The observed lower BMI in ET is consistent with the neurodegenerative hypothesis of ET. The data also suggest that some mechanism other than decreased daily caloric intake or an involuntary movement-related increased burning of calories is likely to account for this case-control difference.

Prevalence and correlates of rest tremor in essential tremor: cross-sectional survey of 831 patients across four distinct cohorts.

BACKGROUND AND PURPOSE: Essential tremor (ET) is amongst the most commonly encountered neurological disorders. Its hallmark feature is kinetic tremor. However, other tremors may also occur in ET patients, creating considerable diagnostic confusion amongst treating physicians. Hence, characterizing the prevalence and clinical accompaniments of these other tremors is of value. Surprisingly, there are few data on the prevalence of rest tremor in ET patients, and even fewer data on the clinical correlates of such tremor. METHODS: Eight hundred and thirty-one patients in four distinct settings (population, genetics study, study of environmental epidemiology, brain bank) underwent a detailed videotaped neurological examination that was reviewed by a senior movement disorders neurologist. Rest tremor was evaluated in several positions (seated, standing, lying down). RESULTS: The prevalence of rest tremor whilst seated or standing was lowest in the population-based setting (1.9%), highest in the brain bank study (46.4%) and intermediate in the remaining two settings (9.6% and 14.7%, respectively). Rest tremor was restricted to the arms and was not observed in the legs. Rest tremor was associated with older age, longer disease duration (in some studies), greater tremor severity and, to some extent, the presence of cranial tremors. CONCLUSIONS: Rest tremor can be a common clinical feature of ET. Its prevalence is highly dependent on the setting in which patients are evaluated, ranging from as low as 1% to nearly 50%. Rest tremor seems to emerge as a clinical feature with advancing disease. The anatomical substrates for this type of tremor remain unknown at present.

Challenges in essential tremor genetics.

The field of essential tremor (ET) genetics remains extremely challenging. The relative lack of progress in understanding the genetic etiology of ET, however, does not reflect the lack of a genetic contribution, but rather, the presence of substantial phenotypic and genotypic heterogeneity. A meticulous approach to phenotyping is important for genetic research in ET. The only tool for phenotyping is the clinical history and examination. There is currently no ET-specific serum or imaging biomarker or defining neuropathological feature (e.g., a protein aggregate specific to ET) that can be used for phenotyping, and there is considerable clinical overlap with other disorders such as Parkinson's disease (PD) and dystonia. These issues greatly complicate phenotyping; thus, in some studies, as many as 30-50% of cases labeled as "ET" have later been found to carry other diagnoses (e.g., dystonia, PD) rather than ET. A cursory approach to phenotyping (e.g., merely defining ET as an "action tremor") is likely a major issue in some family studies of ET, and this as well as lack of standardized phenotyping across studies and patient centers is likely to be a major contributor to the relative lack of success of genome wide association studies (GWAS). To dissect the genetic architecture of ET, whole genome sequencing (WGS) in carefully characterized and well-phenotyped discovery and replication datasets of large case-control and familial cohorts will likely be of value. This will allow specific hypotheses about the mode of inheritance and genetic architecture to be tested. There are a number of approaches that still remain unexplored in ET genetics, including the contribution of copy number variants (CNVs), 'uncommon' moderate effect alleles, 'rare' variant large effect alleles (including Mendelian and complex/polygenic modes of inheritance), de novo and gonadal mosaicism, epigenetic changes and non-coding variation. Using these approaches is likely to yield new ET genes.

The microtubule associated protein tau H1 haplotype and risk of essential tremor.

BACKGROUND AND PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The primary type of tremor in essential tremor is kinetic rather than postural: cross-sectional observation of tremor phenomenology in 369 cases.

BACKGROUND: Essential tremor (ET) is amongst the most commonly misdiagnosed neurological diseases. The current aim was to provide observational data on a basic characteristic of ET, namely, the relative severity of postural to kinetic tremor. METHODS: A total of 369 ET cases were enrolled in a cross-sectional study. Postural tremor scores (0-3) and kinetic tremor scores (0-3) were assigned during a standardized neurological examination. RESULTS: In the vast bulk of cases (~95%), kinetic tremor was more severe than postural tremor. In nearly one-in-three cases (32.8%), the kinetic tremor score was ≥ 1 points higher than the postural tremor score. Conversely, in only a few cases (~5%) was postural tremor even marginally (<1 point) more severe than kinetic tremor, and in no case was the postural tremor score ≥ 1 point higher than the kinetic tremor score. At each postural tremor score, nearly all cases had that amount of kinetic tremor or more. CONCLUSION: The primary type of tremor in ET is kinetic rather than postural. Recognition of the simple, empirical features of tremor phenomenology has potential diagnostic value for practicing clinicians.

Is there a one-way street from essential tremor to Parkinson's disease? Possible biological ramifications.

There is considerable evidence for an association between essential tremor (ET) and Parkinson's disease (PD), although the topic remains somewhat controversial. An important issue, not previously addressed, is what seems to be the unidirectional nature of the relationship (ET→ET + PD and not PD→PD + ET). The aims of this review are (i) to discuss the evidence for and against a unidirectional relationship and (ii) to discuss the implications of such a unidirectional relationship, if it exists, for disease mechanisms. Evidence 'for' a unidirectional relationship includes (i) abundant clinical anecdotal observation and (ii) clinical and epidemiological studies. Evidence 'against' is theoretical rather than empirical. Overall, the evidence 'for' is stronger, although additional studies are needed in order to be certain; for the time being, it might be best to leave this as an open question. The biological ramifications/extensions of such a unidirectional relationship include (i) that the association is causal (i.e., some aspect of ET pathophysiology predisposes an individual to develop PD) and (ii) that some ET cases may have a circumscribed form of Lewy body disease, and the secondary development of PD may represent a spread of those Lewy bodies in the brainstem. The presence and nature of the links between ET and PD are controversial. Further primary data (epidemiological and pathological) are needed to improve understanding of the relationship and its implications for the pathogenesis of both disorders.

Essential tremor 10, 20, 30, 40: clinical snapshots of the disease by decade of duration.

BACKGROUND AND PURPOSE: Essential tremor (ET) is a chronic, progressive neurological disorder in which disease burden may slowly accrue. There are few long-term studies, and the clinical and functional status of patients, with each decade of disease duration, has not been documented in detail. We used cross-sectional data on 335 patients with ET (disease duration 1-81 years) to produce clinical snapshots of the disease at each 10-year milestone (i.e. < 10, 10-19, 20-29, 30-39, ≥ 40 years). We hope these data will be of value in clinical-prognostic settings both to patients and their treating physicians. METHODS: In this cross-sectional, clinical-epidemiological study at Columbia-University Medical Center, each patient underwent a single evaluation, including self-reported measures of tremor-related disability, performance-based measures of function, and neurologist-assessments of tremor type, location and severity. RESULTS: A variety of metrics of tremor severity increased across the 10-year time intervals. By ≥ 40 years duration, one-third of patients had tremor in at least two cranial locations (neck, voice, jaw), and the proportion with high-amplitude tremor reached 20.3% (while drawing spirals), 33.8% (spilling while drinking) and 60.8% (spilling while using a spoon). Yet even in the longest tremor duration group, very few (< 10%) were incapacitated (i.e. completely unable to perform the above-mentioned tasks), and one-third continued to exhibit no cranial tremor. CONCLUSIONS: These data paint a picture of progressive decade-by-decade decline in ET. Yet patients with long disease duration did not relentlessly converge at the same end-stage of severe, functionally incapacitating, diffuse tremor. In this respect, long-duration ET patients presented a heterogeneous picture.

Genetic analysis of the FUS/TLS gene in essential tremor.

BACKGROUND AND PURPOSE: Although essential tremor (ET) has a genetic basis, specific genes have not been identified. Recently, in a large ET family (FET1) from Quebec, a non-sense mutation (p.Q290X) in the amyotrophic lateral sclerosis (ALS) gene fused in sarcoma/translated in liposarcoma (FUS/TLS) was identified by exome sequencing. No confirmatory studies have been published. METHODS: Two-hundred and fifty-nine ET cases and 262 controls were enrolled in a study at Columbia University. We performed a comprehensive analysis of the FUS/TLS gene by sequencing all exons in a subsample of 116 ET cases with early-onset (≤40 years) ET. We evaluated an association between ET and SNPs in the FUS/TLS gene by genotyping four haplotype tagging SNPs in all 259 ET cases and 262 controls. Additionally, seven variants associated with ALS, two variants of unknown pathogenicity detected in ALS cases, eight mis-sense variants predicted to be damaging, and six rare variants were genotyped in these 259 ET cases and 262 controls. RESULTS: FUS/TLS mutations previously reported in ALS, the FET1 family, or novel mutations were not found in any of the 116 early-onset ET cases. In the case-control analyses, although the power of the performed associations was limited, no significant association between tagging SNPs in FUS/TLS and ET was observed, and none of the analyzed SNPs showed evidence of association with ET. CONCLUSION: Our study suggests that pathogenic mutations in FUS/TLS are rare in a sample of early-onset ET cases in North America. We did not find evidence that the FUS/TLS gene is a risk factor for ET.

Color vision: a study of essential tremor cases versus normal controls.

BACKGROUND AND PURPOSE: Patients with essential tremor (ET) and Parkinson's disease (PD) may exhibit overlapping clinical features. Also, a growing number of non-motor features are being documented in ET. Color vision abnormalities, although well known to occur in PD, have not been studied extensively in ET. We assessed color vision in ET cases and controls. We furthermore assessed subgroups of ET cases with clinical features that might link them to PD (i.e., ET cases with a family history of PD, and ET cases with rest tremor) to determine whether these cases had greater color vision abnormalities than ET cases without those features. METHODS: Participants were enrolled in a case-control study at Columbia University Medical Center. Color discrimination testing was performed using the Farnsworth-Munsell 100 Hue test. The total error score (TES) for the hue test was determined. RESULTS: The TES was similar in 55 ET cases and 55 controls (144.6 ± 91.8 vs. 145.6 ± 96.6, P = 0.96). ET cases with rest tremor (n = 8) were similar to ET cases without rest tremor (n = 47) with respect to the TES (117.0 ± 73.4 vs. 149.3 ± 94.4, P = 0.36), as were ET cases with a family history of PD (n = 9) versus without (n = 46) (144.4 ± 57.0 vs. 144.6 ± 97.6, P = 0.996). CONCLUSIONS: Although a number of links exist between ET and PD, and non-motor features have been described in both, a color vision abnormality does not seem to be a feature of ET.

Depressive traits in essential tremor: impact on disability, quality of life, and medication adherence.

BACKGROUND: There is growing study of the psychiatric features of essential tremor. Depressive symptoms occur in a considerable number of patients. Yet their impact, as a primary factor, has received almost no attention. We assessed whether, independent of tremor severity, patients with more depressive symptoms have more perceived tremor-related disability, lower tremor-related quality of life, and poorer compliance with tremor medication. METHODS: On the basis of their Center for Epidemiological Studies Depression Scale score, we stratified 70 essential tremor patients into three groups: 41 with minimal depressive symptoms, 24 with moderate depressive symptoms, and five with severe depressive symptoms. Importantly, the three groups had similar tremor severity on neurological examination. We assessed self-reported tremor-related disability, tremor-related quality of life (Quality of Life in Essential Tremor) (QUEST) score, and medication compliance. RESULTS: Cases with minimal depressive symptoms had the lowest QUEST scores (i.e., highest quality of life), cases with moderate depressive symptoms had intermediate scores, and those with severe depressive symptoms had the highest QUEST scores (i.e., lowest quality of life) (P < 0.001). Depressive symptoms were a stronger predictor of tremor-related quality of life than was the main motor feature of essential tremor (ET) itself (tremor). Self-reported medication compliance was lowest in cases with severe depressive symptoms and highest in cases with minimal depressive symptoms. CONCLUSIONS: The physical disability caused by the tremor of ET has traditionally been regarded as the most important feature of the disease that causes distress, and it has received the most attention in the management of patients with this disease. Our data indicate that this may not be the case.

Increased number of Purkinje cell dendritic swellings in essential tremor.

BACKGROUND AND PURPOSE: Essential Tremor (ET) is among the most prevalent neurologic disorders. Growing clinical and neuro-imaging evidence implicates cerebellar dysfunction in the pathogenesis of ET and emerging postmortem studies have identified structural changes in the cerebellum, particularly in Purkinje cells. In this study we systematically quantified focal Purkinje cell dendritic swellings (DS) in 20 ET vs. 19 control brains. METHODS: In each brain, a standard parasagittal neocerebellar tissue block was harvested. DS were quantified in one 7-µm thick section stained with Luxol Fast Blue/Hematoxylin and Eosin (LH&E) and one section stained with Bielschowsky method. RESULTS: The number of DS were higher in cases than controls by LH&E (1.50 ± 1.79 vs. 0.05 ± 0.23, P = 0.002) and Bielschowsky methods (2.70 ± 3.10 vs. 0.37 ± 0.50, P = 0.002). The number of DS was correlated with the number of torpedoes and marginally inversely correlated with the number of Purkinje cells. CONCLUSION: The current study documents and quantifies an additional structural abnormality in the ET cerebellum, adding to the growing list of such changes in this disease. The mechanisms that underlie this and other structural changes observed in ET are currently unknown, and they deserve additional exploration.

Frailty in elderly persons with essential tremor: a population-based study (NEDICES).

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.

Update on essential tremor.

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.

Subclinical tremor in normal controls with versus without a family history of essential tremor: data from the United States and Turkey.

BACKGROUND AND PURPOSE: Mild action tremor is very common in the population. One fundamental question is whether this tremor is related to the neurological disease essential tremor (ET), which occurs in a much smaller segment of the population? ET is often genetic, and variable phenotypic expression is well-documented in the literature. We determined whether normal controls who report a family history of ET have greater action tremor than normal controls who do not report such a history. METHODS: Controls, enrolled in two epidemiological studies (New York and Turkey), were examined in detail and action tremor was rated using a valid and reliable clinical rating scale, resulting in a total tremor score (range 0-36). RESULTS: In New York, the total tremor score was higher in 44/406 (10.8%) controls who reported a family history of ET than in 362/406 controls with no such history (4.25 +/- 2.51 vs. 3.78 +/- 2.93, P = 0.02). Controls who reported a first-degree relative with ET had the highest total tremor scores. In Turkey, the total tremor score was higher in 7/89 (7.9%) controls with a family history than in 82/89 controls with no family history (3.43 +/- 4.54 vs. 1.13 +/- 2.54, P = 0.048). All affected relatives in Turkey were first-degree. CONCLUSIONS: These data suggest that some of the normal tremor exhibited by people in the population is likely to be subclinical, partially expressed ET and that the sphere of ET is wider than is apparent from a consideration of clinically diagnosed cases.

How are we doing with the treatment of essential tremor (ET)?: Persistence of patients with ET on medication: data from 528 patients in three settings.

BACKGROUND: The pharmacological treatment of essential tremor (ET) is not optimal. There are only two first-line medications and troublesome side effects are common. It is not uncommon for patients to simply stop taking medication. Yet, no published data substantiate or quantify this anecdotal impression. OBJECTIVES: To determine, amongst patients with ET who were prescribed medication for tremor, what proportion are still taking medication and what proportion have stopped? METHODS: Five hundred and twenty-eight patients with ET from three distinct study settings (clinical, brain donors, population) were interviewed. RESULTS: A clear pattern that emerged across settings was that the proportion of patients with ET who had stopped medication was sizable and consistently similar (nearly one-third): 31.4% (clinical), 24.3% (brain donors), 30.0% (population), 29.8% (overall). A similarly high proportion of cases with severe tremor had stopped their medication: 31.9% (clinical), 36.4% (brain donors). For the four most commonly used medications (propranolol, primidone, diazepam, topiramate), one-half or more of the treated patients had stopped the medication; amongst the less commonly used medications, the proportion who stopped was even higher. CONCLUSIONS: Nearly one of every three patients with ET who had been prescribed medication for tremor had discontinued pharmacotherapy. Even more revealing was that a similar proportion of cases with severe tremor had stopped medication. These data make tangibly evident that there is a sizable population of patients with ET who are untreated and disabled, and underscore the inadequacy of current pharmacotherapeutic options for this common neurological disease.

Faster rate of cognitive decline in essential tremor cases than controls: a prospective study.

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.

Risk of incident Parkinson's disease and parkinsonism in essential tremor: a population based study.

BACKGROUND: A longstanding literature suggests an association between essential tremor (ET) and Parkinson's disease (PD). However, the risk of incident PD has not been quantified in cases of ET compared with controls. OBJECTIVE: To estimate the risk of incident PD in a population based cohort study of 3813 older people (including ET cases and controls) in central Spain. RESULTS: After a median of 3.3 years, 12 (5.8%) of 207 ET cases developed parkinsonism compared with 56 (1.6%) of 3606 controls (adjusted relative risk (RR) 3.47, 95% CI 1.82 to 6.59; p<0.001). Six (3.0%) of 201 ET cases developed incident PD versus 24 (0.7%) of 3574 controls (adjusted RR 4.27, 95% CI 1.72 to 10.61; p = 0.002). CONCLUSIONS: Patients with ET were four times more likely than controls to develop incident PD during prospective follow-up. These data confirm and begin to quantify the link between these two diseases.

Population-based study of baseline ethanol consumption and risk of incident essential tremor.

BACKGROUND: Recent postmortem studies have demonstrated pathological changes, including Purkinje cell loss, in the cerebellum in essential tremor (ET). Toxic exposures that compromise cerebellar tissue could lower the threshold for developing ET. Ethanol is a well-established cerebellar toxin, resulting in Purkinje cell loss. OBJECTIVE: To test whether higher baseline ethanol consumption is a risk factor for the subsequent development of incident ET. METHODS: Lifetime ethanol consumption was assessed at baseline (1994-1995) in a prospective, population-based study in central Spain of 3285 elderly participants, 76 of whom developed incident ET by follow-up (1997-1998). RESULTS: In a Cox proportional hazards model adjusting for cigarette pack-years, depressive symptoms and community, the baseline number of drink-years was marginally associated with a higher risk of incident ET (relative risk, RR = 1.003, p = 0.059). In an adjusted Cox model, the highest baseline drink-year quartile doubled the risk of incident ET (RR = 2.29, p = 0.018), while other quartiles were associated with more modest elevations in risk (RR(3rd quartile) = 1.82 (p = 0.10), RR(2nd quartile) = 1.75 (p = 0.10), RR(1st quartile) = 1.43 (p = 0.34) vs non-drinkers (RR = 1.00)). With each higher drink-year quartile, the risk of incident ET increased an average of 23% (p = 0.01, test for trend). CONCLUSIONS: Higher levels of chronic ethanol consumption increased the risk of developing ET. Ethanol is often used for symptomatic relief; studies should explore whether higher consumption levels are a continued source of underlying cerebellar neurotoxicity in patients who already manifest this disease.