Elevated serum neurofilament light chain protein in patients with essential tremor.

BACKGROUND AND PURPOSE: Quantification of neurofilament light chain protein in serum (sNfL) enables the neuro-axonal damage in peripheral blood to be reliably assessed and monitored. There is a long-standing debate whether essential tremor represents a 'benign' tremor syndrome or whether it is linked to neurodegeneration. This study aims to investigate sNfL concentrations in essential tremor compared to healthy controls (cross-sectionally and longitudinally) and to assess whether sNfL is associated with motor and nonmotor markers of disease progression. METHODS: Data of patients with essential tremor from our prospective registry on movement disorders (PROMOVE) were retrospectively analysed. Age-, sex- and body-mass-index-matched healthy controls were recruited from an ongoing community-dwelling aging cohort. sNfL was quantified by an ultra-sensitive single molecule array (Simoa). All participants underwent detailed clinical examination at baseline and after approximately 5 years of follow-up. RESULTS: Thirty-seven patients with clinically diagnosed essential tremor were included and 37 controls. The essential tremor group showed significantly higher sNfL levels compared to healthy controls at baseline and follow-up. sNfL levels increased over time in both groups, and the slope of sNfL increase was similar in the essential tremor and healthy control groups. Comparing patients with a disease duration under 5 years to those with a longer disease duration, the former group had a significantly greater increase of sNfL over time, which strongly correlated to worsening of tremor and cognition. CONCLUSION: Our findings indicate that neurodegeneration, possibly happening at an early disease stage, might play a role in the pathophysiology of essential tremor.

Quantification of tremor severity with a mobile tremor pen.

BACKGROUND: An objective evaluation of tremor severity is necessary to document the course of disease, the efficacy of treatment, or interventions in clinical trials. Most available objective quantification devices are complex, immobile, or not validated. NEW METHOD: We used the TREMITAS-System that comprises a pen-shaped sensor for tremor quantification. The Power of Main Peak and the Total Power were used as surrogate markers for tremor amplitude. Tremor severity was assessed by the TREMITAS-System and relevant subscores of the MDS-UPDRS and TETRAS rating scales in 14 patients with Parkinson's disease (PD) and 16 patients with Essential tremor (ET) off and on therapy. We compared tremor amplitudes assessed during wearable and hand-held constellations. RESULTS: We found significant correlations between tremor amplitudes captured by TREM and tremor severity assessed by the MDS-UPDRS in PD (r = 0.638-0.779) and the TETRAS in ET (r = 0.597-0. 704) off and on therapy. The TREMITAS-System captured the L-Dopa-induced improvement of tremor in PD patients (p = 0.027). Tremor amplitudes did not differ between the handheld and wearable constellation (p > 0.05). COMPARISON WITH EXISTING METHODS: We confirm the results of previous studies using inertial based sensors that tremor severity and drug-induced changes of tremor severity can be quantified using inertial based sensors. The assessment of tremor amplitudes was not influenced by using a handheld or wearable constellation. CONCLUSIONS: The TREMITAS-System can be used to quantify rest tremor in PD and postural tremor in ET and is capable of detecting clinically relevant changes in tremor in clinical and research settings.

Minor Structural Differences in the Cervical Spine Between Patients With Cervical Dystonia and Age-Matched Healthy Controls.

Background: Cervical dystonia is the most common form of focal dystonia. The frequency and pattern of degenerative changes of the cervical spine in patients with cervical dystonia and their relation to clinical symptoms remain unclear as no direct comparison to healthy controls has been performed yet. Here, we used magnetic resonance imaging (MRI) to investigate (1) whether structural abnormalities of the cervical spine are more common in patients with cervical dystonia compared to age-matched healthy controls, (2) if there are clinical predictors for abnormalities on MRI, and (3) to calculate the inter-rater reliability of the respective radiological scales. Methods: Twenty-five consecutive patients with cervical dystonia and 20 age-matched healthy controls were included in the study. MRI scans of the cervical spine were analyzed separately by three experienced raters blinded to clinical information, applying different MRI rating scales. Structural abnormalities were compared between groups for upper, middle, and lower cervical spine segments. The associations between scores differentiating both groups and clinical parameters were assessed in dystonia patients. Additionally, inter-rater reliability of the MRI scales was calculated. Results: Comparing structural abnormalities, we found minor differences in the middle cervical spine, indicated by a higher MRI total score in patients but no significant correlation between clinical parameters and MRI changes. Inter-rater reliability was satisfying for most of the MRI rating scales. Conclusion: Our results do not provide evidence for a role of MRI of the cervical spine in the routine work-up of patients with cervical dystonia in the absence of specific clinical signs or symptoms.

Nigral iron deposition in common tremor disorders.

OBJECTIVE: We investigated R2* relaxation rates as a marker of iron content in the substantia nigra in patients with common tremor disorders and explored their diagnostic properties. METHODS: Mean nigral R2* rates were measured in 40 patients with tremor-dominant Parkinson's disease (PD), 15 with tremor in dystonia, 25 with essential tremor, and 25 healthy controls. RESULTS: Tremor-dominant PD patients had significantly higher nigral R2* values (34.1 ± 5.7) than those with tremor in dystonia (30.0 ± 3.9), essential tremor (30.6 ± 4.8), and controls (30.0 ± 2.8). An R2* threshold of 31.15 separated tremor-dominant PD from controls with a sensitivity and specificity of 67.5% and 72%. The sensitivity and specificity for discrimination between PD and non-PD tremor patients was 67.5% and 60%. CONCLUSION: Iron content in the substantia nigra is significantly higher in tremor-dominant PD than in tremor in dystonia, essential tremor, and controls. Because of the considerable overlap, nigral R2* cannot be suggested as a useful diagnostic tool. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Quantitative Susceptibility Mapping in Parkinson's Disease.

BACKGROUND: Quantitative susceptibility mapping (QSM) and R2* relaxation rate mapping have demonstrated increased iron deposition in the substantia nigra of patients with idiopathic Parkinson's disease (PD). However, the findings in other subcortical deep gray matter nuclei are converse and the sensitivity of QSM and R2* for morphological changes and their relation to clinical measures of disease severity has so far been investigated only sparsely. METHODS: The local ethics committee approved this study and all subjects gave written informed consent. 66 patients with idiopathic Parkinson's disease and 58 control subjects underwent quantitative MRI at 3T. Susceptibility and R2* maps were reconstructed from a spoiled multi-echo 3D gradient echo sequence. Mean susceptibilities and R2* rates were measured in subcortical deep gray matter nuclei and compared between patients with PD and controls as well as related to clinical variables. RESULTS: Compared to control subjects, patients with PD had increased R2* values in the substantia nigra. QSM also showed higher susceptibilities in patients with PD in substantia nigra, in the nucleus ruber, thalamus, and globus pallidus. Magnetic susceptibility of several of these structures was correlated with the levodopa-equivalent daily dose (LEDD) and clinical markers of motor and non-motor disease severity (total MDS-UPDRS, MDS-UPDRS-I and II). Disease severity as assessed by the Hoehn & Yahr scale was correlated with magnetic susceptibility in the substantia nigra. CONCLUSION: The established finding of higher R2* rates in the substantia nigra was extended by QSM showing superior sensitivity for PD-related tissue changes in nigrostriatal dopaminergic pathways. QSM additionally reflected the levodopa-dosage and disease severity. These results suggest a more widespread pathologic involvement and QSM as a novel means for its investigation, more sensitive than current MRI techniques.

Validation of "laboratory-supported" criteria for functional (psychogenic) tremor.

BACKGROUND: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity. OBJECTIVES: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty. METHODS: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor. RESULTS: We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P < .001), and the predefined cut-off score for laboratory-supported functional tremor yielded a test sensitivity of 89.5% and a specificity of 95.9%. CONCLUSION: We now propose this test battery as the basis of laboratory-supported criteria for the diagnosis of functional tremor, and we encourage its use in clinical and research practice.

Intact emotion recognition and experience but dysfunctional emotion regulation in idiopathic Parkinson's disease.

BACKGROUND: A specific non-motor impairment in Parkinson's disease (PD) concerns difficulties to accurately identify facial emotions. Findings are numerous but very inconsistent, ranging from general discrimination deficits to problems for specific emotions up to no impairment at all. By contrast, only a few studies exist about emotion experience, altered affective traits and states in PD. OBJECTIVE: To investigate the decoding capacity for affective facial expressions, affective experience of emotion-eliciting images and affective personality traits in PD. METHODS: The study sample included 25 patients with mild to moderate symptom intensity and 25 healthy controls (HC) of both sexes. The participants were shown pictures of facial expressions depicting disgust, fear, and anger as well as disgusting and fear-relevant scenes. Additionally, they answered self-report scales for the assessment of affective traits. RESULTS: PD patients had more problems in controlling anger and disgust feelings than HC. Higher disgust sensitivity in PD was associated with lower functioning in everyday life and lower capacity to recognize angry faces. Furthermore, patients reported less disgust towards poor hygiene and spoiled food and they stated elevated anxiety. However, the clinical group displayed intact facial emotion decoding and emotion experience. Everyday life functionality was lowered in PD and decreased with stronger motor impairment. Furthermore, disease duration was negatively associated to correct classification of angry faces. CONCLUSIONS: Our data indicate that problems with emotion regulation may appear already in earlier disease stages of PD. By contrast, PD patients showed appropriate emotion recognition and experience. However, data also point to a deterioration of emotion recognition capacity with the course of the disease. Compensatory mechanisms in PD patients with less advanced disease are discussed.

Levodopa-responsive Holmes' Tremor Caused by a Single Inflammatory Demyelinating Lesion.

BACKGROUND: Holmes' tremor is characterized by a combination of rest, postural, and kinetic tremor that is presumably caused by interruption of cerebello-thalamo-cortical and nigrostriatal pathways. Medical treatment remains unsatisfactory. CASE REPORT: A 16-year-old girl presented with Holmes' tremor caused by a transient midbrain abnormality on magnetic resonance imaging (MRI). To explore the discrepancy between persistent tremor and resolved MRI changes, we performed dopamine transporter single-photon emission computed tomography (DaT-SPECT) with a 123I-ioflupane that revealed nearly absent DaT binding in the right striatum. Levodopa dramatically improved the tremor. DISCUSSION: This is only the second report of a transient midbrain MRI abnormality disrupting nigrostriatal pathways. The case highlights the sometimes limited sensitivity of morphologic imaging for identifying the functional consequences of tissue damage and confirms that DaT imaging may serve as a predictor for levodopa responsiveness in Holmes' tremor.

Facial Emotion Recognition in Parkinson's Disease: An fMRI Investigation.

BACKGROUND: Findings of behavioral studies on facial emotion recognition in Parkinson's disease (PD) are very heterogeneous. Therefore, the present investigation additionally used functional magnetic resonance imaging (fMRI) in order to compare brain activation during emotion perception between PD patients and healthy controls. METHODS AND FINDINGS: We included 17 nonmedicated, nondemented PD patients suffering from mild to moderate symptoms and 22 healthy controls. The participants were shown pictures of facial expressions depicting disgust, fear, sadness, and anger and they answered scales for the assessment of affective traits. The patients did not report lowered intensities for the displayed target emotions, and showed a comparable rating accuracy as the control participants. The questionnaire scores did not differ between patients and controls. The fMRI data showed similar activation in both groups except for a generally stronger recruitment of somatosensory regions in the patients. CONCLUSIONS: Since somatosensory cortices are involved in the simulation of an observed emotion, which constitutes an important mechanism for emotion recognition, future studies should focus on activation changes within this region during the course of disease.

Role of disgust proneness in Parkinson's disease: a voxel-based morphometry study.

The knowledge about personality traits in Parkinson's disease (PD) is still limited. In particular, disgust proneness has not been investigated as well as its neuronal correlates. Although several morphometric studies demonstrated that PD is associated with gray matter volume (GMV) reduction in olfactory and gustatory regions involved in disgust processing, a possible correlation with disgust proneness has not been investigated. We conducted a voxel-based morphometry analysis to compare GMV between 16 cognitively normal male PD patients with mild to moderate symptoms and 24 matched control subjects. All participants had answered questionnaires for the assessment of disgust proneness, trait anger and trait anxiety. We correlated questionnaire scores with GMV in both groups. The clinical group reported selectively reduced disgust proneness toward olfactory stimuli associated with spoilage. Moreover, they showed GMV reduction in the central olfactory system [orbitofrontal cortex (OFC) and piriform cortex]. Disgust items referring to olfactory processing were positively correlated with OFC volume in PD patients. Our data suggest an association between PD-associated neurodegeneration and olfactory related facets of the personality trait disgust proneness.

A priori collaboration in population imaging: The Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement consortium.

INTRODUCTION: Virchow-Robin spaces (VRS), or perivascular spaces, are compartments of interstitial fluid enclosing cerebral blood vessels and are potential imaging markers of various underlying brain pathologies. Despite a growing interest in the study of enlarged VRS, the heterogeneity in rating and quantification methods combined with small sample sizes have so far hampered advancement in the field. METHODS: The Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement (UNIVRSE) consortium was established with primary aims to harmonize rating and analysis (www.uconsortium.org). The UNIVRSE consortium brings together 13 (sub)cohorts from five countries, totaling 16,000 subjects and over 25,000 scans. Eight different magnetic resonance imaging protocols were used in the consortium. RESULTS: VRS rating was harmonized using a validated protocol that was developed by the two founding members, with high reliability independent of scanner type, rater experience, or concomitant brain pathology. Initial analyses revealed risk factors for enlarged VRS including increased age, sex, high blood pressure, brain infarcts, and white matter lesions, but this varied by brain region. DISCUSSION: Early collaborative efforts between cohort studies with respect to data harmonization and joint analyses can advance the field of population (neuro)imaging. The UNIVRSE consortium will focus efforts on other potential correlates of enlarged VRS, including genetics, cognition, stroke, and dementia.

Motor sequence learning and motor adaptation in primary cervical dystonia.

Motor sequence learning and motor adaptation rely on overlapping circuits predominantly involving the basal ganglia and cerebellum. Given the importance of these brain regions to the pathophysiology of primary dystonia, and the previous finding of abnormal motor sequence learning in DYT1 gene carriers, we explored motor sequence learning and motor adaptation in patients with primary cervical dystonia. We recruited 12 patients with cervical dystonia and 11 healthy controls matched for age. Subjects used a joystick to move a cursor from a central starting point to radial targets as fast and accurately as possible. Using this device, we recorded baseline motor performance, motor sequence learning and a visuomotor adaptation task. Patients with cervical dystonia had a significantly higher peak velocity than controls. Baseline performance with random target presentation was otherwise normal. Patients and controls had similar levels of motor sequence learning and motor adaptation. Our patients had significantly higher peak velocity compared to controls, with similar movement times, implying a different performance strategy. The preservation of motor sequence learning in cervical dystonia patients contrasts with the previously observed deficit seen in patients with DYT1 gene mutations, supporting the hypothesis of differing pathophysiology in different forms of primary dystonia. Normal motor adaptation is an interesting finding. With our paradigm we did not find evidence that the previously documented cerebellar abnormalities in cervical dystonia have a behavioral correlate, and thus could be compensatory or reflect "contamination" rather than being directly pathological.

Tremor associated with Klinefelter syndrome--a case series and review of the literature.

BACKGROUND: Previous case series suggested a link between Klinefelter syndrome (KS) and essential tremor (ET) or an ET-like syndrome. METHODS: We investigated three KS-patients with tremor including tremor-analyzes and discuss our data in context to findings from a literature review. The clinical outcome after deep brain stimulation (DBS) is also reviewed. RESULTS: Tremor in KS is predominantly a postural and kinetic tremor that resembles ET. Our patients were further characterized by absent family history for tremor in first degree relatives, lack of subjective alcohol responsiveness inquired by history, and tremor onset in childhood. One of our patients and two cases from literature improved after DBS of the ventral intermediate nucleus (VIM) of the thalamus. CONCLUSIONS: Tremor in KS shares several features with ET. If other characteristics such as family history, alcohol responsiveness, and age at tremor onset may serve as discriminating factors from ET, needs to be further investigated. First observations suggest that VIM-DBS may be efficacious.

Cerebellar learning distinguishes inflammatory neuropathy with and without tremor.

OBJECTIVES: This study aims to investigate if patients with inflammatory neuropathies and tremor have evidence of dysfunction in the cerebellum and interactions in sensorimotor cortex compared to nontremulous patients and healthy controls. METHODS: A prospective data collection study investigating patients with inflammatory neuropathy and tremor, patients with inflammatory neuropathy without tremor, and healthy controls on a test of cerebellar associative learning (eyeblink classical conditioning), a test of sensorimotor integration (short afferent inhibition), and a test of associative plasticity (paired associative stimulation). We also recorded tremor in the arms using accelerometry and surface EMG. RESULTS: We found impaired responses to eyeblink classical conditioning and paired associative stimulation in patients with neuropathy and tremor compared with neuropathy patients without tremor and healthy controls. Short afferent inhibition was normal in all groups. CONCLUSIONS: Our data strongly suggest impairment of cerebellar function is linked to the production of tremor in patients with inflammatory neuropathy.