11 research outputs found
Fatigue in multiple sclerosis: Associations with clinical, MRI and CSF parameters
Background: Damage of different brain structures has been related to fatigue. Alternatively, functional alterations of central nervous system (CNS) cells by the inflammatory milieu within the CNS may be responsible for the development of fatigue. Aim: To investigate the effect of structural brain damage and inflammatory cerebrospinal fluid (CSF) changes on fatigue in multiple sclerosis (MS). Methods: We determined the association of different clinical, CSF and magnetic resonance imaging (MRI) parameters with prevalence and severity of fatigue, as measured by the Fatigue Scale for Motor and Cognitive Functions in 68 early MS patients (discovery cohort). We validated our findings in two MS cohorts: the MRI validation cohort (N=233) for the clinical and MRI parameters, and the CSF validation cohort (N=81) for the clinical and CSF parameters. Results: Fatigue was associated with clinical disability. Fatigue did not correlate with any CSF parameter but correlated negatively with total and cortical grey matter volume. However, when controlling for Expanded Disability Status Scale (EDSS) in a multivariate model, these associations lost significance. Conclusion: Disability and disease duration best explain fatigue severity but none of the tested MRI or CSF parameter was reliably associated with fatigue
Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis
OBJECTIVE: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS). METHODS: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany. RESULTS: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts. CONCLUSION: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS
Treatment choices and neuropsychological symptoms of a large cohort of early MS
Objective To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS. Methods The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms. Results Of 1,124 patients, with a 2.2: 1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06-40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively. Conclusion Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients
A study on the cerebellar mutants Staggerer, Nervous and Lurcher
Titelblatt
Inhaltsverzeichnis
1\. Einführung
1.1 Allgemeine Einleitung
1.2 Das Cerebellum
1.3 Organisation und Projektionsziele corticofugaler Efferenzen
1.4 Cerebelläre Afferenzen
1.5 Histogenese
1.6 Cerebelläre Mutationen bei der Maus
1.7 Calcium-bindende Proteine als selektive Nervenzell-Marker
1.8 Funktionen und Störungen des Cerebellums
1.9 Frühere Untersuchungen als Basis zur Formulierung der Arbeitshypothese
1.10 Arbeitshypothese und Fragestellungen
2\. Material und Methoden
2.1 Versuchstiere
2.2 Antikörper
2.3 Immuncytochemie
2.4 Auswertung und Datenerhebung
3\. Ergebnisse
3.1 Einführende Bemerkungen
3.2 Bestimmung des Purkinje-Zell Verlustes und der Denervation der
Kleinhirnkerne anhand von Calbindin D-28k Immuncytochemie
3.3 Parvalbumin in Neuronen der Kleinhirnkerne
3.4 Chronologische Korrelation des Purkinje-Zell Verlustes mit dem Erscheinen
Parvalbumin-positiver Neurone in den Kleinhirnkernen
3.5 Bestimmung der Volumina der Kleinhirnkerne
4\. Diskussion
4.1 Technik
4.2 Existenz einer Abhängigkeit zwisachen Purkinje-Zell Verlust und
Parvalbumin Expression in den Kleinhirnkernen
4.3 Bedingungen für eine Parvalbumin-Elevation in den Kleinhirnkernen
4.4 Vergleich mit Studien an anderen Mutanten
4.5 Funktionelle Implikationen der Parvalbumin-Expression für die Motorik
4.6 Weitere anterograde Effekte des Purkinje-Zell Verlustes
5\. Zusammenfassung
6\. Literaturverzeichnis
7\. Appendix
8\. DanksagungDiese Arbeit beschreibt morphologische Veränderungen in den Projektionsarealen
der PC, den DCN, bei den Mäusemutanten sg, nr und Lc, die sich durch ihren
selektiven Neuronenverlust im Cerebellum als Modelle für die Untersuchung von
mutationsbedingten Störungen und ihren Folgeerscheinungen eignen. Durch die
Auswirkungen der Mutation kommt es zu einer Umorganisation der synaptischen
Verbindungen des cerebellären Cortex und damit auch zu einer Veränderung
funktioneller Eigenschaften, die sich in einer Alteration motorischer
Fähigkeiten äußert. Gegenstand dieser Arbeit war die Frage, inwieweit es bei
diesen Mutanten in den DCN zu Veränderungen kommt, die eventuell mit einer
Kompensation mutationsbedingter Defizite in Zusammenhang gebracht werden
können. Entscheidend ist dabei immer der Vergleich mit dem intakten System.
Der Arbeit zugrunde liegen Untersuchungen in den DCN von pcd-Mutanten, die
unter einer fast vollständigen Degeneration der PC-Population leiden.
Immuncytochemisch konnte in den Neuronen der DCN dieser Mutanten die
Expression des Calcium-bindenden Proteins Parv nachgewiesen werden, was in
Wildtypen nicht möglich ist. Hieraus wurde die Hypothese abgeleitet, dass die
Parv-Expression bei Mutationen mit PC-Verlust eine generelle Antwort als Folge
des reduzierten PC-Inputs darstellen könnte. Immuncytochemisch wurde diese
These an den DCN der Mutanten sg, nr und Lc überprüft. Die quantitative
Reduktion der PC-Population wurde durch Antikörper gegen Calbindin D-28k,
einem spezifischen PC-Marker, dokumentiert. In alternierenden Schnitten wurde
die Immuncytochemie mit Antikörpern gegen Parvalbumin durchgeführt. Die
Ergebnisse zeigten, dass eine Abhängigkeit zwischen der Expression von Parv in
den DCN und dem PC-Verlust besteht, wobei das quantitative Ausmaß, die
Topographie und Chronologie des PC-Verlustes die entscheidenden Einflussgrößen
sind, die über Vorhandensein oder Fehlen von Parv in den DCN entscheiden. Es
konnte bewiesen werden, dass 1.) nur ein extremer PC-Input Verlust in den DCN,
der eine bestimmte Schwelle überschreitet, zu einer Parv Elevation führt, 2.)
Parv genau in den Arealen, in denen es zum PC-Input Verlust kommt, exprimiert
wird und 3.) der PC-Terminalien Verlust in den DCN beginnen muss, bevor Parv-
positive Neurone in den DCN sichtbar werden, also auch ein chronologischer
Zusammenhang zwischen Terminalienverlust und Parv Elevation besteht.
Trotz ihres nahezu kompletten PC-Verlustes weisen pcd-Mutanten relativ geringe
motorische Defizite auf. Dies ist bei nahezu allen Mutanten, die Parv in
Neuronen der DCN exprimieren, zu beobachten. Das Vorhandensein von Parv wird
mit erhöhter Aktivität entsprechender Neurone in Verbindung gebracht, und Parv
wird vorwiegend in inhibitorischen Neuronen lokalisiert. Möglicherweise kommt
es also durch die Expression von Parv in den DCN zur Wiederherstellung
verlorengegangener Hemmung, was sich stabilisierend auf die motorischen
Fähigkeiten auswirkt. Die Elevation von Parv in den DCN der Mutanten stellt
demnach einen Kompensationsmechanismus dar, der von Nutzen für die Motorik
ist. Die Bedeutung der Parv-Elevation für die Motorik wurde im Vergleich mit
Untersuchungen an anderen Mutanten und mit Transplantationsversuchen
embryonaler PC, die über einen anderen Weg die Rekonstituierung verlorener
Hemmung erreichen sollen, kritisch diskutiert.The present paper describes morphological changes in the projection areas of
the PC, the DCN, with the cerebellar mutant mice sg, nr and Lc, which by their
selective loss of cerebellar neurons, are particularly suited to serve as
models for the study of disorders caused by mutations and their consequences.
The mutation leads to a reorganisation of the synaptic connections of the
cerebellar cortex and with it to a change of functional qualities which are
expressed by motor impairment. The topic of this paper was to find out to
which extent changes in the DCN of these mutants are brought about that could
compensate for mutation-caused deficits. The comparison with the wildtype is
in this context of crucial importance. The paper is based on studies in the
DCN of pcd-mutants which suffer from an almost complete degeneration of the
PC-population. By means of immunocytochemical investigations the expression of
the calcium-binding protein Parv in neurons of the DCN of these mutants could
be shown, which is not possible in wildtypes. From these observations the
hypothesis was proposed that the Parv-expression in cerebellar mutants with
PC-loss might be a general answer following the reduced PC-input.
Immunocytochemically this thesis was tried to be confirmed within the DCN of
the mutants sg, nr and Lc. The quantitative reduction of the PC population was
proved by means of antibodies against Calbindin D-28 k, a specific PC marker.
In alternating sections immunocytochemical investigations with antibodies
against Parv were performed. The results show a clear dependence between the
expression of Parv in the DCN and the PC-loss. The amount, the topographic
localization and the chronology of PC-loss are the key factors deciding wether
Parv is expressed in the DCN or not. It could be shown that 1.) only an
extreme PC-input loss, which exceeds a certain threshold leads to an elevation
of Parv in the DCN, 2.) Parv is expressed exactly in those areas where the PC-
input loss takes place and 3.) Parv-positive neurons become visible only after
the onset of PC terminal degeneration, indicating a chronolgic order between
loss of PC-terminals and Parv-elevation in the DCN. In spite of their almost
complete PC-loss pcd-mutants show only slight motor impairment. This is also
true for all mutants, that express Parv in DCN neurons. The existence of Parv
is a sign for increased activity of corresponding neurons and Parv is
localized predominantly in inhibitory neurons. Possibly the expression of Parv
indicates the reconstitution of lost inhibition which is a stabilizing factor
for the motor activity. Thus the elevation of Parv in the DCN of the mutants
could compensate for motor impairment caused by PC input loss. The
significance of the elevation of Parv, concerning the motor abilities was
critically discussed in context with experiments on other mutants, where
embryonic PC were transplanted in order to obtain the reconstitution of lost
inhibition
Prognostic value of white matter lesion shrinking in early multiple sclerosis: An intuitive or naïve notion?
Background and purpose New or enlarging T2-hyperintense white matter lesions (WML) are associated with clinical disease progression in multiple sclerosis (MS). The prognostic value of WML shrinking is unclear. Assuming that waning of acute inflammation and repair processes would be the main drivers of WML shrinking, we aimed to assess the prognostic value of WML shrinking in early MS. Methods We retrospectively analyzed a cohort of 144 early MS patients with three brain MRI scans at baseline and after 1 and 3 years available. All patients were therapy naive at baseline and 70.5% of them treated with disease modifying drugs at year 1. We determined the volume of WML shrinking between MRI scans, total WML volumes, number of gadolinium-enhancing and new WML, white matter (WM) and gray matter volumes at each MRI scan. Clinical disability was measured by Expanded Disability Status Scale. We performed the correlation analyses of WML shrinking with other MRI parameters and clinical outcome. Results White matter lesions shrinking was highly variable between patients and correlated with the initial number of gadolinium-enhancing WML and with WM volume decrease. WML shrinking was not associated with clinical outcome. Conclusion We found no indication of a prognostic value of WML shrinking in early MS patients. WML shrinking seems to be related to waning of acute inflammation
Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German national early MS cohort (KKNMS)
Ocrelizumab Treatment in Patients with Primary Progressive Multiple Sclerosis: Short-term Safety Results from a Compassionate Use Programme in Germany
Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis
Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German National early MS cohort (KKNMS)
BackgroundCognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors predicting CI and progression after initial diagnosis.MethodsNeuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes.ResultsAt baseline, 22% of patients had CI (impairment in 2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year.ConclusionsIdentification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction