Neurologische Klinik und Poliklinik
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Recent advances in proteomic technologies now allow unparalleled assessment of the molecular composition of a wide range of sample types. However, the application of such technologies and techniques should not be undertaken lightly. Here, we describe why the design of a proteomics experiment itself is only the first step in yielding high-quality, translatable results. Indeed, the effectiveness and/or impact of the majority of contemporary proteomics screens are hindered not by commonly considered technical limitations such as low proteome coverage but rather by insufficient analyses. Proteomic experimentation requires a careful methodological selection to account for variables from sample collection, through to database searches for peptide identification to standardised post-mass spectrometry options directed analysis workflow, which should be adjusted for each study, from determining when and how to filter proteomic data to choosing holistic versus trend-wise analyses for biologically relevant patterns. Finally, we highlight and discuss the difficulties inherent in the modelling and study of the majority of progressive neurodegenerative conditions. We provide evidence (in the context of neurodegenerative research) for the benefit of undertaking a comparative approach through the application of the above considerations in the alignment of publicly available pre-existing data sets to identify potential novel regulators of neuronal stability.
Freezing of gait (FOG) is a sudden episodic inability to produce effective stepping despite the intention to walk. It typically occurs during gait initiation (GI) or modulation and may lead to falls. We studied the anticipatory postural adjustments (imbalance, unloading, and stepping phase) at GI in 23 patients with Parkinson’s disease (PD) and FOG (PDF), 20 patients with PD and no previous history of FOG (PDNF), and 23 healthy controls (HCs). Patients performed the task when off dopaminergic medications. The center of pressure (CoP) displacement and velocity during imbalance showed significant impairment in both PDNF and PDF, more prominent in the latter patients. Several measurements were specifically impaired in PDF patients, especially the CoP displacement along the anteroposterior axis during unloading. The pattern of segmental center of mass (SCoM) movements did not show differences between groups. The standing postural profile preceding GI did not correlate with outcome measurements. We have shown impaired motor programming at GI in Parkinsonian patients. The more prominent deterioration of unloading in PDF patients might suggest impaired processing and integration of somatosensory information subserving GI. The unaltered temporal movement sequencing of SCoM might indicate some compensatory cerebellar mechanisms triggering time-locked models of body mechanics in PD.
Background
Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future.
Methods
This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years.
Results
Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy.
Conclusion
These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.
Efficacy of transcranial direct current stimulation in people with multiple sclerosis: a review
(2022)
Background and purpose
Multiple sclerosis (MS) is a chronic inflammatory disease causing a wide range of symptoms including motor and cognitive impairment, fatigue and pain. Over the last two decades, non-invasive brain stimulation, especially transcranial direct current stimulation (tDCS), has increasingly been used to modulate brain function in various physiological and pathological conditions. However, its experimental applications for people with MS were noted only as recently as 2010 and have been growing since then. The efficacy for use in people with MS remains questionable with the results of existing studies being largely conflicting. Hence, the aim of this review is to paint a picture of the current state of tDCS in MS research grounded on studies applying tDCS that have been done to date.
Methods
A keyword search was performed to retrieve articles from the earliest article identified until 14 February 2021 using a combination of the groups (1) ‘multiple sclerosis’, ‘MS’ and ‘encephalomyelitis’ and (2) ‘tDCS’ and ‘transcranial direct current stimulation’.
Results
The analysis of the 30 articles included in this review underlined inconsistent effects of tDCS on the motor symptoms of MS based on small sample sizes. However, tDCS showed promising benefits in ameliorating fatigue, pain and cognitive symptoms.
Conclusion
Transcranial direct current stimulation is attractive as a non-drug approach in ameliorating MS symptoms, where other treatment options remain limited. The development of protocols tailored to the individual's own neuroanatomy using high definition tDCS and the introduction of network mapping in the experimental designs might help to overcome the variability between studies.
Objective: Gait adaptation to environmental challenges is fundamental for independent and safe community ambulation. The possibility of precisely studying gait modulation using standardized protocols of gait analysis closely resembling everyday life scenarios is still an unmet need.
Methods: We have developed a fully-immersive virtual reality (VR) environment where subjects have to adjust their walking pattern to avoid collision with a virtual agent (VA) crossing their gait trajectory. We collected kinematic data of 12 healthy young subjects walking in real world (RW) and in the VR environment, both with (VR/A+) and without (VR/A-) the VA perturbation. The VR environment closely resembled the RW scenario of the gait laboratory. To ensure standardization of the obstacle presentation the starting time speed and trajectory of the VA were defined using the kinematics of the participant as detected online during each walking trial.
Results: We did not observe kinematic differences between walking in RW and VR/A-, suggesting that our VR environment per se might not induce significant changes in the locomotor pattern. When facing the VA all subjects consistently reduced stride length and velocity while increasing stride duration. Trunk inclination and mediolateral trajectory deviation also facilitated avoidance of the obstacle.
Conclusions: This proof-of-concept study shows that our VR/A+ paradigm effectively induced a timely gait modulation in a standardized immersive and realistic scenario. This protocol could be a powerful research tool to study gait modulation and its derangements in relation to aging and clinical conditions.
Background
Long-term support of stroke patients living at home is often delivered by family caregivers (FC). We identified characteristics of stroke patients being associated with receiving care by a FC 3-months (3 M) after stroke, assessed positive and negative experiences and individual burden of FC caring for stroke patients and determined factors associated with caregiving experiences and burden of FC 3 M after stroke.
Methods
Data were collected within TRANSIT-Stroke, a regional telemedical stroke-network comprising 12 hospitals in Germany. Patients with stroke/TIA providing informed consent were followed up 3 M after the index event. The postal patient-questionnaire was accompanied by an anonymous questionnaire for FC comprising information on positive and negative experiences of FC as well as on burden of caregiving operationalized by the Caregiver Reaction Assessment and a self-rated burden-scale, respectively. Multivariable logistic and linear regression analyses were performed.
Results
Between 01/2016 and 06/2019, 3532 patients provided baseline and 3 M-follow-up- data and 1044 FC responded to questionnaires regarding positive and negative caregiving experiences and caregiving burden. 74.4% of FC were older than 55 years, 70.1% were women and 67.5% were spouses. Older age, diabetes and lower Barthel-Index in patients were significantly associated with a higher probability of receiving care by a FC at 3 M. Positive experiences of FC comprised the importance (81.5%) and the privilege (70.0%) of caring for their relative; negative experiences of FC included financial difficulties associated with caregiving (20.4%). Median overall self-rated burden was 30 (IQR: 0–50; range 0–100). Older age of stroke patients was associated with a lower caregiver burden, whereas younger age of FC led to higher burden. More than half of the stroke patients in whom a FC questionnaire was completed did self-report that they are not being cared by a FC. This stroke patient group tended to be younger, more often male with less severe stroke and less comorbidities who lived more often with a partner.
Conclusions
The majority of caregivers wanted to care for their relatives but experienced burden at the same time. Elderly patients, patients with a lower Barthel Index at discharge and diabetes are at higher risk of needing care by a family caregiver.
Trial registration
The study was registered at “German Clinical Trial Register”: DRKS00011696. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011696
Background:
Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning.
Methods
Thirteen adolescent male patients (9–16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-β-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH.
Results
On-MPH status was associated with a highly significant change (−29.9%) of striatal DAT BP as compared to off-MPH (t = −4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04).
Conclusion
Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject’s brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5\(^{-/-}\) mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5\(^{-/-}\) mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry.
In large vessel occlusion stroke, recanalization to restore cerebral perfusion is essential but not necessarily sufficient for a favorable outcome. Paradoxically, in some patients, reperfusion carries the risk of increased tissue damage and cerebral hemorrhage. Experimental and clinical data suggest that endothelial cells, representing the interface for detrimental platelet and leukocyte responses, likely play a crucial role in the phenomenon referred to as ischemia/reperfusion (I/R)-injury, but the mechanisms are unknown. We aimed to determine the role of endoglin in cerebral I/R-injury; endoglin is a membrane-bound protein abundantly expressed by endothelial cells that has previously been shown to be involved in the maintenance of vascular homeostasis. We investigated the expression of membranous endoglin (using Western blotting and RT-PCR) and the generation of soluble endoglin (using an enzyme-linked immunosorbent assay of cell culture supernatants) after hypoxia and subsequent reoxygenation in human non-immortalized brain endothelial cells. To validate these in vitro data, we additionally examined endoglin expression in an intraluminal monofilament model of permanent and transient middle cerebral artery occlusion in mice. Subsequently, the effects of recombinant human soluble endoglin were assessed by label-free impedance-based measurement of endothelial monolayer integrity (using the xCELLigence DP system) and immunocytochemistry. Endoglin expression is highly inducible by hypoxia in human brain endothelial monolayers in vitro, and subsequent reoxygenation induced its shedding. These findings were corroborated in mice during MCAO; an upregulation of endoglin was displayed in the infarcted hemispheres under occlusion, whereas endoglin expression was significantly diminished after transient MCAO, which is indicative of shedding. Of note is the finding that soluble endoglin induced an inflammatory phenotype in endothelial monolayers. The treatment of HBMEC with endoglin resulted in a decrease in transendothelial resistance and the downregulation of VE-cadherin. Our data establish a novel mechanism in which hypoxia triggers the initial endothelial upregulation of endoglin and subsequent reoxygenation triggers its release as a vasoactive mediator that, when rinsed into adjacent vascular beds after recanalization, can contribute to cerebral reperfusion injury.
Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is a mainstay of acute ischemic stroke treatment but is associated with bleeding complications, especially after prolonged large vessel occlusion. Recently, inhibition of the NLRP3 inflammasome led to preserved blood–brain barrier (BBB) integrity in experimental stroke in vivo. To further address the potential of NLRP3 inflammasome inhibition as adjunct stroke treatment we used immortalized brain derived endothelial cells (bEnd5) as an in vitro model of the BBB. We treated bEnd5 with rt-PA in combination with the NLRP3 specific inhibitor MCC950 or vehicle under normoxic as well as ischemic (OGD) conditions. We found that rt-PA exerted a cytotoxic effect on bEnd5 cells under OGD confirming that rt-PA is harmful to the BBB. This detrimental effect could be significantly reduced by MCC950 treatment. Moreover, under ischemic conditions, the Cell Index — a sensible indicator for a patent BBB — and the protein expression of Zonula occludens 1 stabilized after MCC950 treatment. At the same time, the extent of endothelial cell death and NLRP3 expression decreased. In conclusion, NLRP3 inhibition can protect the BBB from rt-PA-induced damage and thereby potentially increase the narrow time window for safe thrombolysis in stroke.