On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia.

Hdl Handle:
http://hdl.handle.net/10147/230512
Title:
On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia.
Authors:
Geser, F; Prvulovic, D; O'Dwyer, L; Hardiman, O; Bede, P; Bokde, A L W; Trojanowski, J Q; Hampel, H
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe-University, Frankfurt am Main, Germany. felix.geser@alumni.i-med.ac.at
Citation:
On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia. 2011, 95 (4):649-62 Prog. Neurobiol.
Journal:
Progress in neurobiology
Issue Date:
Dec-2011
URI:
http://hdl.handle.net/10147/230512
DOI:
10.1016/j.pneurobio.2011.08.011
PubMed ID:
21911035
Abstract:
Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) has been recognized as the major disease protein in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive, tau and α-synuclein negative inclusions (FTLD-U) and the transitional forms between these multisystem conditions. In order to develop TDP-43 into a successful ALS biomarker, the natural history of TDP-43 pathology needs to be characterized and the underlying pathophysiology established. Here we propose a spatial and temporal "two-axes" model of central nervous system vulnerability for TDP-43 linked degeneration and review recent studies on potential biomarkers related to pathological TDP-43 in the cerebrospinal fluid (CSF), blood, and skeletal muscle. The model includes the following two arms: Firstly, a "motor neuron disease" or "spinal cord/brainstem to motor cortex" axis (with degeneration possibly ascending from the lower motor neurons to the upper motor neurons); and secondly, a "dementia" or "corticoid/allocortex to neocortex" axis (with a probable spread of TDP-43 linked degeneration from the mediotemporal lobe to wider mesocortical and neocortical brain areas). At the cellular level, there is a gradual disappearance of normal TDP-43 in the nucleus in combination with the formation of pathological aggregates in the cell body and cellular processes, which can also be used to identify the stage of the disease process. Moreover, TDP-43 lesions in subpial/subependymal or perivascular localizations have been noted, and this might account for increased CSF and blood TDP-43 levels through mechanisms that remain to be elucidated.
Item Type:
Article
Language:
en
MeSH:
Amyotrophic Lateral Sclerosis; DNA-Binding Proteins; Dementia; Humans; Models, Biological; Muscle, Skeletal
ISSN:
1873-5118

Full metadata record

DC FieldValue Language
dc.contributor.authorGeser, Fen_GB
dc.contributor.authorPrvulovic, Den_GB
dc.contributor.authorO'Dwyer, Len_GB
dc.contributor.authorHardiman, Oen_GB
dc.contributor.authorBede, Pen_GB
dc.contributor.authorBokde, A L Wen_GB
dc.contributor.authorTrojanowski, J Qen_GB
dc.contributor.authorHampel, Hen_GB
dc.date.accessioned2012-06-25T12:30:00Z-
dc.date.available2012-06-25T12:30:00Z-
dc.date.issued2011-12-
dc.identifier.citationOn the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia. 2011, 95 (4):649-62 Prog. Neurobiol.en_GB
dc.identifier.issn1873-5118-
dc.identifier.pmid21911035-
dc.identifier.doi10.1016/j.pneurobio.2011.08.011-
dc.identifier.urihttp://hdl.handle.net/10147/230512-
dc.description.abstractPathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) has been recognized as the major disease protein in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive, tau and α-synuclein negative inclusions (FTLD-U) and the transitional forms between these multisystem conditions. In order to develop TDP-43 into a successful ALS biomarker, the natural history of TDP-43 pathology needs to be characterized and the underlying pathophysiology established. Here we propose a spatial and temporal "two-axes" model of central nervous system vulnerability for TDP-43 linked degeneration and review recent studies on potential biomarkers related to pathological TDP-43 in the cerebrospinal fluid (CSF), blood, and skeletal muscle. The model includes the following two arms: Firstly, a "motor neuron disease" or "spinal cord/brainstem to motor cortex" axis (with degeneration possibly ascending from the lower motor neurons to the upper motor neurons); and secondly, a "dementia" or "corticoid/allocortex to neocortex" axis (with a probable spread of TDP-43 linked degeneration from the mediotemporal lobe to wider mesocortical and neocortical brain areas). At the cellular level, there is a gradual disappearance of normal TDP-43 in the nucleus in combination with the formation of pathological aggregates in the cell body and cellular processes, which can also be used to identify the stage of the disease process. Moreover, TDP-43 lesions in subpial/subependymal or perivascular localizations have been noted, and this might account for increased CSF and blood TDP-43 levels through mechanisms that remain to be elucidated.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Progress in neurobiologyen_GB
dc.subject.meshAmyotrophic Lateral Sclerosis-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshDementia-
dc.subject.meshHumans-
dc.subject.meshModels, Biological-
dc.subject.meshMuscle, Skeletal-
dc.titleOn the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia.en_GB
dc.typeArticleen
dc.contributor.departmentDepartment of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe-University, Frankfurt am Main, Germany. felix.geser@alumni.i-med.ac.aten_GB
dc.identifier.journalProgress in neurobiologyen_GB
dc.description.provinceLeinsteren

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