Publications by authors named "Alexander Storch"

222 Publications

One nerve suffices: A clinically guided nerve ultrasound protocol for the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS).

J Neurol 2020 Dec 23. Epub 2020 Dec 23.

German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, 18147, Rostock, Germany.

Objective: To investigate diagnostic accuracy of a nerve ultrasound (US) protocol that is individualized to a patient's clinical deficits for the differentiation of amyotrophic lateral sclerosis with predominant lower motoneuron disease (ALS/LMND) and multifocal motor neuropathy (MMN).

Methods: Single-center, prospective, examiner-blinded, diagnostic study in two cohorts. Cohort I (model development): Convenience sample of subjects with ALS/LMND or MMN according to revised El-Escorial or EFNS guidelines. Cohort II (model validation): Consecutively recruited treatment-naïve subjects with suspected diagnosis of ALS/LMND or MMN. Cutoffs for 28 different US values were determined by Receiver Operating Curve (ROC) in cohort I. Area Under The Curve (AUC) of US was compared to nerve conduction studies (NCS). Diagnostic accuracy of US protocols, individualized according to clinical deficits, was compared to former rigid non-individualized protocols and to random examination site selection in cohort II.

Results: 48 patients were recruited. In cohort I (28 patients), US had higher ROC AUCs than NCS, US 0.82 (0.12) (mean (standard deviation)), NCS (compound muscle action potential (CMAP) 0.60 (0.09), p < .001; two-sided t-test). US models based on the nerve innervating the clinically most affected muscles had higher correct classification rates (CCRs, 93%) in cohort II than former rigid protocols (85% and 80%), or models with random measurement site selection (66% and 80%).

Conclusions: Clinically guided US protocols for differentiation of ALS/LMND from MMN increase diagnostic accuracy when compared to clinically unguided protocols. They also require less measurements sites to achieve this accuracy.
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http://dx.doi.org/10.1007/s00415-020-10323-6DOI Listing
December 2020

Dangerous sweets: severe hypokalemia with rhabdomyolysis and tetraparesis from chronic consumption of licorice.

J Neurol 2021 Feb 19;268(2):707-708. Epub 2020 Dec 19.

Department of Diagnostic and Interventional Radiology, University Medical Centre Rostock, University of Rockstock, Rockstock, Germany.

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http://dx.doi.org/10.1007/s00415-020-10347-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880938PMC
February 2021

Dissonance in Music Impairs Spatial Gait Parameters in Patients with Parkinson's Disease.

J Parkinsons Dis 2021 ;11(1):363-372

Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

Background: It is known that music influences gait parameters in Parkinson's disease (PD). However, it remains unclear whether this effect is merely due to temporal aspects of music (rhythm and tempo) or other musical parameters.

Objective: To examine the influence of pleasant and unpleasant music on spatiotemporal gait parameters in PD, while controlling for rhythmic aspects of the musical signal.

Methods: We measured spatiotemporal gait parameters of 18 patients suffering from mild PD (50%men, mean±SD age of 64±6 years; mean disease duration of 6±5 years; mean Unified PD Rating scale [UPDRS] motor score of 15±7) who listened to eight different pieces of music. Music pieces varied in harmonic consonance/dissonance to create the experience of pleasant/unpleasant feelings. To measure gait parameters, we used an established analysis of spatiotemporal gait, which consists of a walkway containing pressure-receptive sensors (GAITRite®). Repeated measures analyses of variance were used to evaluate effects of auditory stimuli. In addition, linear regression was used to evaluate effects of valence on gait.

Results: Sensory dissonance modulated spatiotemporal and spatial gait parameters, namely velocity and stride length, while temporal gait parameters (cadence, swing duration) were not affected. In contrast, valence in music as perceived by patients was not associated with gait parameters. Motor and musical abilities did not relevantly influence the modulation of gait by auditory stimuli.

Conclusion: Our observations suggest that dissonant music negatively affects particularly spatial gait parameters in PD by yet unknown mechanisms, but putatively through increased cognitive interference reducing attention in auditory cueing.
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http://dx.doi.org/10.3233/JPD-202413DOI Listing
January 2021

Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain.

Front Neuroanat 2020 23;14:558435. Epub 2020 Sep 23.

Department of Neurology, University of Rostock, Rostock, Germany.

The major catecholamines-dopamine (DA) and norepinephrine (NE)-are not only involved in synaptic communication but also act as important trophic factors and might ultimately be involved in mammalian brain development. The catecholaminergic innervation of neurogenic regions of the developing brain and its putative relationship to neurogenesis is thus of pivotal interest. We here determined DA and NE innervation around the ventricular/subventricular zone (VZ/SVZ) bordering the whole ventricular system of the developing mouse brain from embryonic day 14.5 (E14.5), E16.5, and E19.5 until postnatal day zero (P0) by histological evaluation and HPLC with electrochemical detection. We correlated these data with the proliferation capacity of the respective regions by quantification of MCM2 cells. During development, VZ/SVZ catecholamine levels dramatically increased between E16.5 and P0 with DA levels increasing in forebrain VZ/SVZ bordering the lateral ventricles and NE levels raising in midbrain/hindbrain VZ/SVZ bordering the third ventricle, the aqueduct, and the fourth ventricle. Conversely, proliferating MCM2 cell counts dropped between E16.5 and E19.5 with a special focus on all VZ/SVZs outside the lateral ventricles. We detected an inverse strong negative correlation of the proliferation capacity in the periventricular neurogenic regions (log-transformed MCM2 cell counts) with their NE levels ( = -0.932; < 0.001), but not their DA levels ( = 0.440; = 0.051) suggesting putative inhibitory effects of NE on cell proliferation within the periventricular regions during mouse brain development. Our data provide the first framework for further demandable studies on the functional importance of catecholamines, particularly NE, in regulating neural stem/progenitor cell proliferation and differentiation during mammalian brain development.
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http://dx.doi.org/10.3389/fnana.2020.558435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538673PMC
September 2020

Early Chronic Intermittent Maternal Hyperoxygenation Impairs Cortical Development by Inhibition of Pax6-Positive Apical Progenitor Cell Proliferation.

J Neuropathol Exp Neurol 2020 11;79(11):1223-1232

Department of Neurology, University of Rostock.

Maternal hyperoxygenation is a feasible, noninvasive method to treat fetal diseases, such as heart hypoplasia, but effects of maternal hyperoxygenation on the developing brain remain poorly understood. Previous studies showed that short-term maternal hyperoxygenation during midneurogenic phase (E14-E16) but not in earlier development (E10-E12) increases oxygen tension and enhances neurogenesis in the developing mouse cortex. We investigated effects of early chronic maternal hyperoxygenation (CMH) as a potential clinical treatment. Pregnant C57BL/6J mice were housed in a chamber at 75% atmospheric oxygen and the brains of E16 fetuses were analyzed using immunohistochemistry. The mitosis marker phH3 showed a significant reduction of proliferation in the dorsolateral cortices of CMH-treated E16 fetuses. Numbers of Tbr2-positive intermediate progenitor cells were unaffected whereas numbers of Pax6-positive apical progenitor cells were significantly reduced in CMH-treated mice. This resulted in altered cortical plate development with fewer Satb2-positive upper layer neurons but more Tbr1-positive neurons corresponding to the deeper layer 6. Thus, maternal hyperoxygenation affects the developing cortex depending on timing and length of applied oxygen. Early CMH causes a severe reduction of neuroprogenitor proliferation likely affecting cortical development. Further studies are needed to investigate the mechanisms underlying these findings and to assess the clinical and neurodevelopmental outcomes of the pups.
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http://dx.doi.org/10.1093/jnen/nlaa072DOI Listing
November 2020

Sleep Disturbances and Sleep Disordered Breathing Impair Cognitive Performance in Parkinson's Disease.

Front Neurosci 2020 6;14:689. Epub 2020 Aug 6.

Department of Neurology, University of Rostock, Rostock, Germany.

Background: Sleep disturbances and impairment of cognitive function are among the most frequent non-motor symptoms in Parkinson's disease (PD) with negative implications on quality of life of patients and caregivers. Despite the fact that sleep disturbances are a major issue in PD patients, only limited data are available regarding interactions of sleep disturbances and cognitive performance.

Objective: This analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD.

Methods: Twenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients' subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG). Cognitive performance was assessed by Parkinson Neuropsychometric Dementia Assessment (PANDA) and Test of Attentional Performance (TAP), and associations of sleep and cognitive function were evaluated.

Results: We did not detect differences in cognitive performance between patients with and without rapid eye movement (REM) sleep behavior disorder (RBD). Instead, cognitive impairment, particularly affecting cognitive domains attention, executive function/working memory, and semantic memory, was associated with impaired PSG-measured sleep quality (e.g., sleep efficiency) and sleep disordered breathing (SDB) (Apnea-Hypopnea Index > 5/h). Global cognitive performance was decreased in patients with SDB (PANDA score 23.2 ± 3.5 vs. 26.9 ± 2.2, = 0.020, unpaired two-sided -test).

Conclusion: Sleep apnea and other sleep disturbances impair cognitive performance in PD and should be evaluated in routine care, and treatment options such as continuous airway pressure therapy should be considered.
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http://dx.doi.org/10.3389/fnins.2020.00689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438827PMC
August 2020

Detection of arrhythmia using an implantable cardiac monitor following a cryptogenic stroke: a single-center observational study.

Eur J Med Res 2020 Jun 29;25(1):25. Epub 2020 Jun 29.

University Hospital of Rostock, Rostock, Germany.

Background: Detection of atrial fibrillation (AF) after cryptogenic stroke (CS) has therapeutic implications, but the most effective type and optimal duration of monitoring have still to be defined. This study that involved patients with CS or transient ischemic attack (TIA), all of whom carried an implantable cardiac monitor (ICM), sought to assess the incidence of AF and other arrhythmia detected using tele-monitoring or interval-based follow-up by an internal cardiologist at the university medical center of Rostock (UMR) or an external cardiologist.

Methods: The ICM implantation was performed during the inpatient stay in the neurology department, with inclusion and exclusion criteria jointly determined by the neurology and cardiology departments. Cardiologists programmed individual threshold values during ICM implantation, which were designed to instantly trigger an episode being recording and an alarm message being sent out. Outpatient care consisted of tele-monitoring of implants or interval-based follow-up care.

Results: The indication for ICM implantation was made for 102 patients, 88 of whom underwent ICM implantation, with full documentation available for these 88 study patients. Within a median observation period of 21.5 months, AF occurred in 19 patients, with a median observation time to the event of 7 months. In all cases, AF detection was followed by immediate medical intervention. Comparing patients with and without AF revealed that the median age of the AF group exceeded by 10 years that of the other patients. Stroke recurrence was recorded in five patients, with a median observation time to the event of 9 months. Comparing patients with and without stroke recurrence revealed that the median age in the stroke recurrence group tended to be higher by 14 years. No statistically significant between-group differences were found with regard to integration into tele-monitoring, nor were there any differences identified between outpatient care at the UMR or in the outpatient sector.

Conclusions: This study confirmed the feasibility of using an interdisciplinary and intersectoral therapeutic approach for monitoring CS patients with implanted ICMs. Further randomized studies are warranted to confirm these encouraging data. An open discussion concerning optimal care forms and opportunities for introducing digitizing care pathways appears warranted.
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http://dx.doi.org/10.1186/s40001-020-00424-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325047PMC
June 2020

[The role of inhibitors of COMT and MAO-B in the therapy of Parkinson's disease].

Fortschr Neurol Psychiatr 2020 Sep 25;88(9):620-633. Epub 2020 Jun 25.

Inhibitors of COMT and MAO-B are well established in the pharmacotherapy of Parkinson's disease (PD). MAO-B inhibitors are used as monotherapy as well as in combination with levodopa, whereas COMT inhibitors exert their effects only in conjungtion with levodopa. Both classes of compounds prolong the response duration of levodopa and optimise its clinical benefit. As a result, the ON-times are prolonged significantly. In the past, MAO-B inhibitors were also adminstered for neuroprotection; however, despite convincing scientific reasoning in support of neuroprotective effects, these could not be substantiated in clinical studies performed so far.
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http://dx.doi.org/10.1055/a-1149-9308DOI Listing
September 2020

Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche.

Stem Cells 2020 09 25;38(9):1188-1201. Epub 2020 Jun 25.

Department of Neurology, University of Rostock, Rostock, Germany.

The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell-extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ-olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4-fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus-related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.
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http://dx.doi.org/10.1002/stem.3232DOI Listing
September 2020

Frequency and risk factors of antibody-induced secondary failure of botulinum neurotoxin therapy.

Neurology 2020 05 24;94(20):e2109-e2120. Epub 2020 Apr 24.

From the Department of Neurology (U.W., C.M., R.B., E.M., J.A., M.W., A.D., A.S., C.K.), University of Rostock; German Centre for Neurodegenerative Diseases (DZNE) (U.W., A.S.), Rostock; and Movement Disorders Section, Department of Neurology (D.D.), Hannover Medical School, Germany.

Objective: To investigate the risk factors of neutralizing antibody (NAB)-induced complete secondary treatment failure (cSTF) during long-term botulinum neurotoxin (BoNT) treatment in various neurologic indications.

Methods: This monocenter retrospective cohort study analyzed the data of 471 patients started on BoNT therapy between 1995 and 2015. Blood samples of 173 patients were investigated for NABs using the mouse hemidiaphragm test (93 with suspected therapy failure, 80 prospective study participants). The frequency of NAB-cSTF was assessed for various indications: hemifacial spasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. A priori defined potential risk factors for NAB-cSTF were evaluated, and a stepwise binary logistic regression analysis was performed to identify independent risk factors.

Results: Treatment duration was 9.8 ± 6.2 years (range, 0.5-30 years; adherence, 70.6%) and number of treatment cycles 31.2 ± 22.5 (3-112). Twenty-eight of 471 patients (5.9%) had NAB-cSTF at earliest after 3 and at latest after 103 treatment cycles. None of the 49 patients treated exclusively with incobotulinumtoxinA over 8.4 ± 4.2 (1-14) years developed NAB-cSTF. Independent risk factors for NAB-cSTF were high BoNT dose per treatment, switching between onabotulinumtoxinA and other BoNT formulations (except for switching to incobotulinumtoxinA), and treatment of neck muscles.

Conclusions: We present a follow-up study with the longest duration to date on the incidence of NAB-cSTF in patients treated with various BoNT formulations, including incobotulinumtoxinA. Whereas the overall risk of NAB-cSTF is low across indications and BoNT formulations, our findings underpin the recommendations to use the lowest possible dose particularly in cervical dystonia, and to avoid unnecessary switching between different formulations.
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http://dx.doi.org/10.1212/WNL.0000000000009444DOI Listing
May 2020

Stereotactically Injected Kv1.2 and CASPR2 Antisera Cause Differential Effects on CA1 Synaptic and Cellular Excitability, but Both Enhance the Vulnerability to Pro-epileptic Conditions.

Front Synaptic Neurosci 2020 25;12:13. Epub 2020 Mar 25.

Oscar Langendorff Institute of Physiology, University of Rostock, Rostock, Germany.

Purpose: We present a case of voltage-gated potassium channel (VGKC) complex antibody-positive limbic encephalitis (LE) harboring autoantibodies against Kv1.2. Since the patient responded well to immunotherapy, the autoantibodies were regarded as pathogenic. We aimed to characterize the pathophysiological role of this antibody in comparison to an antibody against the VGKC-associated protein contactin-associated protein-2 (CASPR2).

Methods: Stereotactic injection of patient sera (anti-Kv1.2-associated LE or anti-CASPR2 encephalopathy) and a control subject was performed into the hippocampus of the anesthetized rat , and hippocampal slices were prepared for electrophysiological purposes. Using extra- and intracellular techniques, synaptic transmission, long-term potentiation (LTP) and vulnerability to pro-epileptic conditions were analyzed.

Results: We observed that the slope of the field excitatory postsynaptic potential (fEPSP) was significantly increased at Schaffer collateral-CA1 synapses in anti-Kv1.2-treated and anti-CASPR2-treated rats, but not at medial perforant path-dentate gyrus synapses. The increase of the fEPSP slope in CA1 was accompanied by a decrease of the paired-pulse ratio in anti-Kv1.2, but not in anti-CASPR2 tissue, indicating presynaptic site of anti-Kv1.2. In addition, anti-Kv1.2 tissue showed enhanced LTP in CA1, but dentate gyrus LTP remained unaltered. Importantly, LTP in slices from anti-CASPR2-treated animals did not differ from control values. Intracellular recordings from CA1 neurons revealed that the resting membrane potential and a single action potential were not different between anti-Kv1.2 and control tissue. However, when the depolarization was prolonged, the number of action potentials elicited was reduced in anti-Kv1.2-treated tissue compared to both control and anti-CASPR2 tissue. In contrast, polyspike discharges induced by removal of Mg occurred earlier and more frequently in both patient sera compared to control.

Conclusion: Patient serum containing anti-Kv1.2 facilitates presynaptic transmitter release as well as postsynaptic depolarization at the Schaffer-collateral-CA1 synapse, but not in the dentate gyrus. As a consequence, both synaptic transmission and LTP in CA1 are facilitated and action potential firing is altered. In contrast, anti-CASPR2 leads to increased postsynaptic potentials, but without changing LTP or firing properties suggesting that anti-Kv1.2 and anti-CASPR2 differ in their cellular effects. Both patient sera alter susceptibility to epileptic conditions, but presumably by different mechanisms.
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http://dx.doi.org/10.3389/fnsyn.2020.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110982PMC
March 2020

Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis.

Int J Mol Sci 2020 Mar 5;21(5). Epub 2020 Mar 5.

Section for Translational Neurodegeneration "Albrecht Kossel", Department of Neurology, Universitätsmedizin Rostock, 18057 Rostock, Germany.

Chorea acanthocytosis (ChAc), an ultra-rare devastating neurodegenerative disease, is caused by mutations in the gene, which encodes for the protein chorein. Affected patients suffer from chorea, orofacial dyskinesia, epilepsy, parkinsonism as well as peripheral neuropathy. Although medium spinal neurons of the striatum are mainly affected, other regions are impaired as well over the course of the disease. Animal studies as well as studies on human erythrocytes suggest Lynkinase inhibition as valuable novel opportunity to treat ChAc. In order to investigate the peripheral neuropathy aspect, we analyzed induced pluripotent stem cell derived midbrain/hindbrain cell cultures from ChAc patients in vitro. We observed dendritic microtubule fragmentation. Furthermore, by using in vitro live cell imaging, we found a reduction in the number of lysosomes and mitochondria, shortened mitochondria, an increase in retrograde transport and hyperpolarization as measured with the fluorescent probe JC-1. Deep phenotyping pointed towards a proximal axonal deterioration as the primary axonal disease phenotype. Interestingly, pharmacological interventions, which proved to be successful in different models of ChAc, were ineffective in treating the observed axonal phenotypes. Our data suggests that treatment of this multifaceted disease might be cell type and/or neuronal subtype specific, and thus necessitates precision medicine in this ultra-rare disease.
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http://dx.doi.org/10.3390/ijms21051797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084777PMC
March 2020

Increased Neuronal Differentiation Efficiency in High Cell Density-Derived Induced Pluripotent Stem Cells.

Stem Cells Int 2019 4;2019:2018784. Epub 2019 Dec 4.

Department of Neurology, Technische Universität Dresden, Dresden, Germany.

Human pluripotent stem cells (hPSCs), including induced pluripotent stem cells (iPSCs), provide access to hard-to-obtain cells for studies under physiological and disease conditions. For the study of neurodegenerative diseases, especially sporadic cases where the "disease condition" might be restricted towards the neuroectodermal lineage, obtaining the affected neurons is important to help unravel the underlying molecular mechanism leading to the diseases. Although differentiation of iPSCs to neural lineage allows acquisition of cell types of interest, the technology suffers from low efficiency leading to low yield of neurons. Here, we investigated the potential of adult neuroprogenitor cells (aNPCs) for iPSC derivation and possible confounders such as cell density of infected NPCs on their subsequent neuronal differentiation potential from reprogrammed cells under isogenic conditions. Characterized hiPSCs of defined cell densities generated from aNPCs were subjected to neuronal differentiation on PA6 stromal cells. The results showed that hiPSC clones obtained from low seeding density (iPSC-aNPC) differentiated less efficiently compared to those from higher density (iPSC-aNPC). Our findings might help to further improve the yield and quality of neurons for modelling of neurodegenerative diseases.
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http://dx.doi.org/10.1155/2019/2018784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913159PMC
December 2019

Olfactory dysfunction correlates with putaminal dopamine turnover in early de novo Parkinson's disease.

J Neural Transm (Vienna) 2020 01 20;127(1):9-16. Epub 2019 Dec 20.

Department of Neurology, University of Rostock, Gehlsheimer Strasse 20, 18147, Rostock, Germany.

Although olfactory dysfunction is one of the most well-established prodromal symptoms in Parkinson's disease (PD), its correlation with clinical disease progression or dopaminergic dysfunction still remains unclear. We here evaluated the association of striatal dopamine metabolism and olfactory function in a homogenous cohort of 30 patients with early untreated de novo PD. Striatal dopamine metabolism was assessed by the extended Fluorodopa PET scanning protocol to measure Fluorodopa uptake (K) and the effective dopamine distribution volume ratio (EDVR) as the inverse of dopamine turnover. Olfactory function was estimated by the "Sniffin' Sticks" test including odor threshold (T), discrimination (D) and identification (I) assessment. We detected moderate correlations of the EDVR in the posterior putamen with the TDI composite score (r = 0.412; p = 0.024; Pearson's correlation test) and the odor identification score (r = 0.444; p = 0.014). These correlations were confirmed by multivariate regression analyses using age, sex, symptom duration and disease severity as measured by UPDRSIII motor score as candidate covariates. No other associations were observed between olfaction measures and K and EDVR in all striatal regions. Together, olfactory dysfunction in early PD is not correlated with striatal Fluorodopa uptake as a measure for dopaminergic degeneration, but with putaminal dopamine turnover as a marker for dopaminergic presynaptic compensatory processes in early PD. These results should be treated as hypothesis generating and require confirmation by larger multicenter studies.
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http://dx.doi.org/10.1007/s00702-019-02122-9DOI Listing
January 2020

Longitudinal brain atrophy distribution in advanced Parkinson's disease: What makes the difference in "cognitive status" converters?

Hum Brain Mapp 2020 04 2;41(6):1416-1434. Epub 2019 Dec 2.

Department of Neurology, University of Ulm, Ulm, Germany.

We investigated the brain atrophy distribution pattern and rate of regional atrophy change in Parkinson's disease (PD) in association with the cognitive status to identify the morphological characteristics of conversion to mild cognitive impairment (MCI) and dementia (PDD). T1-weighted longitudinal 3T MRI data (up to four follow-up assessments) from neuropsychologically well-characterized advanced PD patients (n = 172, 8.9 years disease duration) and healthy elderly controls (n = 85) enrolled in the LANDSCAPE study were longitudinally analyzed using a linear mixed effect model and atlas-based volumetry and cortical thickness measures. At baseline, PD patients presented with cerebral atrophy and cortical thinning including striatum, temporoparietal regions, and primary/premotor cortex. The atrophy was already observed in "cognitively normal" PD patients (PD-N) and was considerably more pronounced in cognitively impaired PD patients. Linear mixed effect modeling revealed almost similar rates of atrophy change in PD and controls. The group comparison at baseline between those PD-N whose cognitive performance remained stable (n = 42) and those PD-N patients who converted to MCI/PDD ("converter" cPD-N, n = 26) indicated suggested cortical thinning in the anterior cingulate cortex in cPD-N patients which was correlated with cognitive performance. Our results suggest that cortical brain atrophy has been already expanded in advanced PD patients without overt cognitive deficits while atrophy progression in late disease did not differ from "normal" aging regardless of the cognitive status. It appears that cortical atrophy begins early and progresses already in the initial disease stages emphasizing the need for therapeutic interventions already at disease onset.
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http://dx.doi.org/10.1002/hbm.24884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267933PMC
April 2020

Asymmetry of Periodic Leg Movements in Sleep (PLMS) in Parkinson's Disease.

J Parkinsons Dis 2020 ;10(1):255-266

Department of Neurology, University of Rostock, Rostock, Germany.

Background: Periodic limb movements in sleep (PLMS) are repetitive movements usually of the legs strongly associated with Restless-legs syndrome (RLS), which appear more frequently in males, older age and other sleep disturbances, such as sleep-disordered breathing (SDB). Patients with Parkinson's disease (PD) suffer from various sleep disturbances including REM sleep behavior disorder, RLS and PLMS. Although a dopaminergic pathophysiology of PLMS is discussed, no systematic data on PLMS side-to-side distribution in PD and its correlation with asymmetry of motor symptoms are available.

Objective: This study aimed at elucidating PLMS asymmetry in correlation to that of motor symptoms in PD compared to SDB and RLS.

Methods: Cross-sectional, retrospective analysis of two polysomnography (PSG) recordings per patient scoring PLMS separately for both legs.

Results: Of 105 patients (44 PD, 44 age- and sex-matched SDB and 17 RLS patients) PLMS measures (number of PLM, PLM-Index, PLM-arousal index) showed significant side-to-side differences in all disease entities in both PSGs (P < 0.001; Wilcoxon rank test). PLM-Index asymmetry (PLM-I difference of >5/h between both sides) was observed less frequently in PD (34% of patients) compared to RLS (77% , P < 0.05) and SDB (59% , P < 0.05; χ2 test). In asymmetric PD patients, predominant side of PLMS was more stable than in SDB and RLS comparing the two PSGs, but we did not detect an agreement between PLMS predominant side with that of motor symptoms in PD patients.

Conclusions: Only the minority of PD patients shows asymmetric PLMS distribution with relatively high night-to-night stability but no correlation with motor symptom asymmetry.
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http://dx.doi.org/10.3233/JPD-191667DOI Listing
January 2020

Validation of a self-completed Dystonia Non-Motor Symptoms Questionnaire.

Ann Clin Transl Neurol 2019 10 27;6(10):2054-2065. Epub 2019 Sep 27.

Department of Neurology, Technical University Dresden, Dresden, Germany.

Objective: To develop and validate a novel 14-item self-completed questionnaire (in English and German) enquiring about the presence of non-motor symptoms (NMS) during the past month in patients with craniocervical dystonia in an international multicenter study.

Methods: The Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest) covers seven domains including sleep, autonomic symptoms, fatigue, emotional well-being, stigma, activities of daily living, sensory symptoms. The feasibility and clinimetric attributes were analyzed.

Results: Data from 194 patients with CD (65.6% female, mean age 58.96 ± 12.17 years, duration of disease 11.95 ± 9.40 years) and 102 age- and sex-matched healthy controls (66.7% female, mean age 55.67 ± 17.62 years) were collected from centres in Germany and the UK. The median total NMS score in CD patients was 5 (interquartile range 3-7), significantly higher than in healthy controls with 1 (interquartile range 0.75-2.25) (P < 0.001, Mann-Whitney U-test). Evidence for intercorrelation and convergent validity is shown by moderate to high correlations of total DNMSQuest score with motor symptom severity (TWSTRS: r  = 0.61), clinical global impression (r  = 0.40), and health-related quality of life measures: CDQ-24 (r  = 0.74), EQ-5D index (r  = -0.59), and scale (r  = -0.49) (all P < 0.001). Data quality and acceptability was very satisfactory.

Interpretation: The DNMSQuest, a patient self-completed questionnaire for NMS assessment in CD patients, appears robust, reproducible, and valid in clinical practice showing a tangible impact of NMS on quality of life in CD. As there is no specific, comprehensive, validated tool to assess the burden of NMS in dystonia, the DNMSQuest can bridge this gap and could easily be integrated into clinical practice.
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http://dx.doi.org/10.1002/acn3.50900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801169PMC
October 2019

Epileptic seizures and outcome in different subtypes of subarachnoid haemorrhage - Results of a single-center retrospective analysis.

J Clin Neurosci 2019 Dec 16;70:123-126. Epub 2019 Aug 16.

Department of Neurology, University Medicine Rostock, Germany.

Background: Symptomatic epileptic seizures are an important complication in subarachnoid haemorrhage (SAH) with a frequency of 0.9-25% with importance for patient outcome. The majority of previous studies investigated the incidence of symptomatic epileptic seizures after aneurysmatic SAH. Here we compared the seizure incidence and its impact on the outcome between non-aneurysmatic and aneurysmatic SAH.

Methods: We analysed retrospectively 109 consecutive patients with spontaneous, non-traumatic SAH. Patients were divided in three groups (perimesencephalic, non-aneurysmatic and aneurysmatic SAH). All patients received standard-of-care treatment. The occurrence of acute (0-7 days after SAH) and remote symptomatic epileptic seizures (7 days or more after SAH), severity of SAH as well as clinical outcome parameters (modified Rankin scale [mRS]) at discharge and the frequency of in-house complications were assessed. mRS scores were dichotomized in 0-3 vs. 4-6 to stratify for good versus bad outcome.

Results: Perimesencephalic SAH patients did not experience acute seizures whereas non-aneurysmatic and aneurysmatic SAH patients showed acute seizures with similar frequency (9% and 11%, p = 0.23). The frequency of remote symptomatic seizures was similar in all subgroups (12% vs. 9% vs. 7%, p = 0.72). Seizure occurrence was not predictive for a poor outcome (mRS >4; acute seizures: OR 0.35 [95%CI: 0.02-6.96], p = 0.49; remote seizures: OR 1.72 [95%CI: 0.14-20.1], p = 0.67).

Conclusions: Seizures are important neurologic complications of SAH of all etiologies. Nevertheless, acute as well as remote symptomatic seizures are unrelated to the short-term outcome. These results should be treated as hypothesis generating and require confirmation.
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http://dx.doi.org/10.1016/j.jocn.2019.08.055DOI Listing
December 2019

Putaminal Dopamine Turnover in de novo Parkinson's Disease Predicts Later Neuropsychiatric Fluctuations but Not Other Major Health Outcomes.

J Parkinsons Dis 2019 ;9(4):693-704

Department of Neurology, University of Rostock, Rostock, Germany.

Background And Objective: To investigate the predictive value of striatal dopamine turnover in patients with de novo Parkinson's disease (PD) for later occurrence of major non-motor health outcomes.

Methods: This retrospective, observer-blinded cohort study followed up 29 patients with de novo PD for a median of 10.7 years, who completed 18Fluorodopa PET imaging to measure striatal effective distribution volume ratio (EDVR, inverse of dopamine turnover) prior to antiparkinsonian treatment. Outcomes were assessed with a battery of non-motor, health-related quality-of-life and non-motor fluctuation (WOQ-19) measures and survival.

Results: During follow-up, 52% of patients developed wearing-off, 43% neuropsychiatric fluctuations, 35% sensory fluctuations, 32% dementia, 46% depression, 30% psychosis, and PD-related mortality was 26%. Patients with wearing-off and neuropsychiatric fluctuations showed significantly lower baseline EDVR (higher dopamine turnover) in the putamen but not in the caudate nucleus than those without these fluctuations. Consistently, baseline EDVR in the putamen predicted development of wearing-off and neuropsychiatric fluctuations with a lower risk with higher EDVR (lower dopamine turnover), whereas EDVR in caudate nucleus did not correlate with these fluctuations. No relationships were observed between baseline PET measures and the presence of other major health outcomes including survival.

Conclusions: Lower putaminal dopamine turnover in de novo PD is associated with reduced risk for later neuropsychiatric fluctuations comprising a disease-intrinsic predisposing factor for their development, similar as reported for levodopa-induced motor complications. Striatal (putaminal/caudate) dopamine turnover is not predictive for other long-term major health outcomes. These results should be treated as hypothesis generating and require confirmation.
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http://dx.doi.org/10.3233/JPD-191672DOI Listing
July 2020

α-Synuclein in Parkinson's disease: causal or bystander?

J Neural Transm (Vienna) 2019 07 25;126(7):815-840. Epub 2019 Jun 25.

Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.

Parkinson's disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aβ) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration.
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http://dx.doi.org/10.1007/s00702-019-02025-9DOI Listing
July 2019

Disease stage dependency of motor and non-motor fluctuations in Parkinson's disease.

J Neural Transm (Vienna) 2019 07 19;126(7):841-851. Epub 2019 Jun 19.

Division of Neurology, Department of Clinical Sciences, Lund University, 22185, Lund, Sweden.

Recent data suggested a decrease in non-motor fluctuations in late-stage Parkinson's disease (PD), but systematic data on non-motor fluctuations over the whole disease course are mainly lacking. We performed a meta-analysis of two studies with very similar cross-sectional cohort designs, namely the German multicenter Non Motor Fluctuation in PD study and the Swedish part of the European multicenter study Care for Late Stage Parkinsonism. We included only patients with documented motor fluctuations in the analyses. Disease stage was estimated using the Hoehn and Yahr score, motor symptoms using the Unified PD Rating Scale part III motor score and non-motor symptom (NMS) fluctuations using the modified version of the NMS scale assessing a broad range of NMS in motor On and Off state. We included 101 patients (55% men; median age: 71 (interquartile range, IQR 65-78) years with Hoehn and Yahr stages ranging from 1 to 5 [median (IQR) 3.0 (2.0-4.0); distribution of patients in Hoehn and Yahr stages was n = 42 (42%) in stages 2/3 and n = 48 (48%) in stages 4/5]. We found a clear dependency of non-motor burden on Hoehn and Yahr stage with increasing symptom severity, but decreasing fluctuation amplitudes for motor and NMS (difference of symptom severity between On and Off state) with disease stage progression. Indeed, in Hoehn and Yahr stage 5, we did not detect significant NMS fluctuations. Multivariate regression with major demographic and clinical covariates confirmed these results. In conclusion, NMS fluctuations showed a similar disease stage dependency as observed for motor fluctuations with decreasing fluctuation amplitude with disease progression.
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http://dx.doi.org/10.1007/s00702-019-02033-9DOI Listing
July 2019

Structural brain signature of cognitive decline in Parkinson's disease: DTI-based evidence from the LANDSCAPE study.

Ther Adv Neurol Disord 2019 16;12:1756286419843447. Epub 2019 May 16.

Department of Neurology, University of Ulm, RKU, Oberer Eselsberg 45, Ulm 89081, Germany.

Background: The nonmotor symptom spectrum of Parkinson's disease (PD) includes progressive cognitive decline mainly in late stages of the disease. The aim of this study was to map the patterns of altered structural connectivity of patients with PD with different cognitive profiles ranging from cognitively unimpaired to PD-associated dementia.

Methods: Diffusion tensor imaging and neuropsychological data from the observational multicentre LANDSCAPE study were analyzed. A total of 134 patients with PD with normal cognitive function (56 PD-N), mild cognitive impairment (67 PD-MCI), and dementia (11 PD-D) as well as 72 healthy controls were subjected to whole-brain-based fractional anisotropy mapping and covariance analysis with cognitive performance measures.

Results: Structural data indicated subtle changes in the corpus callosum and thalamic radiation in PD-N, whereas severe white matter impairment was observed in both PD-MCI and PD-D patients including anterior and inferior fronto-occipital, uncinate, insular cortices, superior longitudinal fasciculi, corona radiata, and the body of the corpus callosum. These regional alterations were demonstrated for PD-MCI and were more pronounced in PD-D. The pattern of involved regions was significantly correlated with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score.

Conclusions: The findings in PD-N suggest impaired cross-hemispherical white matter connectivity that can apparently be compensated for. More pronounced involvement of the corpus callosum as demonstrated for PD-MCI together with affection of fronto-parieto-temporal structural connectivity seems to lead to gradual disruption of cognition-related cortico-cortical networks and to be associated with the onset of overt cognitive deficits. The increase of regional white matter damage appears to be associated with the development of PD-associated dementia.
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http://dx.doi.org/10.1177/1756286419843447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535714PMC
May 2019

No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors.

Transl Neurodegener 2019 3;8:11. Epub 2019 Apr 3.

1Department of Neurology, University Hospital Schleswig Holstein, Arnold-Heller Str. 3, 24105 Kiel, Germany.

Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment ( = 296) and controls ( = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.

Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.

Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.

Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
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http://dx.doi.org/10.1186/s40035-019-0153-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446289PMC
April 2019

Prognostic factors in ALS: a comparison between Germany and China.

J Neurol 2019 Jun 28;266(6):1516-1525. Epub 2019 Mar 28.

Department of Neurology, Universitätsklinik Ulm, RKU, Oberer Eselsberg 45, 89081, Ulm, Germany.

Objective: Several independent prognostic factors, such as age of onset, type of onset, body mass index (BMI), and progression rate have been identified for amyotrophic lateral sclerosis (ALS) in Caucasians. The aim of this study was to identify such factors in Chinese patients and to compare their impact with German patients.

Methods: Comparison of prognostic factors was based on two hospital-based registries. The registry of the German Network for Motor Neuron Diseases contains 3100 patients with ALS. The Chinese registry comprises 2101 patients who were collected between 2003 and 2015 in the metropolitan area of Beijing.

Results: Disease progression was slower in China [median loss of 0.50 points (IQR 0.26-0.87 points) versus 0.55 points (IQR 0.28-1.00 points) of ALS functional rating scale revised (ALS-FRS-R) score per month; p < 0.0001]. Survival of patients with ALS was similar in Germany and China (p > 0.05). We found that younger age of onset (p < 0.0001), spinal onset (p < 0.0001), high BMI (p < 0.0001) and low progression rate (p < 0.0001) were positive prognostic factors in China as well as in Germany.

Interpretation: Prognostic factors, which are known to modify the course of disease in Caucasians, apply to Chinese patients as well. The results indicate that despite the apparent differences regarding genotype and clinical phenotype, findings from interventional studies in Caucasians aiming at disease-modifying prognostic factors (such as body weight) may be transferred to Chinese patients.
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http://dx.doi.org/10.1007/s00415-019-09290-4DOI Listing
June 2019

Atrophy of the Vagus Nerve in Parkinson's Disease Revealed by High-Resolution Ultrasonography.

Front Neurol 2018 27;9:805. Epub 2018 Sep 27.

Department of Neurology, University of Rostock, Rostock, Germany.

The vagus nerve has been suggested to represent one major route of disease progression in Parkinson's disease (PD). Here, we examined whether patients with idiopathic PD exhibit an atrophy of the vagus nerve in comparison to age-matched controls. In this cross-sectional study, performed between July 2017 and January 2018, we measured the caliber (cross-sectional area) of the mid-cervical vagus, accessory and phrenic nerves in 20 patients with PD (disease duration: 10.1 ± 7.4 years) and 61 (including 20 age-matched) controls using high-resolution ultrasonography. Ultrasonography and assessments of autonomic function were performed by blinded raters. Mean vagus nerve calibers were lower in patients with PD compared to age-matched controls (right: 0.64 ± 0.17 vs. 1.04 ± 0.20; left: 0.69 ± 0.18 vs. 0.87 ± 0.15 mm; < 0.001) while accessory and phrenic nerve calibers did not differ. In controls, age correlated negatively with calibers of the accessory and the phrenic nerve (each ≤ 0.001), and trended to correlate with vagus nerve caliber ( = 0.023). In patients with PD and age-matched controls combined, the summed caliber of the right and left vagus nerves correlated with the burden of autonomic symptoms on the PD Non-Motor Symptoms Questionnaire ( = -0.46; = 0.003). Moreover, the caliber of the right but not of the left vagus nerve correlated with the parasympathetic domain of heart rate variability ( = 0.58; = 0.001). PD is associated with a bilateral atrophy of the vagus nerve but not of the spinal accessory or the phrenic nerves. Our findings suggest that viscero-afferent and viscero-efferent vagal fibers are predominantly affected in PD.
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http://dx.doi.org/10.3389/fneur.2018.00805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170613PMC
September 2018

Cognitive decline in Parkinson's disease: the impact of the motor phenotype on cognition.

J Neurol Neurosurg Psychiatry 2019 02 8;90(2):171-179. Epub 2018 Oct 8.

Department of Neurology, RWTH Aachen University, Pauwelsstraße 30, Aachen, Germany

Objectives: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is further associated with progressive cognitive decline. In respect to motor phenotype, there is some evidence that akinetic-rigid PD is associated with a faster rate of cognitive decline in general and a greater risk of developing dementia.The objective of this study was to examine cognitive profiles among patients with PD by motor phenotypes and its relation to cognitive function.

Methods: Demographic, clinical and neuropsychological cross-sectional baseline data of the DEMPARK/LANDSCAPE study, a multicentre longitudinal cohort study of 538 patients with PD were analysed, stratified by motor phenotype and cognitive syndrome. Analyses were performed for all patients and for each diagnostic group separately, controlling for age, gender, education and disease duration.

Results: Compared with the tremor-dominant phenotype, akinetic-rigid patients performed worse in executive functions such as working memory (Wechsler Memory Scale-Revised backward; p=0.012), formal-lexical word fluency (p=0.043), card sorting (p=0.006), attention (Trail Making Test version A; p=0.024) and visuospatial abilities (Leistungsprüfungssystem test 9; p=0.006). Akinetic-rigid neuropsychological test scores for the executive and attentive domain correlated negatively with non-tremor motor scores. Covariate-adjusted binary logistic regression analyses showed significant odds for PD-mild cognitive impairment for not-determined as compared with tremor-dominant (OR=3.198) and akinetic-rigid PD (OR=2.059). The odds for PD-dementia were significant for akinetic-rigid as compared with tremor-dominant phenotype (OR=8.314).

Conclusion: The three motor phenotypes of PD differ in cognitive performance, showing that cognitive deficits seem to be less severe in tremor-dominant PD. While these data are cross-sectional, longitudinal data are needed to shed more light on these differential findings.
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http://dx.doi.org/10.1136/jnnp-2018-319008DOI Listing
February 2019

Functional monoamine oxidase B gene intron 13 polymorphism predicts putaminal dopamine turnover in de novo Parkinson's disease.

Mov Disord 2018 09 14;33(9):1496-1501. Epub 2018 Sep 14.

Department of Neurology, University of Rostock, Rostock, Germany.

Objective: The objective of this study was to evaluate the effects of common functional polymorphisms in genes involved in dopamine metabolism on striatal dopamine turnover in de novo Parkinson's disease (PD).

Methods: This was an observer-blinded cohort study investigating effects of common functional polymorphisms in dopa decarboxylase (DDC, rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT, rs4680), and dopamine transporter/solute carrier family 6 member 3 (DAT/SLC6A3, variable number tandem repeats) genes on F-fluorodopa uptake and an effective distribution volume ratio (inverse of dopamine turnover) measured by F-fluorodopa PET in 28 untreated PD patients.

Results: Patients carrying the MAOB genotype (low/intermediate enzyme activity) had a lower dopamine turnover in the putamen (higher mean effective distribution volume ratio) when compared with patients with MAOB genotype (high enzyme activity). Striatal PET measures were not different between variants in the remaining genes.

Conclusions: The MAOB (rs1799836) polymorphism predicts putaminal dopamine turnover in early PD with the MAOB allele linked to high enzyme activity leading to higher intrinsic dopamine turnover, which has been demonstrated to constitute a risk factor for motor complications. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27466DOI Listing
September 2018

Psychometric Properties of an Abbreviated Version of the Apathy Evaluation Scale for Parkinson Disease (AES-12PD).

Am J Geriatr Psychiatry 2018 10 30;26(10):1079-1090. Epub 2018 Jun 30.

Institute of Clinical Psychology and Psychotherapy, Department of Psychology, Technische Universität Dresden, Dresden, Germany; Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology - BIPS GmbH, Bremen, Germany.

Background: Apathy is a frequent symptom in Parkinson's disease (PD), substantially aggravating the course of PD. Regarding the accumulating evidence of the key role of apathy in PD, time-efficient assessments are useful for fostering progress in research and treatment. The Apathy Evaluation Scale (AES) is widely used for the assessment of apathy across different nosologies.

Objective: To facilitate the application of the AES in PD, we reduced the AES to two-thirds its length and validated this abbreviated version.

Design: Data sets of 339 PD patients of the DEMPARK/LANDSCAPE study without dementia and depression were randomly split into two samples. Data of sample 1 were used to develop a brief version of the AES (AES-12PD). A cross-validation was conducted in sample 2 and in a subsample of 42 PD patients with comorbid dementia and depressive symptomatology. Receiver operating characteristic analysis was applied to determine the optimal cutoff of the AES-12PD as an indicator of apathy.

Results: The AES-12PD featured high internal consistency that was better compared to the AES. The abbreviated scale was well differentiated from motor impairment and cognitive deficits. The AES-12PD cutoff of 27/28 was the optimal cutoff for apathy in PD patients without dementia and depression. The cutoff of 25/26 indicated apathy in PD patients with comorbid dementia and depression.

Conclusion: Results confirm a high internal consistency and good discriminant validity of the AES-12PD. The AES-12PD represents a reliable tool for the efficient assessment of apathy that can be applied in PD patients with and without dementia and depression.
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http://dx.doi.org/10.1016/j.jagp.2018.06.012DOI Listing
October 2018

Defective mitochondrial and lysosomal trafficking in chorea-acanthocytosis is independent of Src-kinase signaling.

Mol Cell Neurosci 2018 10 3;92:137-148. Epub 2018 Aug 3.

Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany; Universitäts Centrum für seltene Erkrankungen, Technische Universität Dresden, Dresden, Germany. Electronic address:

Mutations in the VPS13A gene leading to depletion of chorein protein are causative for Chorea Acanthocytosis (ChAc), a rare devastating disease, which is characterized by neurodegeneration mainly affecting the basal ganglia as well as deformation of erythrocytes. Studies on patient blood samples highlighted a dysregulation of Actin cytoskeleton caused by downregulation of the PI3K pathway and hyper-activation of Lyn-kinase, but to what extent these mechanisms are present and relevant in the affected neurons remains elusive. We studied the effects of the absence of chorein protein on the morphology and trafficking of lysosomal and mitochondrial compartments in ChAc patient-specific induced pluripotent stem cell-derived medium spiny neurons (MSNs). Numbers of both organelle types were reduced in ChAc MSNs. Mitochondrial length was shortened and their membrane potential showed significant hyperpolarization. In contrast to previous studies, showing Lyn kinase dependency of ChAc-associated pathological events in erythrocytes, pharmacological studies demonstrate that the impairment of mitochondria and lysosomes are independent of Lyn kinase activity. These data suggest that impairment in mitochondrial and lysosomal morphologies in MSNs is not mediated by a dysregulation of Lyn kinase and thus the pathological pathways in ChAc might be - at least in part - cell-type specific.
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http://dx.doi.org/10.1016/j.mcn.2018.08.002DOI Listing
October 2018