Propionic acid promotes neurite recovery in damaged multiple sclerosis neurons.

Neurodegeneration in the autoimmune disease multiple sclerosis still poses a major therapeutic challenge. Effective drugs that target the inflammation can only partially reduce accumulation of neurological deficits and conversion to progressive disease forms. Diet and the associated gut microbiome are currently being discussed as crucial environmental risk factors that determine disease onset and subsequent progression. In people with multiple sclerosis, supplementation of the short-chain fatty acid propionic acid, as a microbial metabolite derived from the fermentation of a high-fiber diet, has previously been shown to regulate inflammation accompanied by neuroprotective properties. We set out to determine whether the neuroprotective impact of propionic acid is a direct mode of action of short-chain fatty acids on CNS neurons. We analysed neurite recovery in the presence of the short-chain fatty acid propionic acid and butyric acid in a reverse-translational disease-in-a-dish model of human-induced primary neurons differentiated from people with multiple sclerosis-derived induced pluripotent stem cells. We found that recovery of damaged neurites is induced by propionic acid and butyric acid. We could also show that administration of butyric acid is able to enhance propionic acid-associated neurite recovery. Whole-cell proteome analysis of induced primary neurons following recovery in the presence of propionic acid revealed abundant changes of protein groups that are associated with the chromatin assembly, translational, and metabolic processes. We further present evidence that these alterations in the chromatin assembly were associated with inhibition of histone deacetylase class I/II following both propionic acid and butyric acid treatment, mediated by free fatty acid receptor signalling. While neurite recovery in the presence of propionic acid is promoted by activation of the anti-oxidative response, administration of butyric acid increases neuronal ATP synthesis in people with multiple sclerosis-specific induced primary neurons.

1H-magnetic resonance spectroscopy in diffuse and focal cervical cord lesions in multiple sclerosis.

OBJECTIVES: To investigate differences between focal and diffuse cervical lesions in multiple sclerosis (MS) by proton magnetic resonance spectroscopy ((1)H-MRS) at 1.5 T in comparison to quantitative MR imaging of the upper cervical cord area and T2 relaxometry at baseline and follow-up. METHODS: Including 22 MS patients with persistent spinal cord symptoms by either diffuse or focal lesions and 17 controls, we acquired MRS, the mean cord area and the water T2 relaxation time and disability at baseline and follow-up. Cross-sectional analyses included group-level comparisons and correlation studies. Follow-up studies covered assessment of reproducibility and progression of the baseline results. RESULTS: Compared with focal lesions, diffuse lesions were attended by more cord atrophy, longer T2, elevated levels of creatine (Cre) and reduced N-acetyl aspartate (NAA)/Cre (focal/diffuse: 83 ± 9/73 ± 15 mm(2), 121 ± 21/104 ± 13 ms, 3.6 ± 1.1/5.1 ± 2.4 mM, 2.4 ± 1.1/2.0 ± 0.9). NAA/Cre at baseline was associated significantly with cord atrophy and with clinical progression during follow-up. Baseline MRS results were not significantly correlated to the clinical disability parameters. The reproducibility of MRS was 0.17-0.30. Longitudinal changes of the MRS results were not statistically significant. CONCLUSIONS: MRS indicated differences in demyelination and gliosis between diffuse and focal cervical lesions in MS. Although longitudinal spectral and clinical changes were sparse, NAA/Cre turned out to be the most sensitive spectral parameter.

Cross-sectional analysis of clinical aspects in patients with long-COVID and post-COVID syndrome.

Objective: Regarding pathogenesis, clinical manifestations, at-risk individuals, and diagnostic methods for stratifying patients for therapeutic approaches, our understanding of post-COVID syndrome is limited. Here, we set out to assess sociodemographic and clinical aspects in patients with the long-COVID and post-COVID syndrome. Methods: We performed a cross-sectional analysis of patients presenting at our specialized university hospital outpatient clinic. We assessed patients' clinical presentation, fatigue, symptoms of depression and anxiety, and impairment of smell. Results: A total of 101 patients were included (73.3% female), of whom 78.2% had a mild course of COVID-19. At presentation, 93.1% suffered from fatigue, 82.2% from impaired concentration, and 79.2% from impaired memory, 53.5% had impaired sleep. The most common secondary diagnosis found in our cohort was thyroid disease. Fatigue analysis showed that 81.3% of female and 58.8% of male patients had severe combined fatigue. Female gender was an independent risk factor for severe fatigue (severe cognitive fatigue OR = 8.045, p = 0.010; severe motor fatigue OR = 7.698, p = 0.013). Males suffered from more depressive symptoms, which correlated positively with the duration of symptom onset. 70.3% of patients with anamnestic smell impairment had hyposmia, and 18.9% were anosmic. Interpretation: Most long-COVID patients suffered from severe fatigue, with the female sex as an independent risk factor. Fatigue was not associated with symptoms of depression or anxiety. Patients with long-COVID symptoms should receive an interdisciplinary diagnostic and therapeutic approach depending on the clinical presentation.

Hypoechogenicity of brainstem raphe in long-COVID syndrome-less common but independently associated with depressive symptoms: a cross-sectional study.

OBJECTIVE: Long coronavirus disease (Long-COVID) syndrome is a hitherto poorly understood phenomenon with a broad spectrum of symptoms, including depression and anxiety. Depressive symptoms have been associated with brainstem raphe (BR) alterations in transcranial sonography (TCS) that might reflect dysfunction of the serotonergic system. The primary aim was to investigate the connection of BR alterations with depressive and anxiety symptoms in patients with Long-COVID syndrome. METHODS: In a cross-sectional study design, we included outpatients fulfilling the criteria of Long-COVID syndrome. All patients were examined by TCS in the axial plane with focus on BR signal alterations. The Hospital Anxiety and Depression Scale (HADS) was used to test for symptoms of anxiety and depression. RESULTS: We included n = 70 patients with Long-COVID syndrome, of which 28.6% (n = 20) exhibited a reduced echogenicity of BR in the TCS examination. Patients with hypoechogenic BR had higher subscores for anxiety and depression compared to normoechogenic patients (HADS depression: median 8 versus 5.5, p = 0.006; HADS anxiety: median 9 versus 6.5, p = 0.006). After adjustment for reasonable confounders, only the odds ratio (OR) for relevant depressive symptoms was higher among Long-COVID patients with hypoechogenic raphe (adjusted OR 3.884, 95% CI 1.244-12.123). DISCUSSION: Hypoechogenic BR alterations are independently associated with depressive symptoms in Long-COVID patients but are not highly frequent. Future studies should investigate whether the hypoechogenicity of the BR is a direct consequence or whether it reflects a priori a higher susceptibility to depressive symptoms after COVID-19, thus enabling to identify COVID-19 patients at higher risk of developing Long-COVID depressive symptoms.

Longitudinal study on nerve ultrasound and corneal confocal microscopy in NF155 paranodopathy.

We report the case of a 27-year-old patient with subacute anti-neurofascin-155 neuropathy with bifacial palsy, who showed excellent response to rituximab. We provide longitudinal data of established clinical scores, nerve conduction studies, antibody titers, and novel imaging methods (nerve ultrasonography and corneal confocal microscopy). Clinical and electrophysiological improvement followed the reduction of serum antibody titer and correlated with a reduction of corneal inflammatory cellular infiltrates whereas the increase in the cross-sectional area of the peripheral nerves remained 12 months after first manifestation. Our findings suggest that novel techniques provide useful follow-up parameters in paranodopathies.

Prospective Study of the Clinical, Electrophysiologic, and Sonographic Characteristics of Oxaliplatin-Induced Neuropathy.

BACKGROUND AND PURPOSE: Oxaliplatin-induced neuropathy is a major dose limiting side effect of the highly effective combination chemotherapy with oxaliplatin, irinotecan, and 5-fluorouracil (FOLFIRINOX) in patients with metastastic pancreatic cancer. We present the first longitudinal sonographical-electrophysiological study on oxaliplatin-induced neuropathy. METHODS: Thirteen patients with metastatic pancreatic cancer underwent clinical, sonographic, and electrophysiological evaluation before, 3 and 7 months after treatment with 12 two-week cycles of FOLFIRINOX. RESULTS: The majority of patients (61%) developed symptoms and electrophysiological signs of a length-dependent sensorimotor axonal neuropathy 7 months after treatment initiation. Oxaliplatin-induced neuropathy presented with a cross-sectional area (CSA) increase of mostly the tibial and fibular nerve, which developed parallel or prior to clinical signs and electrophysiological changes. Furthermore, isolated CSA at entrapment sites of the upper and lower extremities was measured without relevant symptoms. No correlation between sonographic and electrophysiological findings or clinical severity was detected. CONCLUSIONS: Oxaliplatin-induced neuropathy is characterized by an axonal length-dependent nerve affection presenting with a combination of sonographical and electrophysiological alterations.

Clinical, Sonographic, and Electrophysiologic Longitudinal Features of Chronic Inflammatory Demyelinating Polyneuropathy.

BACKGROUND AND PURPOSE: Several studies have aimed to find potential biomarkers to simplify the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) and to monitor and predict the disease course. However, reliable markers are still lacking. We aimed to investigate whether high-resolution nerve ultrasound (HRUS) is suitable for monitoring the long-term clinical course of CIDP. METHODS: Twenty patients fulfilling the definite diagnostic criteria of CIDP received clinical examination, evaluation of the INCAT (inflammatory neuropathy cause and treatment) overall disability sum score (ODSS) as well as nerve conduction studies, and HRUS every 6 months over a median follow-up time of 34 months. Patients were divided into clinically stable/regressive disease course or progressive disease course according to the development of the ODSS. RESULTS: The intranerve cross-sectional-area (CSA) variability of the nerves of the lower extremity increased with disease progression, whereas it remained unchanged in patients with a stable or remitting disease course. CONCLUSION: Nerve ultrasound can be used as a method to objectify the long-term disease course in CIDP patients. The intranerve CSA variability is suitable for monitoring the clinical course of patients with CIDP.

Monozygotic twins with a new compound heterozygous SPG11 mutation and different disease expression.

BACKGROUND: A pair of monozygotic 22-year-old twins with complicated hereditary spastic paraplegia caused by a novel SPG11 mutation is described. METHODS: Genetic testing and thorough clinical examination, magnetic resonance imaging (MRI) and MR-spectroscopy were performed. RESULTS: The twins were compound heterozygous for a known frameshift as well as a novel splice site mutation in the SPG11 gene. Clinically the patients showed a similar spectrum of symptoms but different disease presentation. MRI studies including morphometry and regional microstructural analysis by diffusion tensor imaging (DTI) of the corpus callosum (CC) by 3T MRI revealed marked thinning and corresponding increases of radial diffusivity (RD) and apparent diffusion coefficient (ADC) and reduction of the fractional anisotropy (FA) as compared to controls in all CC sections, particularly in the anterior callosal body. There was marked mainly supratentorial white matter reduction and to a lesser extent grey matter reduction in both patients. Involvement of the cortico-spinal tracts was reflected by FA and RD alterations. The more strongly affected patient showed a higher degree of callosal microstructural damage and cervical cord atrophy. CONCLUSIONS: This study shows a similar symptom spectrum, but distinct clinical and imaging findings in monozygotic twins suffering from SPG 11, suggesting individual downstream genetic effects and/or non-genetic modifiers.

Treatment failure of intrathecal baclofen and supra-additive effect of nabiximols in multiple sclerosis-related spasticity: a case report.

Multiple sclerosis (MS)-related spasticity is associated with disability and impairment in quality of life. We report on a patient with secondary progressive MS and spastic tetraparesis (Expanded Disability Status Scale score 8.5). The right arm exhibited flexor spasticity resulting in functional disability despite multimodal symptomatic treatment. Intrathecal baclofen led to side effects despite decreasing efficacy. Low-dose nabiximols improved spasticity and function with recovery of daily-life activities and spasticity-related symptoms. Reduction of intrathecal baclofen ameliorated adverse drug reactions. Add-on cannabinoid therapy was effective in therapy-refractory spasticity with supra-additive effect in combining intrathecal baclofen and nabiximols, hypothetically explained by mutually complementing mechanisms of action.