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Chronic Progressive Multiple Sclerosis - Pathogenesis of Neurodegeneration and Therapeutic Strategies
No full textMultiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating disease of the central nervous system (CNS) that usually starts as a relapsing-remitting disease. In most patients the disease evolves into a chronic progressive phase characterized by continuous accumulation of neurological deficits. While treatment of relapsing-remitting MS (RRMS) has improved dramatically over the last decade, the therapeutic options for chronic progressive MS, both primary and secondary, are still limited. In order to find new pharmacological targets for the treatment of chronic progressive MS, the mechanisms of the underlying neurodegenerative process that becomes apparent as the disease progresses need to be elucidated. New animal models with prominent and widespread progressive degenerative components of MS have to be established to study both inflammatory and non-inflammatory mechanisms of neurodegeneration. Here, we discuss disease mechanisms and treatment strategies for chronic progressive MS.ERC; EMB
Chronic Progressive Multiple Sclerosis - Pathogenesis of Neurodegeneration and Therapeutic Strategies
No full textMultiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating disease of the central nervous system (CNS) that usually starts as a relapsing-remitting disease. In most patients the disease evolves into a chronic progressive phase characterized by continuous accumulation of neurological deficits. While treatment of relapsing-remitting MS (RRMS) has improved dramatically over the last decade, the therapeutic options for chronic progressive MS, both primary and secondary, are still limited. In order to find new pharmacological targets for the treatment of chronic progressive MS, the mechanisms of the underlying neurodegenerative process that becomes apparent as the disease progresses need to be elucidated. New animal models with prominent and widespread progressive degenerative components of MS have to be established to study both inflammatory and non-inflammatory mechanisms of neurodegeneration. Here, we discuss disease mechanisms and treatment strategies for chronic progressive MS.ERC; EMB
Impaired Verbal Memory Recall in Patients With Axonal Degeneration and Serum Glycine-Receptor Autoantibodies—Case Series
No full textBackground Glycine receptor antibody-associated neuropsychiatric disease is currently known to be dominated by the phenotypes stiff-person syndrome and progressive encephalomyelitis entailing rigidity and myoclonus. In our case series we aim to depict the less-often reported feature of cognitive impairment associated with glycine receptor antibodies. Methods We investigated five patients with cognitive impairment varying from mild cognitive impairment to dementia associated with serum glycine receptor antibodies. Mild and major neurocognitive disorders were diagnosed according to the DSM-5 (fifth edition of the Diagnostic and Statistical Manual of Mental Disorders). Neuropsychology via Consortium to Establish a Registry for Alzheimer's Disease (CERAD) testing results, psychopathology data via the Manual for the Assessment and Documentation of Psychopathology in Psychiatry (AMDP), cerebrospinal fluid analysis and magnetic resonance imaging data were retrospectively analyzed from patient files. Results We identified five patients with cognitive impairment as the main neuropsychiatric feature associated with serum glycine receptor antibodies. One patient also presented akinetic rigidity syndrome. The psychopathology comprised disorders of attention and memory, orientation, formal thought, and affect. In addition to suffering deficits in verbal memory function, figural recall, phonematic fluency, and globally deteriorated cognitive function, these patients presented seriously impaired memory recall in particular. Tau protein and phosphorylated tau protein 181 were elevated in 75% of patients. Conclusions Our results suggest that axonal neurodegeneration and especially impaired verbal memory recall in addition to deficits in verbal and figural memory characterize patients with progressive cognitive impairment associated with glycine receptor antibodies. This unresolved issue should be clarified by researchers to discover whether axonal degeneration is merely an age-related phenomenon or one related to glycine-receptor autoantibodies in old age. Cognitive impairment as a neuropsychiatric syndrome of glycine-receptor antibody disease is a potential, conceivable, but so far unproven additional feature requiring deeper large-scale investigations and consideration during differential diagnosis in memory clinics.Open-Access-Publikationsfonds 202
Investigation of axonal neurodegeneration in anti-neural autoantibody-associated psychiatric syndromes
No full textCerebrospinal fluid biomarkers in psychiatric autoimmune encephalitis: a retrospective cohort study
No full textBackground: Psychiatric autoimmune encephalitis (pAE) is a growing field of interest in diagnosis and therapy in psychiatric hospitals and institutions. This study investigates the relevant extent to which there are potential biomarkers in cerebrospinal fluid (CSF) that can differentiate against a cohort with neurodegenerative disease.
Methods: We included in this study a total of 27 patients with possible and definite psychiatric autoimmune encephalitis and compared with a cohort with CSF-based AD (n = 27) different biomarkers in CSF such as lactate, cell count, % lymphocytes, % monocytes, total protein content, albumin, immunoglobulins G (IgG), M (IgM) and A (IgA), CSF/serum albumin ratio, CSF/serum IgG ratio, CSF/serum IgA ratio, intrathecal IgG synthesis, blood–brain barrier disruption, specific antibody synthesis for measles, rubella, herpes simplex virus, varicella zoster virus, Ebstein-Barr virus and cytomegalovirus, total tau protein (t-tau), phosphorylated tau protein 181 (p-tau181), amyloid beta 42 (Aß42), amyloid beta 40 (Aß40) and the amyloid beta 42/ amyloid beta 40 (Aß42/40) ratio.
Results: The p-tau 181 was elevated above cut-off values in both possible pAE and AD. However, in definitive pAE, p-tau181 levels were not elevated. When elevated p-tau181 levels in possible AE were compared with those in AD, we found relevant differences, such as a relative increase in p-tau181 in AD patients. Elevated p-tau181 levels were detected in possible psychiatric AEs with IgLON5, glycine, recoverin, titin, and nonspecific neuropil antibodies in serum and IgLON5, titin, Yo, and nonspecific neuropil autoantibodies in CSF. In addition, we detected elevated levels of p-tau181 and IgLON5 autoantibodies in serum and CSF, and Yo autoantibodies in CSF in patients with definitive pAE. Interestingly, we observed a higher CSF/serum IgM ratio in possible and definitive pAE than in AD patients.
Conclusion: Our results suggest that neuroaxonal brain damage may occur in specific psychiatric AEs associated with IgLON5, glycine, recoverin, and titin autoantibodies. Further research should focus on the CSF/serum IgM ratio as an early marker of autoantibody production in pAE compared to AD as a potential biomarker for differential diagnosis.Open-Access-Publikationsfonds 202
Identification of Tmem10/Opalin as a novel marker for oligodendrocytes using gene expression profiling
Full text linkAbstract Background During the development of the central nervous system, oligodendrocytes generate large amounts of myelin, a multilayered insulating membrane that ensheathes axons, thereby allowing the fast conduction of the action potential and maintaining axonal integrity. Differentiation of oligodendrocytes to myelin-forming cells requires the downregulation of RhoA GTPase activity. Results To gain insights into the molecular mechanisms of oligodendrocyte differentiation, we performed microarray expression profiling of the oligodendroglial cell line, Oli-neu, treated with the Rho kinase (ROCK) inhibitor, Y-27632 or with conditioned neuronal medium. This resulted in the identification of the transmembrane protein 10 (Tmem10/Opalin), a novel type I transmembrane protein enriched in differentiating oligodendrocytes. In primary cultures, Tmem10 was abundantly expressed in O4-positive oligodendrocytes, but not in oligodendroglial precursor cells, astrocytes, microglia or neurons. In mature oligodendrocytes Tmem10 was enriched in the rims and processes of the cells and was only found to a lesser extent in the membrane sheets. Conclusion Together, our results demonstrate that Tmem10 is a novel marker for in vitro generated oligodendrocytes.</p
Mild Cognitive Impairment in Chronic Brain Injury Associated with Serum Anti-AP3B2 Autoantibodies: Report and Literature Review
No full textBackground: Chronic traumatic brain injury is a condition that predisposes the brain to activate B-cells and produce neural autoantibodies. Anti-adaptor protein 3, subunit B2 (AP3B2) autoantibodies have thus far been associated with diseases affecting the cerebellum or vestibulocerebellum. Through this case report, we aim to broaden the spectrum of anti-AP3B2-associated disease. Case description: We report on a 51-year-old woman with a brain injury approximately 28 years ago who recently underwent neuropsychological testing, magnetic resonance imaging of the brain (cMRI), and cerebrospinal fluid (CSF) analysis. Neural autoantibodies were determined in serum and CSF. Our patient suffered from mild cognitive impairment (amnestic MCI, multiple domains) with stable memory deficits and a decline in verbal fluency and processing speed within a two-year interval after the first presentation in our memory clinic. Brain MRI showed brain damage in the right temporoparietal, frontolateral region and thalamus, as well as in the left posterior border of the capsula interna and white matter in the frontal region. Since the brain damage, she suffered paresis of the upper extremities on the left side and lower extremities on the right side as well as gait disturbance. Our search for autoantibodies revealed anti-AP3B2 autoantibodies in serum. Conclusions: Our report expands the spectrum of symptoms to mild cognitive impairment in addition to a gait disturbance associated with anti-AP3B2 autoantibodies. Furthermore, it is conceivable that a prior traumatic brain injury could initiate the development of anti-AP3B2-antibody-associated brain autoimmunity, reported here for the first time
Actomyosin contractility controls cell surface area of oligodendrocytes
Full text linkAbstract Background To form myelin oligodendrocytes expand and wrap their plasma membrane multiple times around an axon. How is this expansion controlled? Results Here we show that cell surface area depends on actomyosin contractility and is regulated by physical properties of the supporting matrix. Moreover, we find that chondroitin sulfate proteoglycans (CSPG), molecules associated with non-permissive growth properties within the central nervous system (CNS), block cell surface spreading. Most importantly, the inhibitory effects of CSPG on plasma membrane extension were completely prevented by treatment with inhibitors of actomyosin contractility and by RNAi mediated knockdown of myosin II. In addition, we found that reductions of plasma membrane area were accompanied by changes in the rate of fluid-phase endocytosis. Conclusion In summary, our results establish a novel connection between endocytosis, cell surface extension and actomyosin contractility. These findings open up new possibilities of how to promote the morphological differentiation of oligodendrocytes in a non-permissive growth environment. See related minireview by Bauer and ffrench-Constant: http://www.jbiol.com/content/8/8/78</p
Longitudinally persisting KCNA2-autoantibodies in mild amnestic dementia with Alzheimer´s pathology – Report and literature review
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