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Background: Tremor is commonly found among healthy humans or prevalently a symptom of neurological dysfunctions. However, the distinction between physiological and pathological tremor is dependent on the examiner's competence. Archimedes Spiral Rating (ASR) is a valid and reproducible semi-quantitative method to assess the severity of action tremor., Objectives: (1) To assess the range and percentiles of ASR in a large sample seemingly free of tremor-related conditions or symptoms from the population-based CHRIS-study. (2) To analyze the influence of sex, age, and the drawing hand on ASR. (3) To define ASR limits of normal. (4) To supply exemplary Archimedes spiral drawings by each rating to favor consistent and proficient clinical evaluation., Methods: Accurately investigated participants were randomly sampled over 14 sex-age strata. 2686 paired spirals drawn with both hands by 1343 participants were expertly assessed on a tremor rating scale from 0 to 9., Results: ASR had a quadratic increase with age in both sexes, while it was relatively lower in the dominant compared to the non-dominant hand and in women compared to men. ASRs above sex-age specific 97.5th percentiles of 4 and 5, below and above 60 years of age, respectively, were conceivably of non-physiological nature., Conclusions: In a large population-based sample we show a steeper increase of action tremor by age as age progresses. Relatively higher ratings among the elderly, males and the non-dominant hands, appear compatible with ASR limits of "normal" across sex-age groups. The current operational evidence may support practitioners differentiating physiological and pathological hand tremor., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Head tremor is common in dystonia syndromes and difficult to treat. Deep brain stimulation (DBS) is a therapeutic option in medically-refractory cases. In most DBS-centers, the globus pallidus internus (GPi) is targeted in patients with predominant dystonia and the ventrointermediate nucleus of the thalamus (Vim) in predominant tremor. The aim of the study was to evaluate the effect of GPi- versus Vim-DBS in dystonic or essential head tremor., Methods: All patients with dystonia or essential tremor (ET) (n = 381) who underwent DBS surgery at our institution between 1999 and 2020 were screened for head tremor in our database according to predefined selection criteria. Of the 33 patients meeting inclusion criteria tremor and dystonia severity were assessed at baseline, short- (mean 10 months) and long-term follow-up (41 months) by two blinded video-raters., Results: Twenty-two patients with dystonic head tremor received either GPi- (n = 12) or Vim-stimulation (n = 10), according to the prevailing clinical phenotype. These two groups were compared with 11 patients with ET, treated with Vim-stimulation. The reduction in head tremor from baseline to short- and long-term follow-up was 60-70% and did not differ significantly between the three groups., Conclusions: GPi-DBS effectively and sustainably reduced head tremor in idiopathic dystonia. The effect was comparable to the effect of Vim-DBS on head tremor in dystonia patients with predominant limb tremor and to the effect of Vim-DBS on head tremor in ET., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Essential tremor (ET) amplitude is modulated by visual feedback during target driven movements and in a grip force task. It has not been examined yet whether visual feedback exclusively modulates target force tremor amplitude or if other afferent inputs like auditory sensation has a modulatory effect on tremor amplitude as well. Also, it is unknown whether the enhanced sensory feedback causes an increase of arousal in persons with ET (p-ET). We hypothesized that (1) amplitude of tremor is modulated by variation of auditory feedback in the absence of visual feedback in a force tremor paradigm; (2) increase of tremor amplitude coincides with pupillary size as a measure of arousal. 14 p-ET and 14 matched healthy controls (HC) conducted a computer-based experiment in which they were asked to match a target force on a force sensor using their thumb and index finger. The force-induced movement was fed back to the participant visually, auditory or by a combination of both. Results showed a comparable deviation from the target force (RMSE) during the experiment during all three sensory feedback modalities. The ANOVA revealed an effect of the high vs. low feedback condition on the tremor severity (Power 4-12 Hz) for the visual- and also for the auditory feedback condition in p-ET. Pupillometry showed a significantly increased pupil diameter during the auditory involved high feedback conditions compared to the low feedback conditions in p-ET. Our findings suggest that action tremor in ET is firstly modulated not only by visual feedback but also by auditory feedback in a comparable manner. Therefore, tremor modulation seems to be modality independent. Secondly, high feedback was associated with a significant pupil dilation, possibly mirroring an increased arousal/perceived effort., (© 2024. The Author(s).)

Essential tremor (ET) is a progressive movement disorder whose pathophysiology is not fully understood. Current evidence supports the view that the cerebellum is critically involved in the genesis of the tremor in ET. However, it is still unknown whether cerebellar dysfunction affects not only the control of current movements but also the prediction of future movements through dynamic adaptation toward a changed environment. Here, we tested the capacity of 28 patients with ET to adapt in a visuomotor adaptation task known to depend on intact cerebellar function. We found specific impairments in that task compared to age-matched healthy controls. Adaptation to the visual perturbation was disrupted in ET patients, while de-adaptation, the phase after abrupt removal of the perturbation, developed similarly to control subjects. Baseline tremor-independent motor performance was as well similar to healthy controls, indicating that adaptation deficits in ET patients were not rooted in an inability to perform goal-directed movements. There was no association between clinical severity scores of ET and early visuomotor adaptation abilities. These results provide further evidence that the cerebellum is dysfunctional in ET., (© 2022. The Author(s).)

Background: Thalamic deep brain stimulation (DBS) is established for medically refractory tremor syndromes and globus pallidus stimulation (GPi-DBS) for medically refractory dystonia syndromes. For combined tremor and dystonia syndromes, the best target is unclear., Objectives: We present four patients with two different profiles whose clinical course demonstrates that our current analysis of clinical symptomatology is not a sufficient predictor of surgical success., Methods: Outcome parameters were assessed with observer-blinded video ratings and included the Fahn-Tolosa-Marin-Tremor Rating Scale (FTM-TRS) and the Unified Dystonia Rating Scale (UDRS)., Results: Two patients with "predominant lateralized action tremor" of the hands and mild cervical dystonia showed no relevant tremor improvement after GPi-DBS, but UDRS improved (mean, 45%). Rescue ventral intermediate nucleus of the thalamus (Vim)-DBS electrodes were implanted and both patients benefited significantly with a mean tremor reduction of 51%.Two other patients with "axial-predominant action tremor of the trunk and head" associated with cervical dystonia underwent bilateral Vim-DBS implantation with little effect on tremor (24% reduction in mean FTM-TRS total score) and no effect on dystonic symptoms. GPi rescue DBS was implanted and showed a significant effect on tremor (63% reduction in mean FTM-TRS) and dystonia (49% reduction in UDRS)., Conclusions: The diagnosis of dystonic tremor alone is not a sufficient predictor to establish the differential indication of GPi- or Vim-DBS. Further criteria (eg, proximal-distal distribution of tremor/dystonia) are needed to avoid rescue surgery in the future. On the other hand, the course of our patients encourages rescue surgery in such severely disabled patients if the first target fails., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective and evidence-based treatment for idiopathic Parkinson's disease (iPD). A minority of patients does not sufficiently benefit from STN-DBS., Objective: The predictive validity of the levodopa challenge for individual patients is analyzed., Methods: Data from patients assessed with a preoperative Levodopa-test and a follow-up examination (mean ± standard deviation: 9.15 months ±3.39) from Kiel (n = 253), Berlin (n = 78) and Toronto (n = 98) were studied. Insufficient DBS outcome was defined as an overall UPDRS-III reduction <33% compared to UPDRS-III in med-off at baseline or alternatively if the minimal clinically important improvement of 5 points was not reached. Single UPDRS-items and sub-scores were dichotomized. Following exploratory analysis, we trained supervised regression- and classification models for outcome prediction., Results: Data analysis confirmed significant correlation between the absolute UPDRS-III reduction during Levodopa challenge and after stimulation. But individual improvement was inaccurately predicted with a large range of up to 30 UPDRS III points. Further analysis identified preoperative UPDRS-III/med-off-scores and preoperative Levodopa-improvement as most influential factors. The models for UPDRS-III and sub-scores improvement achieved comparably low accuracy., Conclusions: With large prediction intervals, the Levodopa challenge use for patient counseling is limited, though remains important for excluding non-responders to Levodopa. Despite these deficiencies, the current practice of patient selection is highly successful and builds not only on the Levodopa challenge. However, more specific motor tasks and further paraclinical tools for prediction need to be developed., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Questionable signs of dystonia are a common finding in patients with essential tremor (ET). Brain structural alterations in ET patients plus dystonic soft signs (ET + ds) in comparison to ET patients without dystonic soft signs (ET-ds) or patients with tremor associated with manifest dystonia (TAWD) have not been examined yet. Therefore, our study aims to explore alterations of brain grey matter in patients with ET + ds., Methods: A total of 68 elderly patients with ET-ds (n = 32), ET + ds (n = 20) or idiopathic cervical dystonia with dystonia associated action tremor of the upper limbs (TAWD, n = 16) and 42 age-matched healthy controls underwent a clinical and electrophysiological assessment and 3T MRI. For grey matter alterations T1 MRI images were analysed by voxel-based morphometry. Additionally, regression analyses with clinical parameters (tremor frequency, severity and disease duration) were performed., Results: VBM showed a significant increase of grey matter in the right lentiform nucleus in ET + ds and TAWD compared to HC and ET-ds. Further, an increase of cortical grey matter in the middle frontal gyrus in ET + ds was shown. The hypertrophy of the lentiform nucleus in ET + ds was correlated with disease severity and duration., Conclusion: Patients with ET + ds showed grey matter brain structural alterations similar to TAWD. Our findings suggest an involvement of the basal ganglia-cortical loop in ET + ds which may indicate a pathophysiological similarity with TAWD rather than ET., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The various forms of tremor are now classified in two axes: clinical characteristics (axis 1) and etiology (axis 2). Electrophysiology is an extension of the clinical exam. Electrophysiologic tests are diagnostic of physiologic tremor, primary orthostatic tremor, and functional tremor, but they are valuable in the clinical characterization of all forms of tremor. Electrophysiology will likely play an increasing role in axis 1 tremor classification because many features of tremor are not reliably assessed by clinical examination alone. In particular, electrophysiology may be needed to distinguish tremor from tremor mimics, assess tremor frequency, assess tremor rhythmicity or regularity, distinguish mechanical-reflex oscillation from central neurogenic oscillation, determine if tremors in different body parts, muscles, or brain regions are strongly correlated, document tremor suppression or entrainment by voluntary movements of contralateral body parts, and document the effects of voluntary movement on rest tremor. In addition, electrophysiologic brain mapping has been crucial in our understanding of tremor pathophysiology. The electrophysiologic methods of tremor analysis are reviewed in the context of physiologic tremor and pathologic tremors, with a focus on clinical characterization and pathophysiology. Electrophysiology is instrumental in elucidating tremor mechanisms, and the pathophysiology of the different forms of tremor is summarized in this review., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: In this study we used functional magnetic resonance imaging (fMRI) to investigate whether motor imagery (MI) of handwriting and circle drawing activates a similar handwriting network as writing and drawing itself., Methods: Eighteen healthy right-handed participants wrote the German word " Wellen" and drew continuously circles in a sitting (vertical position) and lying position (horizontal position) to capture kinematic handwriting parameters such as velocity, pressure and regularity of hand movements. Afterward, they performed the same tasks during fMRI in a MI and an executed condition., Results: The kinematic analysis revealed a general correlation of handwriting parameters during sitting and lying except of pen pressure during drawing. Writing compared to imagined writing was accompanied by an increased activity of the ipsilateral cerebellum and the contralateral sensorimotor cortex. Executed compared to imagined drawing revealed elevated activity of a fronto-parieto-temporal network. By contrasting writing and drawing directly, executed writing induced an enhanced activation of the left somatosensory and premotor area. The comparison of the MI of these tasks revealed a higher involvement of occipital activation during imagined writing., Conclusion: The kinematic results pointed to a high comparability of writing in a vertical and horizontal position. Overall, we observed highly overlapping cortical activity except of a higher involvement of motor control areas during motor execution. The sparse difference between writing and drawing can be explained by highly automatized writing in healthy individuals., Competing Interests: AB received an intramural research grant from the Department of Neurology, Kiel. CM is the owner and author of the SCWin analysis software. KW served as a consultant for BIAL outside the present work. KZ has received research support from Strathmann and the German Research Council. She reports speaker’s honoraria from Bayer Vital GmbH, BIAL, AbbVie Allergan, and Merz outside the submitted work. She has served as a consultant and received fees from Merz, Ipsen, Alexion, and the German Federal Institute for Drugs and Medical Devices (BfArM). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Baumann, Tödt, Knutzen, Gless, Granert, Wolff, Marquardt, Becktepe, Peters, Witt and Zeuner.)

The process of diagnosing tremor patients often leads to misdiagnoses. Therefore, existing technical methods for analysing tremor are needed to more effectively distinguish between different diseases. For this purpose, a system has been developed that classifies measured tremor signals in real time. To achieve this, the hand tremor of 561 subjects has been measured in different hand positions. Acceleration and surface electromyography are recorded during the examination. For this study, data from subjects with Parkinson's Disease, Essential Tremor, and physiological tremor are considered. In a first signal analysis feature extraction is performed, and the resulting features are examined for their discriminative value. In a second step, three classification models based on different pattern recognition techniques are developed to classify the subjects with respect to their tremor type. With a trained decision tree, the three tremor types can be classified with a relative diagnostic accuracy of 83.14%. A neural network achieves 84.24% and the combination of both classifiers yields a relative diagnostic accuracy of 85.76%. The approach is promising and involving more features of the recorded time series will improve the discriminative value., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Essential tremor (ET) occurs with steeply increasing prevalence in the elderly, and apart from disease duration, age is independently associated with an increase of tremor amplitude and a decrease of frequency. White matter hyperintensities (WMHs) are a common finding in the elderly, and their role in the pathophysiology of ET is unknown. The aims of this study were to examine whether ET patients differ in their total or region-specific WMH volumes from healthy controls and to determine the impact of WMH on tremor characteristics. Methods: A total of 47 elderly ET patients with a mean age of 72 years and 39 age-matched healthy controls underwent a thorough clinical assessment and 3T MRI. Total WMH volumes were derived from T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Additionally, region of interest-based WMH volumes for the Johns Hopkins University (JHU) white matter tracts and labels were calculated, and WMHs were assessed semiquantitatively using the Fazekas scale. Results: Essential tremor patients and healthy controls did not differ in their total or tract-specific WMH volumes or Fazekas scores. However, WMH volume was significantly positively correlated with tremor severity on the TETRAS scale, and there was a significant negative correlation with the mean accelerometric tremor frequency. In a multiple linear regression model including disease duration, age, and age-adjusted total WMH volume, only the WMH volume significantly predicted tremor severity, while age and disease duration were not significant. Conclusion: We found evidence for a direct association between WMH volume and tremor severity. If confirmed by larger studies, our findings could explain the well-known relation between age and tremor severity., Competing Interests: KZ has received research support from an intramural grant from the Christian-Albrechts University of Kiel, from the Benign Essential Blepharospasm Foundation, and with an unrestricted grant from Ipsen. She reports speaker's honoraria from Bayer Vital GmbH, AbbVie Allergan, and Merz outside the submitted work. She has served as a consultant and received fees from Merz, Ipsen, and the German Federal Institute for Drugs and Medical Devices (BfArM). DB has served on scientific advisory boards for UCB Pharma GmbH and Lundbeck; has received speaker honoraria from UCB Pharma GmbH, Lundbeck, BIAL, Bayer, AbbVie, Biogen, and Zambon; and has received grants from Michael J. Fox Foundation, Janssen Pharmaceutica N.V., German Parkinson's Disease Association, BMWi, BMBF, ParkinsonFonds Deutschland gGmbH, UCB Pharma GmbH, TEVA Pharma GmbH, EU, Novartis Pharma GmbH, Lundbeck and Damp foundation. GD received fees for lecturing from Boston Scientific and consulting fees from Boston Scientific, Cavion, Functional modulation. He receives funding for his research to his institution from the German Research Council, SFB 1261, B5, and Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Becktepe, Busse, Jensen-Kondering, Toedt, Wolff, Zeuner, Berg, Granert and Deuschl.)

Background: Freezing of gait (FOG) in Parkinson's disease (PD) is associated with gait asymmetry and switching difficulty. A split-belt treadmill may potentially address those deficits., Objective: To investigate the immediate and retention effects of one-session split-belt treadmill training (SBT) in contrast to regular tied-belt treadmill training (TBT) on gait asymmetry and adaptation in people with PD and FOG (PD + FOG) and healthy controls (HC). Additionally, to investigate differential effects of 3 SBT protocols and compare different gait adaptation outcomes., Methods: PD + FOG (n = 45) and HC (n = 36) were randomized to 1 of 3 SBT groups (belt speeds' ratio 0.75:1; 0.5:1 or changing ratios) or TBT group. Participants were tested at Pre, Post, and Retention after one treadmill training session. Gait asymmetry was measured during a standardized adaptation test on the split-belt treadmill., Results: SBT proved beneficial for gait adaptation in PD + FOG and HC ( P < .0001); however, HC improved more. SBT with changing ratios demonstrated significant effects on gait adaptation from Pre to Post in PD + FOG, supported by strong effect sizes ( d = 1.14) and improvements being retained for 24 hours. Mean step length asymmetry during initial exposure was lower in HC compared with PD + FOG ( P = .035) and differentiated best between the groups., Conclusions: PD + FOG improved gait adaptation after a single SBT session although effects were smaller than in HC. SBT with changing ratios was the most effective to ameliorate gait adaptation in PD + FOG. These promising results warrant future study on whether long-term SBT strengthens adaptation in PD + FOG and has potential to induce a better resilience to FOG. Clinical trial ID: NCT03725215.

Background: Motor and cognitive deficits and consequently mobility problems are common in geriatric patients. The currently available methods for diagnosis and for the evaluation of treatment in this vulnerable cohort are limited. The aims of the ComOn (COgnitive and Motor interactions in the Older populatioN) study are (i) to define quantitative markers with clinical relevance for motor and cognitive deficits, (ii) to investigate the interaction between both motor and cognitive deficits and (iii) to assess health status as well as treatment outcome of 1000 geriatric inpatients in hospitals of Kiel (Germany), Brescia (Italy), Porto (Portugal), Curitiba (Brazil) and Bochum (Germany)., Methods: This is a prospective, explorative observational multi-center study. In addition to the comprehensive geriatric assessment, quantitative measures of reduced mobility and motor and cognitive deficits are performed before and after a two week's inpatient stay. Components of the assessment are mobile technology-based assessments of gait, balance and transfer performance, neuropsychological tests, frailty, sarcopenia, autonomic dysfunction and sensation, and questionnaires to assess behavioral deficits, activities of daily living, quality of life, fear of falling and dysphagia. Structural MRI and an unsupervised 24/7 home assessment of mobility are performed in a subgroup of participants. The study will also investigate the minimal clinically relevant change of the investigated parameters., Discussion: This study will help form a better understanding of symptoms and their complex interactions and treatment effects in a large geriatric cohort.

Introduction: Late-onset essential tremor is characterised by shorter life expectancy and more advanced aging parameters and may therefore be an 'aging-related' tremor. Brainstem functions involved in pupillary responses are hypothesized to reflect such earlier aging. The pupillary light response (PLR) and a task evoked pupillary response (TEPR) were used to test this hypothesis in same-aged patients with early onset (EOET) and late onset (LOET) essential tremor and healthy controls., Subjects and Methods: Age related changes of the PLR and TEPR during the paced auditory serial addition test (PASAT) were tested in 57 normal subjects. Subsequently, 13 patients with LOET and 16 patients with EOET were compared with 15 age matched healthy controls. Standard parameters of PLR were recorded, amongst others the time to maximum acceleration of the PLR (T1) and the time to maximum velocity (T2). The TEPR was determined during the PASAT as the percentage change in pupil size (PCPS). Data were analysed with ANOVA and post-hoc testing., Results: In normal subjects the pupil diameter, latency, maximum acceleration/velocity and percentage amplitude were correlated with age. Latency of the pupillary light response was significantly longer in LOET compared to controls and EOET while no differences were found between EOET and controls. The TEPR showed no significant differences between the three groups., Conclusion: LOET showed a prolonged latency of the PLR compared to EOET possibly indicating premature aging or rather pathophysiological differences on brainstem level. This study further supports the hypothesis of abnormal aging in LOET., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: There is a group of uncommon sporadic tremor syndromes, which are only partially taken into account in the current classification of tremor. Their knowledge is of diagnostic and therapeutic relevance and they should be considered in the differential diagnosis of frequent tremor syndromes., Objective: Differential diagnostics and treatment of uncommon tremor syndromes., Method: Literature search (PubMed, Google Scholar)., Results: Holmes tremor, myorhythmia, palatal tremor, limb-shaking transient ischemic attack (TIA), tardive tremor, neuropathic tremor, tremor induced by peripheral trauma and orthostatic tremor syndrome are described., Conclusion: Uncommon sporadic tremor syndromes are mainly symptomatic with various underlying neurological or systemic pathologies. Their recognition accelerates the diagnostic process and has therapeutic relevance.

Tremor is the most common movement disorder characterized by a rhythmical, involuntary oscillatory movement of a body part. Since distinct diseases can cause similar tremor manifestations and vice-versa, it is challenging to make an accurate diagnosis. This applies particularly for tremor at rest. This entity was only rarely studied in the past, although a multitude of clinical studies on prevalence and clinical features of tremor in Parkinson's disease (PD), essential tremor and dystonia, have been carried out. Monosymptomatic rest tremor has been further separated from tremor-dominated PD. Rest tremor is also found in dystonic tremor, essential tremor with a rest component, Holmes tremor and a few even rarer conditions. Dopamine transporter imaging and several electrophysiological methods provide additional clues for tremor differential diagnosis. New evidence from neuroimaging and electrophysiological studies has broadened our knowledge on the pathophysiology of Parkinsonian and non-Parkinsonian tremor. Large cohort studies are warranted in future to explore the nature course and biological basis of tremor in common tremor related disorders.

Essential tremor is clinically defined but there is increasing evidence that it is not a unique entity. Its pathophysiology has been studied with many methods but may also vary between subtypes. Neurophysiologically, there is strong evidence that a specific cerebello-thalamo-cortical loop is abnormally oscillating. The cause of its uncontrolled oscillation is not yet understood. The clear proof of a degenerative cause is still lacking and abnormal receptors or other causes of altered non-progressive functional disturbance cannot be excluded. Strong evidence supports the major involvement of the cerebellum and there is ample evidence that GABA is the main neurotransmitter involved in the pathophysiology in ET. Genetics have provided so far only a few rare subtypes which are due to specific mutations but there is no doubt that it is mostly a hereditary condition. There is evidence that the large subgroup of late onset tremor is a separate condition and this tremor is an independent risk factor for earlier mortality and comes with signs of premature aging (aging-related tremor). It will be important to improve phenotyping of patients in more detail possibly to include not only features of the tremor itself but also other clinical assessments like force measurements or cognitive testing. Based on these variables, we may be able to better understand the presumably different mechanisms underlying different variants of the disease., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aβ42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Abnormal serotonin transporter (5-HTT) function and autonomic nervous system (ANS) dysregulation has been proposed in panic disorder. However, in contrast to hypothalamo-pituitary-adrenocortical (HPA) functioning, ANS reactivity during panic response has yet not been investigated in humans with respect to the 5-HTT genotype. The present study assessed the influence of challenging by cholecystokinin tetrapeptide (CCK-4) on heart rate variability (HRV) measures, to monitor autonomic reactivity and its relationship to 5-HTT-linked polymorphic region (5-HTTLPR) genotypes. We hypothesized substantial effects of the 5-HTTLPR genotype on autonomic reactivity. We studied 30 healthy young men, 15 of each with the long/long (l/l) or short/short (s/s) genotype for the 5-HTTLPR. All participants received an intravenous application of 50 μg CCK-4. HRV measures were assessed in both groups at baseline and immediately after CCK-4 application. Our results indicated lower parasympathetic activity in s/s carriers during baseline, time and frequency domain measures. CCK-4 application significantly enhanced the sympathetic tone in both groups, leading to diminished group differences. A significant treatment by genotype effect indicated reduced autonomic reactivity to CCK-4 challenge in the s/s compared to l/l carriers. Our findings show enhanced sympathetic and/or diminished cardiac vagal activity under basal conditions and blunted autonomic reactivity in s/s vs. l/l carriers. Our study provides novel data supporting claims that the s/s genotype represents a genetic vulnerability factor associated with inadequate hyporeactivity to stress and extends current knowledge on the impact of the central serotonergic activity on the sympathoadrenal pathway., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The clinical benefit of mechanical recanalization procedures for acute stroke is still a matter of debate. We report the clinical and imaging results of 34 consecutive patients, focusing on time aspects (i.e. vessel occlusion time and procedure duration)., Methods: During a 3-year period, 34 stroke patients with large-vessel occlusion (anterior circulation, n = 19; posterior circulation, n = 15) were treated with several mechanical recanalization devices with (n = 17) or without prior intravenous thrombolysis. Clinical and imaging data before (NIHSS) and after treatment [(mRS) 3 and 6-30 months] were analyzed. The angiographic outcome (TIMI score), complication rates, and procedural issues (i.e. procedure duration and vessel occlusion time) were assessed., Results: The median NIHSS on admission was 17. Successful recanalization (TIMI 2 and 3) was achieved in 23 (68%) patients. The median time from symptom onset to recanalization was 330 min, and the median time from angiography to recanalization was 101 min. Six (18%) patients had a good clinical outcome (3-month mRS ≤2), and 10 (29%) died. The vessel occlusion time was significantly shorter in patients with a good compared to poor clinical outcome (247 vs. 348 min, p = 0.024). In the subgroup of anterior circulation stroke, successful recanalization, and no symptomatic intracranial hemorrhage (n = 11), there was a strong correlation between vessel occlusion time and clinical outcome (r = 0.711, p = 0.014)., Conclusions: The rate of vessel recanalization with endovascular therapy is promising. Nevertheless, the long-term clinical outcome is still disadvantageous in the majority of patients, presumably due to too long vessel occlusion times. Better strategies for patient selection and optimization of recanalization strategies (i.e. shorter time intervals to vessel patency) are warranted., (Copyright © 2011 S. Karger AG, Basel.)