Pathology Of Essential Tremor Research Articles

Neuropathological findings in essential tremor.

Essential tremor (ET) is one of the most common neurological conditions and the most common movement disorder. The pathophysiological mechanisms that underlie this entity have not yet been described. However, recent post-mortem brain studies have provided useful insight into the underlying pathology of ET. Two brain areas have been consistently found to present neuropathological alterations in patients with ET: the brainstem, for presence of Lewy bodies or neuronal depletion, and the cerebellum, regarding Purkinje cells' morphology and density. In the present study we aim to review the literature on the main neuropathological findings in ET brains.

Is the inferior olive central to essential tremor? Yes.

We consider the question whether the inferior olive (IO) is required for essential tremor (ET). Much evidence shows that the olivocerebellar system is the main system capable of generating the widespread synchronous oscillatory Purkinje cell (PC) complex spike (CS) activity across the cerebellar cortex that would be capable of generating the type of bursting cerebellar output from the deep cerebellar nuclei (DCN) that could underlie tremor. Normally, synchronous CS activity primarily reflects the effective electrical coupling of IO neurons by gap junctions, and traditionally, ET research has focused on the hypothesis of increased coupling of IO neurons as the cause of hypersynchronous CS activity underlying tremor. However, recent pathology studies of brains from humans with ET and evidence from mutant mice, particularly the hotfoot17 mouse, that largely replicate the pathology of ET, suggest that the abnormal innervation of multiple Purkinje cells (PCs) by climbing fibers (Cfs) is related to tremor. In addition, ET brains show partial PC loss and axon terminal sprouting by surviving PCs. This may provide another mechanism for tremor. It is proposed that in ET, these three mechanisms may promote tremor. They all involve hypersynchronous DCN activity and an intact IO, but the level at which excessive synchronization occurs may be at the IO level (from abnormal afferent activity to this nucleus), the PC level (via aberrant Cfs), or the DCN level (via terminal PC collateral innervation).

Eye movement abnormalities in essential tremor versus tremor dominant Parkinson’s disease

ObjectiveTo show that eye movement abnormalities differ between essential tremor (ET) and tremor dominant Parkinson’s disease (PD-T), and that these abnormalities reflect cerebellar dysfunction in ET and basal ganglia pathology in PD-T. MethodsIn this exploratory study, in 23 patients with ET, 21 age-matched patients with PD-T, and 19 age-matched healthy controls (HCs), we investigated visually guided saccades, antisaccades, and smooth pursuit eye movements (SPEM). ResultsWhile the ET group had a normal gain (saccade amplitude/target amplitude) and latency of saccades, the PD-T group had hypometric visually guided saccades, and a prolonged latency of visually guided saccades and antisaccades. The SPEM gain was similarly low in both ET and PD-T and was significantly lower in both patient groups than in the HC group. ConclusionsIn ET, SPEM gain was reduced in the presence of normal saccades, whereas in PD-T, the reduced SPEM gain was accompanied by delayed saccade initiation and hypometric saccades, in line with cerebellar dysfunction in ET and basal ganglia dysfunction in PD-T. SignificanceThese findings support the presumed cerebellar pathology in ET. In addition, the difference in saccade features may contribute to the groundwork for a quantitative diagnostic test to differentiate between these disorders.

Climbing fiber synaptic pathology in essential tremor: parallel evidence from both human and mouse models (P6.034)

Climbing fiber synaptic pathology in essential tremor: parallel evidence from both human and mouse models (P6.034)

Evaluation of thickness of retinal nerve fiber layer, ganglion cell layer, and choroidal thickness in essential tremor: can eyes be a clue for neurodegeneration?

The pathology of essential tremor (ET) and underlying mechanisms of the disease are still unclear, but an increasing amount of research has been conducted on the subject. Discussions are ongoing about ET's definition as a neurodegenerative disease. Optic coherence tomography (OCT) provides a window to the brain where direct visualization of central nervous system (CNS) changes may be possible, and it can help us to develop a new point of view on ET. The goal of this study was to examine OCT parameters in ET. 40 ET patients and 40 healthy controls, i.e., a total of 160 eyes were evaluated. Retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and choroid thinning were analyzed using spectral domain OCT. The mean age was 25.77±8.98 in the ET group and 27.25±8.22 in the control group. We found a decreased global RNFL thickness for both eyes in ET patients. All GCL and IPL thickness parameters were lower in the patients with ET (P<0.001, P 0.03). Choroid was significantly thicker in ET patients than the controls (P<0.001). Our study's results suggest that the usefulness of OCT in detecting neurodegeneration in ET. RNFL, GCL, IPL measurements are highly reproduced findings of neurodegeneration. Increased choroid volume may indicate neuroinflammation. Eyes in ET may shed light on nature of the disease, and may be used as a diagnostic tool.

Role of altered cerebello-thalamo-cortical network in the neurobiology of essential tremor

Essential tremor (ET) is the most common movement disorder among adults. Although ET has been recognized as a mono-symptomatic benign illness, reports of non-motor symptoms and non-tremor motor symptoms have increased its clinical heterogeneity. The neural correlates of ET are not clearly understood. The aim of this study was to understand the neurobiology of ET using resting state fMRI. Resting state functional MR images of 30 patients with ET and 30 age- and gender-matched healthy controls were obtained. The functional connectivity of the two groups was compared using whole-brain seed-to-voxel-based analysis. The ET group had decreased connectivity of several cortical regions especially of the primary motor cortex and the primary somatosensory cortex with several right cerebellar lobules compared to the controls. The thalamus on both hemispheres had increased connectivity with multiple posterior cerebellar lobules and vermis. Connectivity of several right cerebellar seeds with the cortical and thalamic seeds had significant correlation with an overall score of Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) as well as the subscores for head tremor and limb tremor. Seed-to-voxel resting state connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical network in patients with ET. These alterations correlated with the overall FTM scores as well as the subscores for limb tremor and head tremor in patients with ET. These results further support the previous evidence of cerebellar pathology in ET.

Deep brain stimulation and climbing fiber synaptic pathology in essential tremor.

Essential tremor (ET) patients have abnormal climbing fiber (CF) synapses in the parallel fiber territory in the cerebellum, and these abnormal CF synapses are inversely correlated with tremor severity. We therefore examined CF synaptic pathology in ET cases with and without thalamic deep brain stimulation (DBS) and assessed the association with tremor severity. We found that CF synaptic pathology was inversely correlated with tremor severity in ET cases without DBS, and this correlation disappeared in ET cases with DBS. Our data suggest that DBS might have effects in modulating excitatory synapses in ET cerebellum, in addition to its symptomatic effects on tremor. Ann Neurol 2016;80:461-465.

Deep Brain Stimulation and Climbing Fiber Synaptic Pathology in Essential Tremor (P4.294)

Deep Brain Stimulation and Climbing Fiber Synaptic Pathology in Essential Tremor (P4.294)

Linking Essential Tremor to the Cerebellum-Neuroimaging Evidence.

Essential tremor (ET) is the most common pathological tremor disorder in the world, and post-mortem evidence has shown that the cerebellum is the most consistent area of pathology in ET. In the last few years, advanced neuroimaging has tried to confirm this evidence. The aim of the present review is to discuss to what extent the evidence provided by this field of study may be generalised. We performed a systematic literature search combining the terms ET with the following keywords: MRI, VBM, MRS, DTI, fMRI, PET and SPECT. We summarised and discussed each study and placed the results in the context of existing knowledge regarding the cerebellar involvement in ET. A total of 51 neuroimaging studies met our search criteria, roughly divided into 19 structural and 32 functional studies. Despite clinical and methodological differences, both functional and structural imaging studies showed similar findings but without defining a clear topography of neurodegeneration. Indeed, the vast majority of studies found functional and structural abnormalities in several parts of the anterior and posterior cerebellar lobules, but it remains to be established to what degree these neural changes contribute to clinical symptoms of ET. Currently, advanced neuroimaging has confirmed the involvement of the cerebellum in pathophysiological processes of ET, although a high variability in results persists. For this reason, the translation of this knowledge into daily clinical practice is again partially limited, although new advanced multivariate neuroimaging approaches (machine-learning) are proving interesting changes of perspective.

Sensorineural Hearing Loss in Non-depressed Essential Tremor Cases and Controls: A Clinical and Audiometric Study.

BackgroundPatients with essential tremor (ET) have an increased prevalence of hearing loss, and depression is a confounding issue for both conditions. We assessed hearing loss in non-depressed ET patients and controls using a questionnaire and audiometric tests.MethodsThe study included 34 patients with ET and 45 volunteers were included. Both groups were asked if they had hearing loss, and pure tone audiometry, speech recognition threshold, tympanogram, short increment sensitivity index (SISI), tone decay, and otoacoustic emission audiological tests were conducted.ResultsSeventeen subjects (50.0%) in the patient group answered “yes” to the question “Do you have hearing loss?” compared to one (2.2%) subject in the control group (p<0.001). The tone decay values of the right ear at 4,000 Hz were higher in the patient group. The number of subjects in which the otoacoustic emissions could not be obtained in the right ear was higher in the ET patients (p = 0.005).DiscussionThe results support the presence of a cochlear pathology in ET and may indicate that ET and sensorineural hearing loss may be components of a common disease process.

Sensorineural Hearing Loss in Non-depressed Essential Tremor Cases and Controls: A Clinical and Audiometric Study

<strong>Background:</strong> Patients with essential tremor (ET) have an increased prevalence of hearing loss, and depression is a confounding issue for both conditions. We assessed hearing loss in non-depressed ET patients and controls using a questionnaire and audiometric tests. <strong>Methods:</strong> The study included 34 patients with ET and 45 volunteers were included. Both groups were asked if they had hearing loss, and pure tone audiometry, speech recognition threshold, tympanogram, short increment sensitivity index (SISI), tone decay, and otoacoustic emission audiological tests were conducted. <strong>Results:</strong> Seventeen subjects (50.0%) in the patient group answered ‘‘yes’’ to the question ‘‘Do you have hearing loss?’’ compared to one (2.2%) subject in the control group (<strong>p&lt;0.001</strong>). The tone decay values of the right ear at 4,000 Hz were higher in the patient group. The number of subjects in which the otoacoustic emissions could not be obtained in the right ear was higher in the ET patients (<strong>p=0.005</strong>). <strong>Discussion:</strong> The results support the presence of a cochlear pathology in ET and may indicate that ET and sensorineural hearing loss may be components of a common disease process.

Neuropathology of Essential Tremor

Whereas the underlying pathology of essential tremor (ET) has been elusive until recently, controlled postmortem studies demonstrated various structural changes in the ET cerebellum, including loss of axonal swellings (“torpedoes”), and abnormal synaptic connections. Athough these changes were not seen in all studies, these and modern neurophysiological studies indicated the involvement of the cerebellum in this neurodegenerative disease.

Is there cerebellar pathology in essential tremor?

Movement DisordersVolume 29, Issue 4 p. 435-436 Editorial Is there cerebellar pathology in essential tremor? Kurt A. Jellinger MD, Corresponding Author Kurt A. Jellinger MD Institute of Clinical Neurobiology, Vienna, AustriaCorrespondence to: Kurt A. Jellinger, Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria; kurt.jellinger@univie.ac.atSearch for more papers by this author Kurt A. Jellinger MD, Corresponding Author Kurt A. Jellinger MD Institute of Clinical Neurobiology, Vienna, AustriaCorrespondence to: Kurt A. Jellinger, Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria; kurt.jellinger@univie.ac.atSearch for more papers by this author First published: 01 March 2014 https://doi.org/10.1002/mds.25852Citations: 11 Funding agencies: The study was partly supported by the Society for the Support of Research in Experimental Neurology (Vienna, Austria). Relevant conflicts of interest/financial disclosures: Nothing to report. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume29, Issue4April 2014Pages 435-436 RelatedInformation

Abnormal Regional Homogeneity in Patients with Essential Tremor Revealed by Resting-State Functional MRI

Essential tremor (ET) is one of the most common movement disorders in human adults. It can be characterized as a progressive neurological disorder of which the most recognizable feature is a tremor of the arms or hands that is apparent during voluntary movements such as eating and writing. The pathology of ET remains unclear. Resting-state fMRI (RS-fMRI), as a non-invasive imaging technique, was employed to investigate abnormalities of functional connectivity in ET in the brain. Regional homogeneity (ReHo) was used as a metric of RS-fMRI to assess the local functional connectivity abnormality in ET with 20 ET patients and 20 age- and gender-matched healthy controls (HC). The ET group showed decreased ReHo in the anterior and posterior bilateral cerebellar lobes, the bilateral thalamus and the insular lobe, and increased ReHo in the bilateral prefrontal and parietal cortices, the left primary motor cortex and left supplementary motor area. The abnormal ReHo value of ET patients in the bilateral anterior cerebellar lobes and the right posterior cerebellar lobe were negatively correlated with the tremor severity score, while positively correlated with that in the left primary motor cortex. These findings suggest that the abnormality in cerebello-thalamo-cortical motor pathway is involved in tremor generation and propagation, which may be related to motor-related symptoms in ET patients. Meanwhile, the abnormality in the prefrontal and parietal regions may be associated with non-motor symptoms in ET. These findings suggest that the ReHo could be utilized for investigations of functional-pathological mechanism of ET.

Macroautophagy Abnormality in Essential Tremor

Macroautophagy is a cellular mechanism for the clearance of protein aggregates and damaged organelles. Impaired macroautophagy has been observed in neurodegenerative disorders. We investigated the macroautophagy pathway in essential tremor (ET) cases compared to age-matched controls. We analyzed microtubule-associated protein light chain 3-II (LC3-II), S6K, phosphorylated S6K, beclin-1, and mitochondrial membrane proteins levels by Western blot in the post-mortem cerebellum of 10 ET cases and 11 controls. We also performed immunohistochemistry in 12 ET cases and 13 controls to quantify LC3 clustering in Purkinje cells (PCs). LC3-II protein levels were significantly lower in ET cases vs. controls on Western blot (0.84±0.14 vs. 1.00±0.14, p = 0.02), and LC3-II clustering in PCs by immunohistochemistry was significantly lower in ET cases vs. controls (2.03±3.45 vs. 8.80±9.81, p = 0.03). In ET cases, disease duration was inversely correlated with LC3-II protein level (r = −0.64, p = 0.046). We found that mitochondrial membrane proteins were accumulated in ET (TIM23: 1.36±0.11 in ET cases vs. 1.00±0.08 in controls, p = 0.02; TOMM20: 1.63±0.87 in ET cases vs. 1.00±0.14 in controls, p = 0.03). Beclin-1, which is involved in macroautophagy, was strikingly deficient in ET (0.42±0.13 vs. 1.00±0.35, p<0.001). Decreased macroautophagy was observed in the ET cerebellum, and this could be due to a decrease in beclin-1 levels, which subsequently lead to mitochondrial accumulation as a result of autophagic failure. This provides a possible means by which perturbed macroautophagy could contribute to PC pathology in ET.

Pathology in essential tremor

The pathology of essential tremor (ET) is increasingly being studied. The main findings include a reduction in cerebellar Purkinje cells, other pathological changes of cerebellar degeneration and restricted Lewy bodies in the locus ceruleus. This paper will review those findings and put them into context with clinical studies in ET and findings in neurodegenerative disorders such as Parkinson's disease.

Brain biochemistry in autopsied patients with essential tremor

The pathology of essential tremor is increasingly being studied; however, there are limited studies of biochemical changes in this condition. We studied several candidate biochemical/anatomical systems in the brain stem, striatum, and cerebellum of 23 essential tremor subjects who came to autopsy, comparing them with a control population. Striatal tyrosine hydroxylase, a marker of dopaminergic neurons, was 91.7 ± 113.2 versus 96.4 ± 102.7 ng/mg (not significant) in cases and controls, respectively. Locus coeruleus dopamine beta-hydroxylase, a marker of noradrenergic neurons, was not significantly different between the essential tremor and control groups. Parvalbumin, a marker of GABAergic neurons, was 199.3 ± 42.0 versus 251.4 ± 74.8 ng/mg (P = .025) in the pons in the region of the locus coeruleus of essential tremor subjects versus controls, whereas there was no difference in cerebellar parvalbumin. These results are supportive of a possible role for reduced GABAergic function in the locus coeruleus in essential tremor. The hypothesis that essential tremor represents early Parkinson's disease was not supported, as striatal dopaminergic markers were not reduced compared with control subjects.

Scaling analysis of the effects of load on hand tremor movements in essential tremor

In this paper we have used the Wavelet Transform (WT) and the Detrended Fluctuation Analysis (DFA) methods to analyze hand tremor movements in essential tremor (ET), in two different recording conditions (before and after the addition of wrist-cuff load). We have analyzed the time series comprised of peak-to-peak (PtP) intervals, extracted from regions around the first three main frequency components of the power spectra (PwS) of the recorded tremors, in order to substantiate results related to the effects of load on ET, to distinguish between multiple sources of ET, and to separate the influence of peripheral factors on ET.Our results show that, in ET, the dynamical characteristics, that is, values of respective scaling exponents, of the main frequency component of recorded tremors change after the addition of load. Our results also show that in all the observed cases the scaling behavior of the calculated functions changes as well—the calculated WT scalegrams and DFA functions display a shift in the position of the crossover when the load is added. We conclude that the difference in behavior of the WT and DFA functions between different conditions in ET could be associated with the expected pathology in ET, or with some additional mechanism that controls movements in ET patients, and causes the observed changes in scaling behavior.

S20-3 Pathology of essential tremor

S20-3 Pathology of essential tremor

Cerebellar Purkinje cell loss is not pathognomonic of essential tremor

BackgroundMost of the literature on pathology of essential tremor (ET) has reported no consistent abnormalities. Some recent studies however indicate that cerebellar Purkinje cell (PC) loss is the pathological basis of ET in most patients. ObjectiveTo compare cerebellar PC loss in ET, with normal and tremor dominant Parkinson’s disease [PD] control brains. MethodsCerebellar PC counts were performed in seven ET, six PD and two normal control brains. Three different counting methods – sectioned through nucleolus, through nucleus and through any part of PC body, were used to count the PC. ResultsThere were individual differences in the PC counts both in the ET and the PD cases. In all three subgroups, there was a reduction in the number of PC with advancing age. When the individuals of comparable age in the three subgroups were considered, there was no clear distinction between ET, PD and normal control subjects. There was no association between the degree of PC loss and the severity or the duration of ET. ConclusionOur study militates against the hypothesis that PC loss is pathognomonic of ET.