Gray matter density loss in essential tremor: a lobule by lobule analysis of the cerebellum

BACKGROUND: The pathophysiological basis for essential tremor (ET) remains unclear, although evidence increasingly links it to a disordered and perhaps degenerative cerebellum. Prior imaging studies have treated the cerebellum en bloc. Our hypothesis was that regional differences in cerebellar gray matter (GM) density may better distinguish ET cases from controls. Forty-seven ET cases and 36 control subjects were imaged using magnetic resonance imaging (MRI). The cerebellum was segmented into 34 lobes using a Spatially Unbiased Infra-Tentorial Template (SUIT) atlas within the Statistical Parametric Mapping (SPM) analysis package. Age, gender and Montreal Cognitive Assessment (MoCA) scores were regressed out from the statistical models to isolate group effects. ET cases were further stratified into phenotypically-defined subgroups. The Benjamini-Hochberg False Discovery Rate procedure (BH FDR) (α = 0.1) was used to correct for multiple comparisons. RESULTS: When all ET cases and controls were compared, none of the regions met the BH FDR criteria for significance. When compared with controls, ET cases with head or jaw tremor (n = 27) had significant changes in GM density in nine cerebellar lobules, with a majority in the left cerebellar region, and each meeting the BH FDR criteria. Likewise, ET cases with voice tremor (n = 22) exhibited significant changes in 11 lobules in both left and right regions and the vermis. These analyses, in sum, indicated decreases in GM density in lobules I-IV, V, VI, VII and VIII as well as the vermis. ET cases with severe tremor (n = 20) did not show regions of change that survived the BH FDR procedure when compared to controls. CONCLUSIONS: We showed that ET cases with various forms of cranial tremor differed from controls with respect to cerebellar GM density, with evidence of GM reduction across multiple cerebellar regions. Additional work, using a lobule-by-lobule approach, is needed to confirm these results and precisely map the regional differences in ET cases, subgroups of ET cases, and controls

Effect of Primidone on Dentate Nucleus γ-Aminobutyric Acid Concentration in Patients With Essential Tremor

OBJECTIVES: It is not known whether current use of the medication primidone affects brain γ-aminobutyric acid (GABA) concentrations. This is an important potential confound in studies of the pathophysiology of essential tremor (ET), one of the most common neurological diseases. We compared GABA concentrations in the dentate nucleus in 6 ET patients taking primidone versus 26 ET patients not taking primidone. METHODS: (1)H magnetic resonance spectroscopy was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in 2 cerebellar volumes of interest (left and right) that included the dentate nucleus. RESULTS: The right dentate GABA concentration was similar in the 2 groups (2.21 ± 0.46 [on primidone] vs 1.93 ± 0.39 [not on primidone], P = 0.15), as was the left dentate GABA concentration (1.61 ± 0.35 [on primidone] vs 1.67 ± 0.34 [not on primidone], P = 0.72). The daily primidone dose was not associated with either right or left dentate GABA concentrations (P = 0.89 and 0.76, respectively). CONCLUSIONS: We did not find a difference in dentate GABA concentrations between 6 ET patients taking daily primidone and 26 ET patients not taking primidone. Furthermore, there was no association between daily primidone dose and dentate GABA concentration. These data suggest that it is not necessary to exclude ET patients on primidone from magnetic resonance spectroscopy studies of dentate GABA concentration, and if assessment of these concentrations was to be developed as a biomarker for ET, primidone usage would not confound interpretation of the results

Cerebral Gray Matter Volume Losses in Essential Tremor: A Case-Control Study Using High Resolution Tissue Probability Maps

Introduction Essential tremor (ET) is increasingly recognized as a multi-dimensional disorder with both motor and non-motor features. For this reason, imaging studies are more broadly examining regions outside the cerebellar motor loop. Reliable detection of cerebral gray matter (GM) atrophy requires optimized processing, adapted to high-resolution magnetic resonance imaging (MRI). We investigated cerebral GM volume loss in ET cases using automated segmentation of MRI T1-weighted images. Methods MRI was acquired on 47 ET cases and 36 controls. Automated segmentation and voxel-wise comparisons of volume were performed using Statistical Parametric Mapping (SPM) software. To improve upon standard protocols, the high-resolution International Consortium for Brain Mapping (ICBM) 2009a atlas and tissue probability maps were used to process each subject image. Group comparisons were performed: all ET vs. Controls, ET with head tremor (ETH) vs. Controls, and severe ET vs. Controls. An analysis of variance (ANOVA) was performed between ET with and without head tremor and controls. Age, sex, and Montreal Cognitive Assessment (MoCA) score were regressed out from each comparison. Results We were able to consistently identify regions of cerebral GM volume loss in ET and in ET subgroups in the posterior insula, superior temporal gyri, cingulate cortex, inferior frontal gyri and other occipital and parietal regions. There were no significant increases in GM volume in ET in any comparisons with controls. Conclusion This study, which uses improved methodologies, provides evidence that GM volume loss in ET is present beyond the cerebellum, and in fact, is widespread throughout the cerebrum as well

Neuroimaging Studies of Essential Tremor: How Well Do These Studies Support/Refute the Neurodegenerative Hypothesis?

Background: Tissue‐based research has recently led to a new patho‐mechanistic model of essential tremor (ET)—the cerebellar degenerative model. We are not aware of a study that has reviewed the current neuroimaging evidence, focusing on whether the studies support or refute the neurodegenerative hypothesis of ET. This was our aim. Methods: References for this review were identified by searches of PubMed (1966 to February 2014). Results: Several neuroimaging methods have been used to study ET, most of them based on magnetic resonance imaging (MRI). The methods most specific to address the question of neurodegeneration are MRI‐based volumetry, magnetic resonance spectroscopy, and diffusion‐weighted imaging. Studies using each of these methods provide support for the presence of cerebellar degeneration in ET, finding reduced cerebellar brain volumes, consistent decreases in cerebellar N‐acetylaspartate, and increased mean diffusivity. Other neuroimaging techniques, such as functional MRI and positron emission tomography (PET) are less specific, but still sensitive to potential neurodegeneration. These techniques are used for measuring a variety of brain functions and their impairment. Studies using these modalities also largely support cerebellar neuronal impairment. In particular, changes in 11C‐flumazenil binding in PET studies and changes in iron deposition in an MRI study provide evidence along these lines. The composite data point to neuronal impairment and likely neuronal degeneration in ET. Discussion: Recent years have seen a marked increase in the number of imaging studies of ET. As a whole, the combined data provide support for the presence of cerebellar neuronal degeneration in this disease

In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls

Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. CONTROLS: One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed

In vivo sodium MR imaging of the abdomen at 3T

URPOSE: Transmembrane sodium ((23)Na) gradient is critical for cell survival and viability and a target for the development of anti-cancer drugs and treatment as it serves as a signal transducer. The ability to integrate abdominal (23)Na MRI in clinical settings would be useful to non-invasively detect and diagnose a number of diseases in various organ systems. Our goal in this work was to enhance the quality of (23)Na MRI of the abdomen using a 3-Tesla MR scanner and a novel 8-channel phased-array dual-tuned (23)Na and (1)H transmit (Tx)/receive (Rx) coil specially designed to image a large abdomen region with relatively high SNR. METHODS: A modified GRE imaging sequence was optimized for (23)Na MRI to obtain the best possible combination of SNR, spatial resolution, and scan time in phantoms as well as volunteers. Tissue sodium concentration (TSC) of the whole abdomen was calculated from the inhomogeneity-corrected (23)Na MRI for absolute quantification. In addition, in vivo reproducibility and reliability of TSC measurements from (23)Na MRI was evaluated in normal volunteers. RESULTS: (23)Na axial images of the entire abdomen with a high spatial resolution (0.3 cm) and SNR (~20) in 15 min using the novel 8-channel dual-tuned (23)Na and (1)H transmit/receive coil were obtained. Quantitative analysis of the sodium images estimated a mean TSC of the liver to be 20.13 mM in healthy volunteers. CONCLUSION: Our results have shown that it is feasible to obtain high-resolution (23)Na images using a multi-channel surface coil with good SNR in clinically acceptable scan times in clinical practice for various body applications

Reproducibility and effect of tissue composition on cerebellar GABA MRS in an elderly population.

Magnetic resonance spectroscopy (MRS) provides a valuable tool to non-invasively detect brain gamma-amino butyric acid (GABA) in vivo. GABAergic dysfunction has been observed in the aging cerebellum. Studying cerebellar GABA changes is of considerable interest in understanding certain age-related motor disorders. However, little is known about the reproducibility of GABA MRS in an aged population. Therefore, this study aimed to explore the feasibility and reproducibility of GABA MRS in the aged cerebellum at 3.0 Tesla and to examine the effect of differing tissue composition on GABA measurements. MRI and 1H MRS exams were performed on 10 healthy elderly volunteers (mean age 75.2 years ± 6.5 years) using a 3.0 Tesla Siemens Tim Trio scanner. Among them, 5 subjects were scanned twice to assess short-term reproducibility. The MEGA-PRESS J-editing sequence was used for GABA detection in two volumes of interest (VOIs) in left and right cerebellar dentate. MRS data processing and quantification were performed with LCModel 6.3-0L using two separate basis sets, generated from density matrix simulations using published values for chemical shifts an

Striatal GABA-MRS predicts response inhibition performance and its cortical electrophysiological correlates

Response inhibition processes are important for performance monitoring and are mediated via a network constituted by different cortical areas and basal ganglia nuclei. At the basal ganglia level, striatal GABAergic medium spiny neurons are known to be important for response selection, but the importance of the striatal GABAergic system for response inhibition processes remains elusive. Using a novel combination of behavior al, EEG and magnetic resonance spectroscopy (MRS) data, we examine the relevance of the striatal GABAergic system for response inhibition processes. The study shows that striatal GABA levels modulate the efficacy of response inhibition processes. Higher striatal GABA levels were related to better response inhibition performance. We show that striatal GABA modulate specific subprocesses of response inhibition related to pre-motor inhibitory processes through the modulation of neuronal synchronization processes. To our knowledge, this is the first study providing direct evidence for the relevance of the striatal GABAergic system for response inhibition functions and their cortical electrophysiological correlates in humans

Toenail Manganese: A Sensitive and Specific Biomarker of Exposure to Manganese in Career Welders

Manganese (Mn) is an essential trace metal. It is also a component of welding fume. Chronic inhalation of manganese from welding fume has been associated with decreased neurological function. Currently, there is not a universally recognized biomarker for Mn exposure; however, hair and toenails have shown promise. In a cohort of 45 male welders and 35 age-matched factory control subjects, we assessed the sensitivity and specificity of toenail Mn to distinguish occupationally exposed subjects from unexposed controls. Further we examined the exposure time window that best correlates with the proposed biomarker, and investigated if non-occupational exposure factors impacted toenail Mn concentrations. Toenail clippings were analyzed for Mn using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Exposure to respirable Mn-containing particles (<4 µm) was estimated using an exposure model that combines personal air monitoring, work history information, and dietary intake to estimate an individual's exposure to Mn from inhalation of welding fume. We assessed the group differences in toenail concentrations using a Student's t-test between welders and control subjects and performed a receiver operating characteristic (ROC) curve analysis to identify a threshold in toenail concentration that has the highest sensitivity and specificity in distinguishing welders from control subjects. Additionally, we performed mixed-model regressions to investigate the association between different exposure windows and toenail Mn concentrations. We observed that toenail Mn concentrations were significantly elevated among welders compared to control subjects (6.87 ± 2.56 versus 2.70 ± 1.70 µg g-1; P < 0.001). Our results show that using a toenail Mn concentration of 4.14 µg g-1 as cutoff allows for discriminating between controls and welders with 91% specificity and 94% sensitivity [area under curve (AUC) = 0.98]. Additionally, we found that a threshold of 4.66 µg g-1 toenail Mn concentration enables a 90% sensitive and 90% specific discrimination (AUC = 0.96) between subjects with average exposure above or below the American Conference of Governmental Industrial Hygienist (ACGIH) Threshold Limit Value (TLV) of 0.02 mg m-3 during the exposure window of 7-12 months prior to the nail being clipped. Investigating which exposure window was best reflected by toenail Mn reproduced the result from another study of toenail Mn being significantly (P < 0.001) associated with exposure 7-12 months prior to the nail being clipped. Lastly, we found that dietary intake, body mass index, age, smoking status, and ethnicity had no significant effect on toenail Mn concentrations. Our results suggest that toenail Mn is a sensitive, specific, and easy-to-acquire biomarker of Mn exposure, which is feasible to be used in an industrial welder population

COMPARISON OF BRAIN METABOLITE CHANGES IN MANGANESE-EXPOSED WELDERS AND SMELTERS

poster abstractExcessive manganese (Mn) exposure is known to cause cognitive, psychiatric and motor deficits. Mn overexposure occurs in different occupational settings, where the type and level of exposure may vary. Magnetic resonance imaging (MRI) and spectroscopy (MRS) can be used to evaluate brain Mn accumulation and to measure Mn-induced metabolite changes non-invasively. The aim of this study was to compare metabolite changes among different brain regions of welders and smelters following occupational Mn exposure. Nine Mn-exposed smelters, 14 Mn-exposed welders and 23 male matched controls were recruited from a cohort of workers from two factories in China (mean airborne Mn level: 0.227 and 0.025 mg/m3 for smelters and welders, respectively). Short-echo-time 1H MRS spectra were acquired in each subject from four volumes of interest: the frontal cortex, posterior cingulate cortex, hippocampus, and thalamus. We found that 1) in the frontal cortex, significantly decreased creatine (Cr), glutamate (Glu) and glutathione (GSH) were found in welders, whereas decreased Glu was found in smelters as compared to controls. 2) In the thalamus, reduced myo-inositol was found in both smelters and welders, while Glu and GSH were decreased in welders. These results suggest that Mn-induced brain metabolite changes may be regional in nature and more extensive in welders than in smelters. The frontal cortex seems to show a more profound change than the other brain areas tested among Mn exposed subjects. Further studies are needed to investigate the effects of exposure type and length on the mechanism of Mn neurotoxicity. (Supported by NIH/NIEHS R21 ES-017498, National Science Foundation of China Grant #81072320 and 30760210)