Analysis of circulating metabolites to differentiate Parkinson's disease and essential tremor.

Parkinson's disease (PD) and essential tremor (ET) are two common adult-onset tremor disorders in which prevalence increases with age. PD is a neurodegenerative condition with progressive disability. In ET, neurodegeneration is not an established etiology. We sought to determine whether an underlying metabolic pattern may differentiate ET from PD. Circulating metabolites in plasma and cerebrospinal fluid (CSF) were analyzed using gas chromatography-mass spectroscopy. There were several disrupted pathways in PD compared to ET plasma including glycolysis, tyrosine, phenylalanine, tyrosine biosynthesis, purine and glutathione metabolism. Elevated α-synuclein levels in plasma and CSF distinguished PD from ET. The perturbed metabolic state in PD was associated with imbalance in the pentose phosphate pathway, deficits in energy production, and change in NADPH, NADH and nicotinamide phosphoribosyltransferase levels. This work demonstrates significant metabolic differences in plasma and CSF of PD and ET patients.

Calpain activity in plasma of patients with essential tremor and Parkinson's disease: a pilot study.

Background: Essential tremor (ET) and Parkinson's disease (PD) are the two most common movement disorders in adults with similar clinical symptoms, which is hinting towards existence of coincident pathogenesis steps.Objectives: The objective of this report is to characterize the relationship between ET and PD severity and the activity of calcium-dependent proteases calpain in plasma.Methods: The study enrolled 12 volunteers for each condition: ET, PD, healthy. We evaluated the stage of PD on the H&Y scale in patients with PD, and the severity of tremor in patients with ET on the FTMS scale. IL-1ß, TNFα, IL6, IL10 were determined in plasma using ELISA. Calpain activity was measured using fluorescent substrate and zymography methods.Results: We demonstrated that the activity of calpains in plasma of patients with PD and ET increased 5.1 and 4.3 times, respectively. The increase of calpain activity in plasma of PD patients correlated with the content of IL-1ß, for ET such a connection was not found. At the advanced stages of PD calpain activity in plasma was significantly higher than that of the PD group at the early stage, and this increase was mediated by the increase in m-calpain activity. The increase in the tremor severity in ET did not lead to an increase in the activity of calpains in plasma.Conclusions: We observed general increase in the activity of calpains in plasma of both PD and ET patients that hints towards presence of the common steps in the pathogenesis of these diseases.

Identification of BAG2 and Cathepsin D as Plasma Biomarkers for Parkinson's Disease.

The current diagnosis of Parkinson's disease (PD) mostly relies on clinical rating scales related to motor dysfunction. Given that clinical symptoms of PD appear after significant neuronal cell death in the brain, it is required to identify accessible, objective, and quantifiable biomarkers for early diagnosis of PD. In this study, a total of 20 patients with idiopathic PD and 20 age-matched patients with essential tremor according to the UK Brain Bank Criteria were consecutively enrolled to identify peripheral blood biomarkers for PD. Clinical data were obtained by clinical survey and assessment. Using albumin-depleted and immunoglobulin G-depleted plasma samples, we performed immunoblot analysis of seven autophagy-related proteins and compared the levels of proteins to those of the control group. We also analyzed the correlation between the levels of candidate proteins and clinical characteristics. Finally, we validated our biomarker models using receiver operating characteristic curve analysis. We found that the levels of BCL2-associated athanogene 2 (BAG2) and cathepsin D were significantly decreased in plasma of patients with PD (P = 0.009 and P = 0.0077, respectively). The level of BAG2 in patients with PD was significantly correlated with Cross-Culture Smell Identification Test score, which indicates olfactory dysfunction. We found that our biomarker model distinguishes PD with 87.5% diagnostic accuracy (area under the curve (AUC) = 0.875, P < 0.0001). Our result suggests BAG2 and cathepsin D as candidates for early-diagnosis plasma biomarkers for PD. We provide the possibility of plasma biomarkers related to the autophagy pathway, by which decreased levels of BAG2 and cathepsin D might lead to dysfunction of autophagy.

Meat Consumption and Meat Cooking Practices in Essential Tremor: A Population-Based Study in the Faroe Islands.

Background: Elevated tissue levels of the tremor-producing neurotoxin, harmane, have been detected in patients with essential tremor (ET) in the USA and Spain. Recently, a study in the Faroe Islands similarly noted an elevation in blood harmane concentrations in probable and definite ET cases. The underlying mechanism is not understood. Possible mechanisms include increased dietary consumption (esp. through cooked meats), impaired metabolism, or increased endogenous production of harmane. To investigate this issue further, we conducted a population-based study in the Faroe Islands to examine meat consumption and meat cooking practices in ET cases and controls. Methods: 1,328 Faroese adults were screened for tremor and 27 ET cases were identified. Meat consumption and meat cooking practices were compared to 200 controls. Detailed data were collected via questionnaires regarding current meat consumption for 14 meat types and meat cooking doneness for 8 meat types. Data were also available on blood harmane concentrations. Results: Current meat consumption was similar in ET cases and controls in 12 out of 14 meat types, with no differences observed after a Bonferroni correction in any meat type; no difference was observed when stratified by gender. No difference was observed in meat doneness between ET cases and controls. Blood harmane concentrations were not correlated with dietary data. Discussion: This is the first population-based study of harmane-linked dietary factors in ET. The study suggests the observed difference in blood harmane in ET is not driven by dietary differences and is likely due to other mechanisms (e.g., impaired metabolism).

Blood Harmane (1-Methyl-9H-Pyrido[3,4-b]indole) and Mercury in Essential Tremor: A Population-Based, Environmental Epidemiology Study in the Faroe Islands.

BACKGROUND: Essential tremor (ET) is among the most prevalent neurological diseases. Its environmental determinants are poorly understood. Harmane (1-methyl-9H-pyrido[3, 4-b]indole), a dietary tremor-producing neurotoxin, has been linked to ET in a few studies in New York and Madrid. Mercury, also a tremor-producing neurotoxin, has not been studied in ET. The Faroe Islands have been the focus of epidemiological investigations of numerous neurological disorders. OBJECTIVE: In this population-based, case-control study, we directly measured blood harmane concentrations (HA) and blood mercury concentrations (Hg) in ET cases and controls. METHODS: In total, 1,328 Faroese adults were screened; 26 ET cases were identified whose (HA) and (Hg) were compared to 197 controls. RESULTS: Although there were no statistically significant differences between diagnostic groups, median (HA) was 2.7× higher in definite ET (4.13 g-10/mL) and 1.5× higher in probable ET (2.28 g-10/mL) than controls (1.53 g-10/mL). Small sample size was a limitation. For definite ET versus controls, p = 0.126. (Hg) were similar between groups. CONCLUSIONS: We demonstrated marginally elevated (HA) in definite and probable ET. These data are similar to those previously published and possibly extend etiological links between this neurotoxin and ET to a third locale. The study did not support a link between mercury and ET.

Central Nervous System-Derived Exosomal Alpha-Synuclein in Serum May Be a Biomarker in Parkinson's Disease.

Parkinson's disease (PD) is a common movement disorder. Alpha-synuclein (α-synuclein) plays a critical role in PD. In this study, we evaluated the level of central nervous system (CNS)-derived exosomal α-synuclein in serum, which may be regarded as a specific peripheral biomarker for PD. We recruited patients with PD in the early stage along with essential tremor (ET), and we recruited age- and gender-matched healthy subjects as healthy controls (HC). We divided patients with PD into the tremor-dominant (TD) group and the non-tremor-dominant (NTD) group. We evaluated the levels of α-synuclein in CNS-derived exosomes in serum samples. As a result, there was a significant difference between four groups (p<0.05). This level was lower in the PD group than in the ET and HC groups (p<0.05). Among the PD group, this level was lower in the NTD group than in the TD group (p<0.05). Furthermore, the performance of serum CNS-derived exosomal α-synuclein was found to moderately aid in PD diagnosis (AUC=0.675, p<0.05) and had a potential to diagnose NTD (AUC=0.761, p<0.05). Therefore, CNS-derived exosomal α-synuclein in the serum may be regarded as a biomarker to identify PD from ET and HC in the early stage. It may also be used to identify different motor types in PD. The pathogenesis of PD in different motor types may be different, which needs further research.

Evaluation of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in essential tremor.

Background and purpose: Although essential tremor (ET) is the most common cause of tremor, the pathology and underlying mechanisms have not fully understood yet. In addition to kinetic tremor, patients may present several types of tremor, gait ataxia, hearing deficits and eye movement abnormalities. Non-motor symptoms and signs have also added to definition of ET. There is significant evidence indicating the neurodegenerative nature of the disease. New studies indicate that inflammation may have a place in the etiology. The neutrophil-to lymphocyte ratio (NLR) and the platelet-to lymphocyte ratio (PLR) have recently begun to be used as a marker of systemic inflammation. Our study aims at finding a clue for systemic inflammation in ET. Methods: 67 patients with ET and 40 healthy controls were recruited for the study. The total white blood cells (WBC), absolute neutrophil count, lymphocyte count and platelet count were retrieved. The NLR was calculated by dividing the neutrophil count by the lymphocyte count and the PLR was calculated by dividing the platelet count by the lymphocyte count. Results: Patient and control groups were similar in terms of age and gender. The mean age of patient group was 25.29 ± 8.24 years and that of control group was 26.77 ± 6.73 years. The NLRs were 1.85 ± 0.58 in the patient group and 1.96 ± 0.53 in the control group. For the patient group and the control group the PLRs were 103.52 ±32.80 and 91.26 ± 31.57 respectively. There were no statistically significant differences between the participants for both NLR and PLR. Conclusion: The pathophysiological mechanism for essential tremor (ET) remains unclear. However, there is an increasing amount of research being conducted on the subject. Discussions about ET's definition as a neurodegenerative disease are ongoing. Although previous studies showed that neuroinflammation could be a part of etiology of disease, this study has failed to demonstrate systemic inflammation in ET.

Peripheral BDNF/TrkB protein expression is decreased in Parkinson's disease but not in Essential tremor.

BDNF-to-TrkB signaling pathways plays an important role in the long-term maintenance of the nigrostriatal system and that its deficiency may contribute to the onset and progression of Parkinson's disease (PD). To our knowledge this is the first study to investigate the expression of the brain-derived neurotrophic factor (BDNF) and phosphorylation status of TrkB in peripheral blood lymphocytes of 28 PD and 28 Essential tremor (ET) patients and 28 healthy controls using western blot analysis. Compared with controls, no significant difference of BDNF and total and phosphorylated TrkB levels were observed in ET, whereas BDNF and phosphorylated TrkB levels were significantly decreased in the PD groups (p < 0.001). Interestingly, BDNF and phosphorylated TrkB levels were positively correlated with disease duration, UPDRS score, Hoehn-Yahr staging, as well as L-DOPA medication in PD patients. These results suggest that the decreased peripheral alteration of BDNF/TrkB levels found in patients with PD is directly related to the dopaminergic neurons neurodegeneration and that decreased expression of BDNF/TrkB may lead to the development of innovative biomarkers of PD, whereas the increased level of BDNF and phosphorylated TrkB at advanced stages may due to L-DOPA medication.

Serum soluble lymphocyte activation gene-3 as a diagnostic biomarker in Parkinson's disease: A pilot multicenter study.

OBJECTIVE: Lymphocyte activation gene-3 (LAG-3) could mediate pathological α-synuclein transmission in neurodegeneration and may be involved in the pathogenesis of Parkinson's disease (PD). The aim of the present study was to explore soluble LAG-3 (sLAG-3) as a potential diagnostic biomarker for PD. METHODS: Serum sLAG-3 concentrations were measured by a quantitative ELISA for patients with PD, essential tremor (ET) and age- and sex-matched controls. The relationships between sLAG-3 and clinical phenotype were assessed via correlation analysis and logistic regression. RESULTS: Serum sLAG-3 levels in patients with PD were significantly higher than those in ET patients and age- and sex-matched controls. The area under the curve of serum sLAG-3 in differentiating PD from age- and sex-matched controls was 0.82. Serum sLAG-3 was associated with non-motor symptoms and excessive daytime sleep. CONCLUSION: sLAG-3 is a candidate novel biomarker for PD. © 2018 International Parkinson and Movement Disorder Society.

Uric acid level may not be reduced in essential tremor.

BACKGROUND: Essential tremor is very common, but characterization is difficult because of its heterogeneity. Neuropathology is important to elucidate the characteristics of neurological disorders. However, pathological findings in essential tremor have been inconsistent among studies. Uric acid is a strong antioxidant and might be a biomarker in neurodegenerative process. We hypothesized that uric acid level would be reduced if essential tremor is a neurodegenerative disease. Our aim was to compare uric acid level between essential tremor patients and healthy individuals. METHODS: This was a prospective, case-control, multicenter study with 92 essential tremor patients and 77 healthy subjects. For homogeneity, the essential tremor group was subdivided into two groups (hereditary and sporadic). Clinical and laboratory findings were compared among the essential tremor and healthy groups. RESULTS: The demographic characteristics were comparable among the groups. The uric acid level was lower in the essential tremor group than in healthy subjects, but the difference did not reach statistical significance. There was a negative correlation between uric acid level and disease duration in the hereditary group (p = .046) and between uric acid level and age at onset in the sporadic group (p = .012). The mean values of total cholesterol were significantly lower in the sporadic group than in the other groups (p = .011). Total cholesterol was positively correlated with age at onset in the hereditary essential tremor group (p = .010). CONCLUSIONS: We did not find any evidence that uric acid levels suggested essential tremor is a neurodegenerative disease. However, further research with more patients might be needed given the negative correlations of disease duration and age at onset with uric acid level.

Serum concentration and clinical significance of brain-derived neurotrophic factor in patients with Parkinson's disease or essential tremor.

Objectives The serum concentration of brain-derived neurotrophic factor (BDNF) was compared among patients with Parkinson's disease (PD), patients with essential tremor (ET), and healthy participants, and its association with clinical features of PD and ET was assessed. Methods Demographic and clinical data were collected from 60 patients with PD at different clinical stages, 60 patients with ET, and 60 controls. All participants' serum BDNF concentrations were measured. Their motor abilities and activity were assessed by the Unified PD Rating Scale and the Hoehn and Yahr (H-Y) staging scale. Results Serum BDNF was significantly lower in patients with PD than in patients with ET and controls. BDNF decreased only in the early disease stages (H-Y stages I and II), but increased markedly in the advanced stages (H-Y stages III-V). There was no significant difference between patients with ET and controls. The BDNF concentration was negatively correlated with age at PD onset and positively associated with disease duration, severity of PD symptoms, and treatment with L-DOPA. Conclusions A low serum BDNF concentration may serve as a biomarker in the early stages of PD, whereas a high concentration with PD progression may be due to treatment with L-DOPA in the advanced stages.

Plasma insulin-like growth factor 1 is associated with cognitive impairment in Parkinson's disease.

OBJECTIVE: The aim of this study was to test plasma insulin-like growth factor 1 (IGF-1) change in Parkinson's disease (PD) and essential tremor (ET), and assess the association of plasma IGF-1 level with motor and nonmotor symptoms in PD and ET. METHODS: Plasma IGF-1 was measured in 100 PD patients, 40 ET patients, and 76 healthy controls. Motor and nonmotor symptoms were assessed by different scales. Spearman correlation test and linear logistic model were used to analyze the correlation of plasma IGF-1 with motor and nonmotor symptoms of PD and ET. RESULTS: The plasma IGF-1 level was significantly increased in PD compared to healthy controls and ET patients. In addition, low plasma IGF-1 was correlated with low Mini-Mental State Examination (MMSE) scores in PD patients. However, no correlation was found between plasma IGF-1 and MMSE scores in ET patients. CONCLUSION: Plasma IGF-1 increased significantly in PD but remained unchanged in ET. A low plasma IGF-1 level was associated with poor cognitive performance in PD but not in ET patients.

Blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentration in essential tremor cases in Spain.

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: 2.09 g(-10)/ml (138 controls), 2.41 g(-10)/ml (68 sporadic ET), and 2.90 g(-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.

Blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor: repeat observation in cases and controls in New York.

Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors are likely to play important etiological roles. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. Previously, elevated blood harmane concentrations were demonstrated in ET cases compared to controls, but these observations have all been cross-sectional, assessing each subject at only one time point. Thus, no one has ever repeat-assayed blood harmane in the same subjects twice. Whether the observed case-control difference persists at a second time point, years later, is unknown. The current goal was to reassess a sample of our ET cases and controls to determine whether blood harmane concentration remained elevated in ET at a second time point. Blood harmane concentrations were quantified by a well-established high-performance liquid chromatography method in 63 ET cases and 70 controls. A mean of approximately 6 yr elapsed between the initial and this subsequent blood harmane determination. The mean log blood harmane concentration was significantly higher in cases than controls (0.30 ± 0.61 g(-10)/ml versus 0.08 ± 0.55 g(-10)/ml), and the median value in cases was double that of controls: 0.22 g(-10)/ml versus 0.11 g(-10)/ml. The log blood harmane concentration was highest in cases with a family history of ET. Blood harmane concentration was elevated in ET cases compared to controls when reassessed at a second time point several years later, indicating what seems to be a stable association between this environmental toxin and ET.

Biomarkers demonstrate increased consumption, but not abuse, of ethanol in essential tremor.

Ethanol is known to improve tremor in a proportion of patients with essential tremor. Increased incidence of alcoholism has been suspected in essential tremor patients; however, no objective evaluation has been performed using laboratory markers to date. Data on alcohol intake in the last 30 days were acquired in 95 essential tremor patients and 35 healthy controls. Blood and urine markers related to alcohol metabolism and liver function were evaluated. Self-reported alcohol intake and biomarker levels were higher in essential tremor, but the difference was only significant for carbohydrate-deficient transferrin. None of the subjects presented with laboratory parameters reflecting chronic alcohol abuse. Our data do not reflect a higher incidence of alcoholism in patients with essential tremor. Their alcohol intake is well controlled and does not exceed the limits of healthy social drinking.

An open-label, single-dose, crossover study of the pharmacokinetics and metabolism of two oral formulations of 1-octanol in patients with essential tremor.

Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer-chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor-suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1-64 mg/kg; n = 4), and (part B) a fixed dose (64 mg/kg; n = 10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg.Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was assessed using spirography, whereas safety was assessed with electrocardiograms, vital signs, adverse effects surveys, and an intoxication assessment. Plasma concentrations of 1-octanol were detectable at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6 minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement. These findings provide preliminary evidence for a new class of compound that may be effective in the treatment of ET.

Blood harmane, blood lead, and severity of hand tremor: evidence of additive effects.

BACKGROUND: Tremor is a widespread phenomenon in human populations. Environmental factors are likely to play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-ß]indole) is a potent tremor-producing ß-carboline alkaloid. Lead is another tremor-producing neurotoxicant. The effects of harmane and lead with respect to tremor have been studied in isolation. OBJECTIVES: We tested the hypothesis that tremor would be particularly severe among individuals who had high blood concentrations of both of these toxicants. METHODS: Blood concentrations of harmane and lead were each quantified in 257 individuals (106 essential tremor cases and 151 controls) enrolled in an environmental epidemiological study. Total tremor score (range = 0-36) was a clinical measure of tremor severity. RESULTS: The total tremor score ranged from 0 to 36, indicating that a full spectrum of tremor severities was captured in our sample. Blood harmane concentration correlated with total tremor score (p = 0.007), as did blood lead concentration (p = 0.045). The total tremor score was lowest in participants with both low blood harmane and lead concentrations (8.4 ± 8.2), intermediate in participants with high concentrations of either toxicant (10.5 ± 9.8), and highest in participants with high concentrations of both toxicants (13.7 ± 10.4) (p=0.01). CONCLUSIONS: Blood harmane and lead concentrations separately correlated with total tremor scores. Participants with high blood concentrations of both toxicants had the highest tremor scores, suggesting an additive effect of these toxicants on tremor severity. Given the very high population prevalence of tremor disorders, identifying environmental determinants is important for primary disease prevention.

Beta-carboline alkaloids and essential tremor: exploring the environmental determinants of one of the most prevalent neurological diseases.

Essential tremor (ET) is among the most prevalent neurological diseases, yet its etiology is not well understood. Susceptibility genotypes undoubtedly underlie many ET cases, although no genes have been identified thus far. Environmental factors are also likely to contribute to the etiology of ET. Harmane (1-methyl-9H-pyrido[3,4-beta]indole) is a potent, tremor-producing beta-carboline alkaloid, and emerging literature has provided initial links between this neurotoxin and ET. In this report, we review this literature. Two studies, both in New York, have demonstrated higher blood harmane levels in ET cases than controls and, in one study, especially high levels in familial ET cases. Replication studies of populations outside of New York and studies of brain harmane levels in ET have yet to be undertaken. A small number of studies have explored several of the biological correlates of exposure to harmane in ET patients. Studies of the mechanisms of this putative elevation of harmane in ET have explored the role of increased dietary consumption, finding weak evidence of increased exogenous intake in male ET cases, and other studies have found initial evidence that the elevated harmane in ET might be due to a hereditarily reduced capacity to metabolize harmane to harmine (7-methoxy-1-methyl-9H-pyrido[3,4-beta]-indole). Studies of harmane and its possible association with ET have been intriguing. Additional studies are needed to establish more definitively whether these toxic exposures are associated with ET and are of etiological importance.

Relationship between blood harmane and harmine concentrations in familial essential tremor, sporadic essential tremor and controls.

INTRODUCTION: Harmane, a potent tremor-producing ß-carboline alkaloid, may play a role in the etiology of essential tremor (ET). Blood harmane concentrations are elevated in ET cases compared with controls yet the basis for this elevation remains unknown. Decreased metabolic conversion (harmane to harmine) is one possible explanation. Using a sample of >500 individuals, we hypothesized that defective metabolic conversion of harmane to harmine might underlie the observed elevated harmane concentration in ET, and therefore expected to find a higher harmane to harmine ratio in familial ET than in sporadic ET or controls. METHODS: Blood harmane and harmine concentrations were quantified by high performance liquid chromatography. RESULTS: There were 78 familial ET cases, 187 sporadic ET cases, and 276 controls. Blood harmane and harmine concentrations were correlated with one another (Spearman's r=0.24, p<0.001). The mean (±SD) harmane/harmine ratio=23.4±90.9 (range=0.1-987.5). The harmane/harmine ratio was highest in familial ET (46.7±140.4), intermediate in sporadic ET (28.3±108.1), and lowest in controls (13.5±50.3) (p=0.03). In familial ET cases, there was no association between this ratio and tremor severity (Spearman's r=0.08, p=0.48) or tremor duration (Spearman's r=0.14, p=0.24). CONCLUSION: The basis for the elevated blood harmane concentration, particularly in familial ET, is not known, although the current findings (highest harmane/harmine ratio in familial ET cases) lends support to the possibility that it could be the result of a genetically-driven reduction in harmane metabolism.