Biomarkers of Neurodegeneration in Autoimmune-Mediated Encephalitis

Progranulin (PGRN), Total-Tau (t-tau), and Neurofilament light chain (NfL) are well known biomarkers of neurodegeneration. The objective of the present study was to investigate whether these parameters represent also biomarkers in autoimmune-mediated Encephalitis (AE) and may give us insights into the pathomechanisms of AE. We retrospectively examined the concentration of PGRN in the cerebrospinal fluid (CSF) and serum of 38 patients suffering from AE in acute phase and/or under treatment. This AE cohort comprises patients with autoantibodies against: NMDAR (n = 18 patients), Caspr2 (n = 8), Lgi-1 (n = 10), GABAB(R) (n = 1), and AMPAR (n = 1). Additionally, the concentrations of NfL (n = 25) and t-tau (n = 13) in CSF were measured when possible. Follow up data including MRI were available in 13 patients. Several age-matched cohorts with neurological diseases besides neuroinflammation or neurodegeneration served as control groups. We observed that PGRN was significantly elevated in the CSF of patients with NMDAR-AE in the acute phase, but normalized at follow up under treatment (p < 0.01). In the CSF of other patients with AE PGRN was in the range of the CSF levels of control groups. T-tau was highly elevated in the CSF of patients with temporal FLAIR-signal in the MRI and in patients developing a hippocampal sclerosis. NfL was exceptionally high initially in Patients with AE with a paraneoplastic or parainfectious cause and also normalized under treatment. The normalizations of all biomarkers were mirrored in an improvement on the modified Rankin scale. The data suggest that the concentration of PGRN in CSF might be a biomarker for acute NMDAR-AE. Pathological high t-tau levels may indicate a risk for hippocampal sclerosis. The biomarker properties of NfL remain unclear since the levels decrease under treatment, but it could not predict severity of disease in this small cohort. According to our results, we recommend to measure in clinical practice PGRN and t-tau in the CSF of patients with AE

Biomarkers of Neurodegeneration in Autoimmune-Mediated Encephalitis.

Progranulin (PGRN), Total-Tau (t-tau), and Neurofilament light chain (NfL) are well known biomarkers of neurodegeneration. The objective of the present study was to investigate whether these parameters represent also biomarkers in autoimmune-mediated Encephalitis (AE) and may give us insights into the pathomechanisms of AE. We retrospectively examined the concentration of PGRN in the cerebrospinal fluid (CSF) and serum of 38 patients suffering from AE in acute phase and/or under treatment. This AE cohort comprises patients with autoantibodies against: NMDAR (n = 18 patients), Caspr2 (n = 8), Lgi-1 (n = 10), GABAB(R) (n = 1), and AMPAR (n = 1). Additionally, the concentrations of NfL (n = 25) and t-tau (n = 13) in CSF were measured when possible. Follow up data including MRI were available in 13 patients. Several age-matched cohorts with neurological diseases besides neuroinflammation or neurodegeneration served as control groups. We observed that PGRN was significantly elevated in the CSF of patients with NMDAR-AE in the acute phase, but normalized at follow up under treatment (p < 0.01). In the CSF of other patients with AE PGRN was in the range of the CSF levels of control groups. T-tau was highly elevated in the CSF of patients with temporal FLAIR-signal in the MRI and in patients developing a hippocampal sclerosis. NfL was exceptionally high initially in Patients with AE with a paraneoplastic or parainfectious cause and also normalized under treatment. The normalizations of all biomarkers were mirrored in an improvement on the modified Rankin scale. The data suggest that the concentration of PGRN in CSF might be a biomarker for acute NMDAR-AE. Pathological high t-tau levels may indicate a risk for hippocampal sclerosis. The biomarker properties of NfL remain unclear since the levels decrease under treatment, but it could not predict severity of disease in this small cohort. According to our results, we recommend to measure in clinical practice PGRN and t-tau in the CSF of patients with AE

The dependency of visual working memory for motion on the spatial separation in psychophysical tasks with humans

Das visuelle Arbeitsgedächtnis (visual working memory, VWM) ist eine Art Notizblock für visuelle Gedächtnisinhalte, welches dazu beiträgt, über die Dauer der sensorischen Stimulation hinaus Eigenschaften der Umwelt erfahrbar zu machen, mit anderen Reizen in Bezug zu setzen und auf dieser Basis Verhalten zu steuern. Üblicher Weise wird die Leistung des Arbeitsgedächtnisses im präfrontalen Kortex angesiedelt, welcher Neurone bereithält, die Reizeigenschaften über die Dauer der Reizdarbietung hinweg zu repräsentieren vermögen. Das frühere Dogma, dass solche Neurone ausschliesslich im phylogentisch jungen Präfrontalkortex anzutreffen sind, mußte durch jüngere Untersuchungen beim Affen revidiert werden, insofern Neurone mit ähnlichen Eigenschaften bereits in frühen visuellen Arealen beschrieben wurden. Ein zentraler Ausgangpunkt der vorliegenden Arbeit ist die Beobachtung, dass sich das Verhalten von Rhesusaffen in Arbeitsgedächtnis-Aufgaben mit Bewegungsreizen sehr gut auf bekannte Eigenschaften der sogenannten Area MT, eines frühen visuellen Areals, das auf die Analyse visueller Bewegung spezialisiert ist, abbilden lässt. Konkret konnte gezeigt werden, dass das Arbeitsgedächtnis für sequenziell präsentierte Bewegungsreize kritisch von deren räumlichem Abstand zueinander abhängt (Zaksas et al. 2001). Die spezifischen räumlichen Bezüge spiegelten hierbei die retinotope Organisation der Area MT wider. Ziel der vorliegenden Arbeit war es, durch Einsatz geeigneter psychophysischer Methoden zu prüfen, ob auch beim Menschen, dessen präfrontaler Kortex ungleich weiter entwickelt ist als beim Rhesusaffen, ähnliche Abhängigkeiten bestehen wie im Tierexperiment. Im Ergebnis zeigte sich eine doppelte Dissoziation. Anders als bei Rhesusafffen, für welche die Leistungen in der Arbeitsgedächtnis-Aufgabe für Bewegungsreize von räumlichen Bezügen in einem engen Raster abhingen (Zaksas et al. 2001), fand sich in der vorliegenden Arbeit eine solche Abhängigkeit bei den Humanprobanden nicht. Räumliche Einflüsse auf Arbeitsgedächtnisleistungen fanden sich stattdessen im Sinne von Hemisphäreneffekten, die nicht auf die Architektur der Area MT abzubilden sind, sondern im Sinne eines als ‚bilateral advantage’ bekannt gewordenen Phänomens zu interpretieren sind. Das Phänomen des ‚bilateral advantage’ wiederum fehlte in den tierexperimentellen Studien (Zaksas et al., 2001). Diese Dissoziation spricht für grundlegende Unterschiede der neuronalen Implementierung des visuellen Arbeitsgedächtnisses zwischen humanen und nicht-humanen Primaten. Während bei Rhesusaffen die Leistung des VWM wesentlich auf frühen visuellen Karten des Kortex zu basieren scheint, werden beim Menschen vermutlich in weit größerem Umfang spätere Areale mit bilateralen Repräsentationen rekrutiert.The visual working memory is a sketchpad for visual impressions encountered in everyday life. This sketchpad has only limited capacity and data is stored for only a limited time. In the prefrontal cortex sustained firing neurons are located building the neuronal basis of this sketchpad. Recently, in a number of monkey experiments neurons in the downstream visual cortex have also been recognized as an important location in visual working memory and also neurons in the Area MT, an area specialized for motion discrimination, located in the middle temporal gyrus seem to play a role in the visual working memory for motion (Zaksas et al., 2001). In these findings the motion discrimination accuracy depended significantly on the distance between the random dot kinematograms used. This distance corresponded well with the receptive field of Area MT neurons. This suggests a critical role of Area MT in visual working memory for motion discrimination. We wanted to psychophysically look at the role of Area MT in humans to see if it plays the same role in the visual working memory for motion in humans as suggested by the monkey experiments. Therefore we conducted three experiments with random-dot-kinematograms with different distances between them. In these experiments we addressed one or both hemispheres sequentially. We had two main results: First of all, the same experiment in humans than in monkeys revealed no significant dependencies of the visual working memory for motion on a spatial distribution of the random dot kinematograms. It seems that Area MT does not play the same role in visual working memory in humans than in monkeys. Secondly the results in our last experiment revealed a new effect on sequential visual motion discrimination. Humans have a better visual working memory for motion when comprising both hemispheres in solving the task. This effect has been shown for simultaneous motion discrimination before (Umemoto et al., 2010) and was called “bilateral advantage”. Here the “bilateral advantage” is shown for the first time in sequential motion discrimination

CSF Biomarkers of Neurodegeneration in Progressive Non-fluent Aphasia and Other Forms of Frontotemporal Dementia: Clues for Pathomechanisms?

Frontotemporal Dementia (FTD) encompasses distinct pathophysiologically heterogenous disorders with different genetic and cellular disease mechanisms. The objective of this study is to compare the constellation of biomarkers of neurodegeneration in the cerebrospinal fluid (CSF) to the FTD type categorized by clinical symptoms. We investigated the levels of Phospho181-tau, Total-tau, Beta-amyloid1−42, Neurofilament light chain, and Progranulin in the CSF of n = 99 FTD patients regarding to the different subtypes of FTD, including semantic dementia (SD), progressive non-fluent aphasia (PNFA), behavioral variant FTD (bvFTD). We compared these groups to patients without neurodegenerative disorders and another cohort encompassing tauopathies with distinct clinical syndromes (Cortico basal syndrome and progressive supranuclear palsy) and logopenic PNFA (lPPA) as another disorder with predominant speech disturbance. CSF-Progranulin levels were significantly lower in FTD type patients with semantic dementia and behavioral variant FTD mainly attributed to the Tar-DNA-Binding-Protein (TDP) 43 compared to predominantly Tau-mediated PNFA (p &lt; 0.05). Also, neurofilament light chain was significantly higher (p &lt; 0.036) in all FTD patients especially in SD patients (p &lt; 0.01). CSF-Nfl levels also distinguished SD patients from logopenic Alzheimers patients (p &lt; 0.05). In sum, CSF-Neurofilament light chain and CSF-Progranulin seem to be promising biomarkers for FTD, the latter predominantly for assumed TDP43-mediated FTD

CSF Biomarkers of Neurodegeneration in Progressive Non-fluent Aphasia and Other Forms of Frontotemporal Dementia: Clues for Pathomechanisms?

Frontotemporal Dementia (FTD) encompasses distinct pathophysiologically heterogenous disorders with different genetic and cellular disease mechanisms. The objective of this study is to compare the constellation of biomarkers of neurodegeneration in the cerebrospinal fluid (CSF) to the FTD type categorized by clinical symptoms. We investigated the levels of Phospho181-tau, Total-tau, Beta-amyloid1-42, Neurofilament light chain, and Progranulin in the CSF of n = 99 FTD patients regarding to the different subtypes of FTD, including semantic dementia (SD), progressive non-fluent aphasia (PNFA), behavioral variant FTD (bvFTD). We compared these groups to patients without neurodegenerative disorders and another cohort encompassing tauopathies with distinct clinical syndromes (Cortico basal syndrome and progressive supranuclear palsy) and logopenic PNFA (lPPA) as another disorder with predominant speech disturbance. CSF-Progranulin levels were significantly lower in FTD type patients with semantic dementia and behavioral variant FTD mainly attributed to the Tar-DNA-Binding-Protein (TDP) 43 compared to predominantly Tau-mediated PNFA (p &lt; 0.05). Also, neurofilament light chain was significantly higher (p &lt; 0.036) in all FTD patients especially in SD patients (p &lt; 0.01). CSF-Nfl levels also distinguished SD patients from logopenic Alzheimers patients (p &lt; 0.05). In sum, CSF-Neurofilament light chain and CSF-Progranulin seem to be promising biomarkers for FTD, the latter predominantly for assumed TDP43-mediated FTD

Progranulin and Its Related MicroRNAs after Status Epilepticus: Possible Mechanisms of Neuroprotection

The current knowledge about neuroprotective mechanisms in humans after status epilepticus is scarce. One reason is the difficulty to measure possible mediators of these neuroprotective mechanisms. The dawn of microRNA detection in the cerebrospinal fluid (CSF) and the recent advancements in measuring proteins in the CSF such as progranulin, which is, e.g., responsible for neurite outgrowth and limiting exceeding neuroinflammatory responses, have given us new insights into putative neuroprotective mechanisms following status epilepticus. This should complement the animal data. In this review, we cover what is known about the role of progranulin as well as the links between microRNA changes and the progranulin pathway following status epilepticus in humans and animals hypothesizing neuroprotective and neurorehabilitative effects. Progranulin has also been found to feature prominently in the neuroprotective processes under hypoxic conditions and initiating neurorehabilitative processes. These properties may be used therapeutically, e.g., through drugs that raise the progranulin levels and therefore the cerebral progranulin levels as well with the goal of improving the outcome after status epilepticus

Data from: NfL is a biomarker for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

No description availabl

Hayer et al ALSP NfL Supplementary Methods

Supplementary information on procedures and statistical analyses

Hayer et al ALSP NfL Supplementary Table S1

Demographic data of ALSP patients, mutation carriers, MS patients, and controls

Serum neurofilament light chain in COVID-19 and the influence of renal function

Abstract COVID-19 is associated with various neurological symptoms. Serum neurofilament light chain (sNfL) is a robust marker for neuroaxonal injury. Recent studies have shown that elevated levels of sNfL are associated with unfavorable outcome in COVID-19 patients. However, neuroaxonal injury is rare in COVID-19, and renal dysfunction and hypoxia, both of which are known in severe COVID-19, can also increase sNfL levels. Thus, the meaning and mechanisms of sNfL elevation in COVID-19 patients remain unclear. We evaluated sNfL levels in 48 patients with COVID-19 (mean age = 63 years) and correlated them to clinical outcome, the form of oxygen therapy, and creatinine. Levels of sNfL were age adjusted and compared with normal values and z-scores. COVID-19 patients treated with nasal cannula had normal sNfL levels (mean sNfL = 19.6 pg/ml) as well as patients with high-flow treatment (mean sNfL = 40.8 pg/ml). Serum NfL levels were statistically significantly higher in COVID-19 patients treated with mechanical ventilation on intensive care unit (ICU) (mean sNfL = 195.7 pg/ml, p < 0.01). There was a strong correlation between sNfL elevation and unfavorable outcome in COVID-19 patients (p < 0.01). However, serum creatinine levels correlated directly and similarly with sNfL elevation and with unfavorable outcome in COVID-19 patients (p < 0.01). Additionally, multivariate analysis for serum creatinine and sNfL showed that both variables are jointly associated with clinical outcomes. Our results identify renal dysfunction as an important possible confounder for sNfL elevation in COVID-19. Thus, serum creatinine and renal dysfunction should be strongly considered in studies evaluating sNfL as a biomarker in COVID-19