Analysen zur Regulation der cerebellaren Bergmann Glia-Differenzierung durch Thyroidhormone

Thyroidhormone sind essentiell für die Gehirnentwicklung, da sie die neuronale Migration, Differenzierung, Myelinisierung und Synaptogenese entscheidend beeinflussen. Besonders die Differenzierung des Cerebellums ist von einer ausreichenden Thyroidhormon-Versorgung abhängig und postnatale Thyroidhormon-Defizienz führt bei Nagern zu einer gestörten Dendritogenese der Purkinjezellen. Da die Dendriten dieser cerebellaren Neuronen strukturell und funktionell eng mit den Fortsätzen der Bergmann Gliazellen assoziiert sind, wurde vermutet, dass die Bergmann Glia-Differenzierung unter athyroiden Bedingungen ebenfalls affektiert ist. Die Thyroidhormon-Wirkung auf die Entwicklung der Bergmann Gliazellen wurde jedoch nur unzureichend erforscht. Die im Rahmen dieser Arbeit durchgeführte Analyse von kongenital athyroiden Pax8-/- Mäusen, die gliaspezifisch GFP exprimieren, zeigte eine ausgeprägte Reduzierung der lateralen Bergmann Glia-Fortsätze, die sich seitlich an den langen Radialfasern herausbilden und in engem Kontakt zu den Purkinjezell-Dendriten stehen. Bei einer Untersuchung der Transkriptspiegel von Kandidatengenen, die putativ in die Ausbildung dieser seitlichen Fortsätze involviert sein könnten, wurde unter athyroiden Bedingungen in Bergmann Gliazellen eine erniedrigte Expression von Septin-4, einem Zytoskelettprotein mit GTPase-Aktivität, und borg4, einem Zielprotein der Rho-GTPase Cdc42, nachgewiesen. Eine Substitution der Pax8-/- Mäuse mit Thyroxin führte über den Thyroidhormon-Rezeptor TRa1 zur Normalisierung der Transkriptspiegel beider Gene. Eine borg4-Überexpression in primären cerebellaren Astrozyten induzierte interessanterweise nicht nur eine veränderte subzelluläre Lokalisation von Septin-4, sondern auch die Ausbildung von langen faserartigen Zellausläufern. Basierend auf diesen Ergebnissen wurde ein neues Modell vorgeschlagen, wie Thyroidhormone die Differenzierung von cerebellaren Bergmann Gliazellen über einen Septin-4 / borg4 Signalweg beeinflussen

A new Purkinje cell antibody (anti-Ca) associated with subacute cerebellar ataxia: immunological characterization

We report on a newly discovered serum and cerebrospinal fluid (CSF) reactivity to Purkinje cells (PCs) associated with subacute inflammatory cerebellar ataxia. The patient, a previously healthy 33-year-old lady, presented with severe limb and gait ataxia, dysarthria, and diplopia two weeks after she had recovered from a common cold. Immunohistochemical studies on mouse, rat, and monkey brain sections revealed binding of a high-titer (up to 1:10,000) IgG antibody to the cerebellar molecular layer, Purkinje cell (PC) layer, and white matter. The antibody is highly specific for PCs and binds to the cytoplasm as well as to the inner side of the membrane of PC somata, dendrites and axons. It is produced by B cell clones within the CNS, belongs to the IgG1 subclass, and activates complement in vitro. Western blotting of primate cerebellum extract revealed binding of CSF and serum IgG to an 80-97 kDa protein. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic antibodies known to be associated with cerebellar ataxia. Screening of >9000 human full length proteins by means of a protein array and additional confirmatory experiments revealed Rho GTPase activating protein 26 (ARHGAP26, GRAF, oligophrenin-1-like protein) as the target antigen. Preadsorption of the patient's serum with human ARHGAP26 but not preadsorption with other proteins resulted in complete loss of PC staining. Our findings suggest a role of autoimmunity against ARHGAP26 in the pathogenesis of subacute inflammatory cerebellar ataxia, and extend the panel of diagnostic markers for this devastating disease

Posterior circulation stroke diagnosis using HINTS in patients presenting with acute vestibular syndrome: A systematic review

PurposeAcute vestibular syndrome – vertigo, nausea/vomiting, nystagmus and gait unsteadiness – is common, and differentiating posterior circulation stroke from a peripheral cause can be challenging. The National Institute of Health Stroke Scale (NIHSS) does not include acute vestibular syndrome, and early computed tomography scanning cannot rule out acute ischaemia. A positive Head Impulse–Nystagmus–Test of Skew (HINTS) test suggests posterior circulation stroke in acute vestibular syndrome when any of three signs are present: normal horizontal head impulse, gaze-direction nystagmus or eye skew deviation. This systematic review examined the accuracy of positive HINTS in identifying posterior circulation stroke in acute vestibular syndrome patients.MethodsWe searched MEDLINE (1966 to 21 December 2017), EMBASE (1980 to December 2017), Web of Science and scanned bibliographies. Two authors independently screened relevant articles and extracted data. We included studies where HINTS was used to identify posterior circulation stroke with diagnosis confirmed using magnetic resonance imaging.FindingsSix studies (n = 644 patients) were identified. Acute stroke was confirmed in 200 (31.1%) patients. There was a 15-fold increased risk of posterior circulation stroke in patients with positive HINTS test compared to those with no abnormality (RR: 15.84, 95% CI: 5.25–47.79). For any stroke, the pooled sensitivity was 95.5% (95% CI: 92.6–98.4%) and specificity was 71.2% (95% CI: 67.0–75.4%).Discussion and ConclusionThe data suggest that the HINTS test as one element of clinical evaluation is useful to differentiate posterior circulation stroke from peripheral causes in acute vestibular syndrome. Further studies are needed to validate HINTS as a clinical prediction tool in emergency department settings and selection of patients for reperfusion treatment

Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [F-18]PI-2620

Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities. Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001), whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE: 0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP (R = 0.641, p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD (R = 0.417, p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.). Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients

Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [18F]PI-2620

Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP). Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities. Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001), whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE: 0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP (R = 0.641, p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD (R = 0.417, p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.). Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients

Transient Vestibulopathy in Wallenberg's Syndrome: Pathologic Analysis

Objective: To report an unusual lateral medullary stroke (LMS) associated with transient unidirectional horizontal, nystagmus, and decreased horizontal vestibulo-ocular reflex (h-VOR) gain that mimicked a peripheral vestibulopathy. MRI suggested involvement of caudal medial vestibular nucleus (MVN);however, the rapid resolution of the nystagmus and improved h-VOR gain favored transient ischemia without infarction. Decreased h-VOR gain is expected with peripheral vestibular lesions within the labyrinth or superior vestibular nerve;less frequently lateral pontine strokes involving the vestibular root entry, the vestibular fascicle, or neurons within the MVN may be responsible. The h-VOR is typically normal in LMS. Methods: Clinicopathologic examination of a 61-year-old man with an acute vestibular syndrome (AVS) and left LMS who died 3 weeks after the stroke. Postmortem brainstem analysis was performed. Results: The stroke involved the lateral medulla and pontomedullary junction, near the MVN, sparing the cerebellum and pons. To explain transient vestibular findings there are two possible hypotheses;the first would be that the MVN survived the ischemic process and would be histologically intact, and the second that vestibular afferents in the horizontal semicircular canal were ischemic and recovered after the ischemic process. Neuropathological examination showed a left LMS whose extent matched that seen by imaging. Non-ocular motor signs correlated well with structures affected by the infarction. Neurons and glia within nearby MVN were spared, as predicted by the rapid normalization of the ocular motor signs. Although unlikely, the possibility of transient intralabyrinthine arteriolar ischemia cannot be excluded. Additionally, truncal lateropulsion was due to combined lateral vestibulospinal tract and lateral reticular nucleus infarction. Conclusion: LMS may rarely be associated with an AVS that either represents or mimics a peripheral vestibulopathy. To our knowledge, this is the first neuropathologic examination of the brainstem of an LMS associated with transient vestibular findings occurring in the context of an anterior/posterior (AICA/PICA) cerebellar arterial variant stroke

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain

Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T 4. In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T 4 into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice. Oatp1c1 knockout (KO) mice were born with the expected frequency, were n

Biosphere reserves as a long-term intervention in a region – strategies, processes, topics and principles of different participative planning and management regimes of biosphere reserves. eco.mont (Journal on Protected Mountain Areas Research)|eco.mont Vol. 3 No. 1 3 1|

The management of protected areas has recently emerged as a new scientific discipline. To date, there is a lack of systematic and theoretical background. This study explored this vast field by combining different disciplines in an inter- and transdisciplinary approach. Taking two existing Austrian biosphere reserves (Großes Walsertal BR, Wienerwald BR) and one national park (Nockberge NP, BR planned) as typical examples, we analysed basic management principles in terms of intervention, participation, regional governance and change management. The broad base and special methodological approach showed the complexity of planning and managing a biosphere reserve. How local stakeholders perceive the process of development very often differs from what the planning regime was meant to do. The overwhelming importance of regional history, the power of established structures and social components (trust, enthusiasm etc.) can turn planning intentions into an unpredictable direction. Only a precise and focused strategic mix of process components can ensure a successful process. What constitutes an effective mix differs from region to region and must be defined individually. It also became clear that different phases of BR development need specific management approaches as intervention takes place in a typical order. Once again, proper participation proved crucial for the success of a BR

Clinicopathologic Correlation in Lateral Medullary Stroke with Transient Ocular Motor Findings Mimicking Peripheral Vestibular Dysfunction (.pdf)

Unilaterally decreased horizontal vestibulo-ocular reflex (h-VOR) gain occurs with peripheral vestibular lesions or lateral pontine strokes involving the fascicle or the medial vestibular nucleus (MVN). Vestibular reflexes are typically normal in (LMS). We describe clinicopathologic findings in an unusual LMS presenting transient unidirectional nystagmus and decreased h-VOR gain, mimicking peripheral vestibulopathy (PV). The MVN neurons, close to the stroke core (ischemic penumbra), appeared pathologically normal, suggesting that the initial vestibular signs related to transient ischemia