Refine
Has Fulltext
- yes (40)
Is part of the Bibliography
- yes (40)
Year of publication
Document Type
- Journal article (40)
Language
- English (40)
Keywords
- Fabry disease (10)
- neuropathic pain (7)
- pain (6)
- fibromyalgia syndrome (5)
- cytokines (4)
- depression (3)
- gene expression (3)
- small fiber neuropathy (3)
- B7-H1 (2)
- Fabry-associated pain (2)
- Fibromyalgia syndrome (2)
- Mechanisms (2)
- chronic pain (2)
- diagnosis (2)
- enzyme replacement therapy (2)
- inflammation (2)
- mouse model (2)
- mouse models (2)
- renal system (2)
- skin punch biopsy (2)
- A-delta fibers (1)
- ALS mimic (1)
- Anxiety (1)
- Arterial Diameters (1)
- Aδ- and C-fibers (1)
- CCI (1)
- CNS imaging (1)
- Capsaicin receptor (1)
- CholinomiRs (1)
- Cognitive behavior (1)
- Cold (1)
- Corneal confocal microscopy (1)
- Cytokines (1)
- El Escorial (1)
- English version (1)
- Expression (1)
- Fabry genotype (1)
- Fabry phenotype (1)
- Factor messenger-RNA (1)
- Gene-expression (1)
- Gland (1)
- Heat Hyperalgesia (1)
- Hyperalgesia (1)
- IL-4 (1)
- Identification (1)
- Immune system (1)
- Innervation (1)
- Interleukin-6 (1)
- Interleukin-6-Deficient mice (1)
- Langerhans cells (1)
- Leukemia Inhibitory Factor (1)
- Mediated Inflammatory Hyperalgesia (1)
- Monopolar depression (1)
- NF-κB (1)
- Necrosis-factor-Alpha (1)
- Nerve growth-factorcopy (1)
- Neurogenic inflammation (1)
- Oncostatin-M-Receptor (1)
- Opioid receptor (1)
- PD-L1 (1)
- PET (1)
- Pain questionnaire (1)
- Pain-related evoked potentials (1)
- Paradoxical heat sensation (1)
- Parkinson's disease (1)
- Peripheral Inflammation (1)
- Pleckstrin homology containing family member 5 (Plekhg5) (1)
- RNA extraction (1)
- Rat Sensory Neurons (1)
- Receptors (1)
- Rheumatoid-Arthritis (1)
- SNI (1)
- Schwann cell (1)
- Schwann-cells (1)
- Sensitivity (1)
- Skin biopsy (1)
- Small fiber neuropathy (1)
- Stimuli (1)
- TNFα (1)
- TRP Channels (1)
- Thermal Hyperalgesia (1)
- X-chromosomal inactivation (1)
- algorithm (1)
- allodynia (1)
- alpha-galactosidase A (1)
- analgesia (1)
- animal behavior (1)
- antagomir (1)
- apheresis technologies (1)
- apheresis-therapeutic (1)
- autophagy (1)
- biomarker (1)
- biopsy (1)
- blood flow (1)
- blood processing (1)
- brain (1)
- burning pain (1)
- capsaicin (1)
- central nervous system (1)
- cerebral arteries (1)
- cholinergic system (1)
- classification (1)
- cognitive impairment (1)
- coping (1)
- corneal confocal microscopy (1)
- cortical activation (1)
- criteria (1)
- crossover trial (1)
- cutaneous innervation (1)
- cutaneous patch (1)
- diagnosis in Fabry disease (1)
- diagnostic medicine (1)
- disability (1)
- epidermis (1)
- expression (1)
- female Fabry patients (1)
- females (1)
- fibromyalgia (1)
- flotillin-1 lipid rafts (1)
- gene variant (1)
- genetics (1)
- genotype/phenotype correlation (1)
- globotriaosylceramide (1)
- guidelines (1)
- haemostasis (1)
- hernia repair (1)
- hyperalgesia (1)
- immune system (1)
- immunofluorescence (1)
- innervation (1)
- interference (1)
- intraepidermal nerve fiber density (1)
- ion channels (1)
- ischemic stroke (1)
- learning (1)
- lesions (1)
- long-term pain (1)
- lyso-Gb3 (1)
- lysosomal storage disease (1)
- macrophages (1)
- magnetic resonance imaging (1)
- miR-182-5p (1)
- miR-21 (1)
- miRNA (1)
- miRNA expression patterns (1)
- miRNA polymorphisms (1)
- miRNA-based analgesic (1)
- miRNA-based diagnostics (1)
- mice (1)
- microRNA (1)
- midbrain (1)
- migraine (1)
- mixed fiber neuropathy (1)
- motoneuron disease (1)
- motor neuron disease (1)
- muscle atrophy (1)
- near-infrared spectroscopy (1)
- nerve fibers (1)
- nerve fibres (1)
- nerve ultrasonography (1)
- nerve-fibers (1)
- neuroborreliosis (1)
- neurological examination (1)
- neurology (1)
- neuropathy (1)
- nociceptor sensitization (1)
- opioid (1)
- opioids (1)
- pain questionnaire (1)
- pain sensation (1)
- pain-associated behavior (1)
- pain-related evoked potentials (1)
- peripheral nerve involvement (1)
- peripheral neuropathy (1)
- plasma (1)
- polymorphism (1)
- polyneuropathy (1)
- postherpetic neuralgia (1)
- proinflammatory cytokine (1)
- quantitative sensory testing (1)
- qutenza (1)
- regulation (1)
- reinnervation (1)
- religiosity (1)
- risk factors (1)
- scale (1)
- sciatic nerves (1)
- shingles (1)
- skin diseases (1)
- skin tumors (1)
- small-fiber neuropathy (1)
- spinal cord (1)
- stroke (1)
- substance-P (1)
- superficial peroneal nerve (1)
- sural nerve (1)
- swimming (1)
- synaptic vesicles (1)
- transient receptor potential vanilloid 1 (TRPV1) (1)
- ultrasound imaging (1)
- validation (1)
- vasculitis (1)
- white blood cells (1)
Institute
- Neurologische Klinik und Poliklinik (38)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (4)
- Medizinische Klinik und Poliklinik I (4)
- Institut für Klinische Epidemiologie und Biometrie (2)
- Institut für Klinische Neurobiologie (2)
- Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie) (2)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (1)
- Institut für Humangenetik (1)
- Institut für Klinische Transfusionsmedizin und Hämotherapie (1)
- Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) (1)
Sonstige beteiligte Institutionen
Polyneuropathy (PNP) is a term to describe diseases of the peripheral nervous system, 50% of which present with neuropathic pain. In some types of PNP, pain is restricted to the skin distally in the leg, suggesting a local regulatory process leading to pain. In this study, we proposed a pro-inflammatory pathway mediated by NF-κB that might be involved in the development of pain in patients with painful PNP. To test this hypothesis, we have collected nerve and skin samples from patients with different etiologies and levels of pain. We performed RT-qPCR to analyze the gene expression of the proposed inflammatory pathway components in sural nerve and in distal and proximal skin samples. In sural nerve, we showed a correlation of TLR4 and TNFα to neuropathic pain, and an upregulation of TNFα in patients with severe pain. Patients with an inflammatory PNP also presented a lower expression of TRPV1 and SIRT1. In distal skin, we found a reduced expression of TLR4 and miR-146-5p, in comparison to proximal skin. Our findings thus support our hypothesis of local inflammatory processes involved in pain in PNP, and further show disturbed anti-inflammatory pathways involving TRPV1 and SIRT1 in inflammatory PNP.
Introduction/Aims
Schwann cell clusters have been described at the murine dermis-epidermis border. We quantified dermal Schwann cells in the skin of patients with small-fiber neuropathy (SFN) compared with healthy controls to correlate with the clinical phenotype.
Methods
Skin punch biopsies from the lower legs of 28 patients with SFN (11 men, 17 women; median age, 54 [range, 19-73] years) and 9 healthy controls (five men, four women, median age, 34 [range, 25-69] years) were immunoreacted for S100 calcium-binding protein B as a Schwann cell marker, protein-gene product 9.5 as a pan-neuronal marker, and CD207 as a Langerhans cell marker. Intraepidermal nerve fiber density (IENFD) and subepidermal Schwann cell counts were determined.
Results
Skin samples of patients with SFN showed lower IENFD (P < .05), fewer Schwann cells per millimeter (P < .01), and fewer Schwann cell clusters per millimeter (P < .05) than controls. When comparing SFN patients with reduced (n = 13; median age, 53 [range, 19-73] years) and normal distal (n = 15, median age, 54 [range, 43-68] years) IENFD, the number of solitary Schwann cells per millimeter (p < .01) and subepidermal nerve fibers associated with Schwann cell branches (P < .05) were lower in patients with reduced IENFD. All three parameters correlated positively with distal IENFD (P < .05 to P < .01), whereas no correlation was found between Schwann cell counts and clinical pain characteristics.
Discussion
Our data raise questions about the mechanisms underlying the interdependence of dermal Schwann cells and skin innervation in SFN. The temporal course and functional impact of Schwann cell presence and kinetics need further investigation.
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with potential severe consequences. Its pathogenesis involves hyperglycemia-linked mechanisms, which may include changes in the expression of neurotrophic growth factors. We analyzed the expression of 29 factors potentially related to nerve degeneration and regeneration in skin biopsies from 13 type 1 diabetic pancreas and kidney recipients with severe DPN including severe depletion of intraepidermal nerve fibers (IENF) in lower limb skin biopsies (group Tx1 1st examination). The investigation was repeated after a median 28-month period of normoglycemia achieved by pancreas transplantation (group Tx1 2nd examination). The same tests were performed in 13 stable normoglycemic pancreas and kidney recipients 6-12 years posttransplantation (group Tx2), in 12 matched healthy controls (group HC), and in 12 type 1 diabetic subjects without severe DPN (group DM). Compared to DM and HC groups, we found a significantly higher (p < 0.05-0.001) expression of NGF (nerve growth factor), NGFR (NGF receptor), NTRK1 (neurotrophic receptor tyrosine kinase 1), GDNF (glial cell-derived neurotrophic factor), GFRA1 (GDNF family receptor alpha 1), and GFAP (glial fibrillary acidic protein) in both transplant groups (Tx1 and Tx2). Enhanced expression of these factors was not normalized following the median 28-month period of normoglycemia (Tx1 2nd examination) and negatively correlated with IENF density and with electrophysiological indices of DPN (vibration perception threshold, electromyography, and autonomic tests). In contrast to our expectation, the expression of most of 29 selected factors related to neural regeneration was comparable in subjects with severe peripheral nerve fiber depletion and healthy controls and the expression of six factors was significantly upregulated. These findings may be important for better understanding the pathophysiology of nerve regeneration and for the development of intervention strategies.
Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson's disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.
Objectives
The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS.
Methods
Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis.
Results
Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p<0.05), but not different from that of patients with depression and accompanying physical pain. Pain and FMS symptom burden did not correlate with midbrain raphe echogenicity as well as the presence and severity of depressive symptoms.
Conclusion
We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression.
Background
Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women.
Patients and Methods
We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity.
Results
43/95 (45%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25% distribution) in 6/87 (7%) mouth epithelial cell samples, 31/88 (35%) blood samples, and 9/27 (33%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome.
Conclusions
X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.
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.
Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.
Background
The role of cytokines in the pathophysiology, diagnosis, and prognosis of small fiber neuropathy (SFN) is incompletely understood. We studied expression profiles of selected pro- and anti-inflammatory cytokines in RNA from white blood cells (WBC) of patients with a medical history and a clinical phenotype suggestive for SFN and compared data with healthy controls.
Methods
We prospectively recruited 52 patients and 21 age- and sex-matched healthy controls. Study participants were characterized in detail and underwent complete neurological examination. Venous blood was drawn for routine and extended laboratory tests, and for WBC isolation. Systemic RNA expression profiles of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-2, IL-8, tumor necrosis factor-alpha (TNF) and the anti-inflammatory cytokines IL-4, IL-10, transforming growth factor beta-1 (TGF) were analyzed. Protein levels of IL-2, IL-8, and TNF were measured in serum of patients and controls. Receiver operating characteristic (ROC)-curve analysis was used to determine the accuracy of IL-2, IL-8, and TNF in differentiating patients and controls. To compare the potential discriminatory efficacy of single versus combined cytokines, equality of different AUCs was tested.
Results
WBC gene expression of IL-2, IL-8, and TNF was higher in patients compared to healthy controls (IL-2: p = 0.02; IL-8: p = 0.009; TNF: p = 0.03) and discriminated between the groups (area under the curve (AUC) ≥ 0.68 for each cytokine) with highest diagnostic accuracy reached by combining the three cytokines (AUC = 0.81, sensitivity = 70%, specificity = 86%). Subgroup analysis revealed the following differences: IL-8 and TNF gene expression levels were higher in female patients compared to female controls (IL-8: p = 0.01; TNF: p = 0.03). The combination of TNF with IL-2 and TNF with IL-2 and IL-8 discriminated best between the study groups. IL-2 was higher expressed in patients with moderate pain compared to those with severe pain (p = 0.02). Patients with acral pain showed higher IL-10 gene expression compared to patients with generalized pain (p = 0.004). We further found a negative correlation between the relative gene expression of IL-2 and current pain intensity (p = 0.02). Serum protein levels of IL-2, IL-8, and TNF did not differ between patients and controls.
Conclusions
We identified higher systemic gene expression of IL-2, IL-8, and TNF in SFN patients than in controls, which may be of potential relevance for diagnostics and patient stratification.
CNS imaging characteristics in fibromyalgia patients with and without peripheral nerve involvement
(2022)
We tested the hypothesis that reduced skin innervation in fibromyalgia syndrome is associated with specific CNS changes. This prospective case–control study included 43 women diagnosed with fibromyalgia syndrome and 40 healthy controls. We further compared the fibromyalgia subgroups with reduced (n = 21) and normal (n = 22) skin innervation. Brains were analysed for cortical volume, for white matter integrity, and for functional connectivity. Compared to controls, cortical thickness was decreased in regions of the frontal, temporal and parietal cortex in the fibromyalgia group as a whole, and decreased in the bilateral pericalcarine cortices in the fibromyalgia subgroup with reduced skin innervation. Diffusion tensor imaging revealed a significant increase in fractional anisotropy in the corona radiata, the corpus callosum, cingulum and fornix in patients with fibromyalgia compared to healthy controls and decreased FA in parts of the internal capsule and thalamic radiation in the subgroup with reduced skin innervation. Using resting-state fMRI, the fibromyalgia group as a whole showed functional hypoconnectivity between the right midfrontal gyrus and the posterior cerebellum and the right crus cerebellum, respectively. The subgroup with reduced skin innervation showed hyperconnectivity between the inferior frontal gyrus, the angular gyrus and the posterior parietal gyrus. Our results suggest that the subgroup of fibromyalgia patients with pronounced pathology in the peripheral nervous system shows alterations in morphology, structural and functional connectivity also at the level of the encephalon. We propose considering these subgroups when conducting clinical trials.