Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal α-motoneurons in sporadic amyotrophic lateral sclerosis

Braak, Heiko; Ludolph, Albert C.; Neumann, Manuela; Ravits, John; Tredici, Kelly Del

doi:10.1007/s00401-016-1633-2

Cited by 71 publications

(79 citation statements)

References 73 publications

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“…This situation provides support for the idea that the driving force behind the origins and relentless progression of the TDP-43 pathology may reside in the cerebral cortex itself (beginning in the neocortical motor fields) mediated via corticofugal axons and the anterograde transport of soluble TDP-43 that is neurotoxic (▶Fig. 1, 2) [19,[30][31][32]. The damage inflicted on selected nerve cells of the cerebral cortex would be, for all intents and purposes, the source that necessarily leads to the subsequent pathological changes in regions of the lower brainstem and spinal cord innervated monosynaptically by these cortical neurons.…”

Section: Corticofugal Projections Control Susceptible Neuronsmentioning

confidence: 64%

“…However, many of the involved Betz cells also fail to display any TDP-43-positive cytoplasmic inclusions (▶ Fig. 2) [32]. Only closer scrutiny of a larger number of these cells reveals the presence of a few that contain very subtle cytoplasmic aggregates.…”

Section: The Pathology In Cortical Betz Cells Differs From That In Bumentioning

confidence: 99%

“…The assumption that cortical neurons (Betz cells) are the first to become involved followed by the α-motor neurons, tends to favor Charcot's theory [35], namely, that ALS originates in the lateral funiculus (i. e., corticospinal tract, where the axons of the Betz cells are located) and only then affects the α-motor neurons in the anterior horn of the spinal cord [36]. The sources of the very first malfunctions within the protein TDP-43 in Betz cells are incompletely understood; but, it is conceivable that the further spread of the pathology to interconnected neurons takes place by means of the phylogenetically 'new' or recent monosynaptic contacts [9,29,32,[37][38][39][40][41]. Whether the same holds true not only for corticobulbar and corticospinal projections but also for corticorubral and corticostriatal connectivities is currently an open question.…”

Section: The Pathology In Cortical Betz Cells Differs From That In Bumentioning

confidence: 99%

“…In the human nervous system, this development reaches a provisional acme [15,16,29,32,34]. The assumption that cortical neurons (Betz cells) are the first to become involved followed by the α-motor neurons, tends to favor Charcot's theory [35], namely, that ALS originates in the lateral funiculus (i. e., corticospinal tract, where the axons of the Betz cells are located) and only then affects the α-motor neurons in the anterior horn of the spinal cord [36].…”

Section: The Pathology In Cortical Betz Cells Differs From That In Bumentioning

confidence: 99%

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Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Braak

Neumann

Ludolph

et al. 2017

Neurology International Open

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IntroductionAmyotrophic lateral sclerosis (ALS) is characterized by rapid progressive paralysis of the striated skeletal musculature [1,2]. The present review focuses on sporadic disease (sALS), which constitutes the majority of cases without a known genetic mutation. Clinically similar but inherited (familial) forms that display very diverse pathologies [3][4][5][6][7] are not taken into account here.The pathological process underlying sALS entails abnormal changes of an endogenous and predominantly intranuclear protein, TDP-43 (transactive response DNA-binding protein 43). Following nuclear clearance, the protein remains delocalized in the cytoplasm of susceptible nerve cells, where it undergoes defective phosphorylation and conformational change followed by ubiquitination, which ultimately prevent its re-entry into the nuclear compartment [7][8][9][10][11].The pathomechanisms that lead to the dysfunction and death of involved cells are still unknown. Along with a "loss of function" attributable to the loss of intranuclear TDP-43 expression accompanied by disrupted RNA metabolism, a "gain of function" mechanism owing to a noxious effect on cells by toxic TDP-43 forms has been discussed [7,12] Which Nerve Cell Types Develop TDP-43-immunoreactive Inclusions in sALS?The abnormal nuclear clearance and development of cytoplasmic TDP-43-immunopositive inclusions are confined to a few types ABsTr AC TThe pathological process underlying sporadic amyotrophic lateral sclerosis (sALS) that is associated with the formation of cytoplasmic inclusions of a nuclear protein (TDP-43) is confined to only a few types of long-axoned projection neurons. The giant Betz pyramidal cells of the primary motor neocortex as well as large α-motor neurons of the lower brainstem and spinal cord become involved early. In the human brain, these 2 neuronal types are to a large extent interconnected by monosynaptic axonal projections. The cell nuclei of affected neurons gradually forfeit their normal expression of the protein TDP-43. In α-motor neurons, this nuclear loss is followed by the formation of insoluble TDP-43-immunopositive inclusions in the cytoplasm, whereas in Betz cells the loss of nuclear expression remains for an unknown period of time unaccompanied by somatodendritic and/or axoplasmic aggregations. It is possible that in cortical pyramidal cells (Betz cells) the nuclear clearing initially leads to the formation of an abnormal but still soluble cytoplasmic TDP-43 which may enter the axoplasm and, following transmission via direct synaptic contacts, induces anew TDP-43 dysregulation and aggregation in recipient neurons. The trajectory of the spreading pattern that consecutively develops during the course of sALS is consistent with the dissemination from chiefly cortical projection neurons via axonal transport through direct synaptic contacts leading to the secondary induction of TDP-43-containing inclusions within recipient nerve cells in involved subcortical regions. E136Braak H et al. Does Sporadic Amyotrophic Lateral … Neurolo...

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Section: Corticofugal Projections Control Susceptible Neuronsmentioning

confidence: 64%

Section: The Pathology In Cortical Betz Cells Differs From That In Bumentioning

confidence: 99%

Section: The Pathology In Cortical Betz Cells Differs From That In Bumentioning

confidence: 99%

Section: The Pathology In Cortical Betz Cells Differs From That In Bumentioning

confidence: 99%

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Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Braak

Neumann

Ludolph

et al. 2017

Neurology International Open

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“…Pathologically altered TDP-43 in Betz cells reacts differently from bulbar and spinal motoneurons 61. In motoneurons, there is formation of phosphorylated TDP-43 aggregates within the cytoplasm, whereas in Betz cells, the loss of normal nuclear TDP-43 expression remains mostly unaccompanied by the development of cytoplasmic aggregations.…”

Section: Introductionmentioning

confidence: 94%

Kinnier Wilson’s puzzling features of amyotrophic lateral sclerosis

Turner

Eisen

Kiernan

et al. 2017

J Neurol Neurosurg Psychiatry

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Multimodal in vivo staging in amyotrophic lateral sclerosis using artificial intelligence

Behler

Müller

Tredici

et al. 2022

Ann Clin Transl Neurol

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Background The underlying neuropathological process of amyotrophic lateral sclerosis (ALS) can be classified in a four‐stage sequential pTDP‐43 cerebral propagation scheme. Using diffusion tensor imaging (DTI), in vivo imaging of these stages has already been shown to be feasible for the specific corticoefferent tract systems. Because both cognitive and oculomotor dysfunctions are associated with microstructural changes at the brain level in ALS, a cognitive and an oculomotor staging classification were developed, respectively. The association of these different in vivo staging schemes has not been attempted to date. Methods A total of 245 patients with ALS underwent DTI, video‐oculography, and cognitive testing using Edinburgh Cognitive and Behavioral ALS Screen (ECAS). A set of tract‐related diffusion metrics, cognitive, and oculomotor parameters was selected for further analysis. Hierarchical and k‐means clustering algorithms were used to obtain an optimal cluster solution. Results According to cluster analysis, differentiation of patients with ALS into four clusters resulted: Cluster A showed the highest fractional anisotropy (FA) values and thereby the best performances in executive oculomotor tasks and cognitive tests, whereas cluster D showed the lowest FA values, the lowest ECAS scores, and the worst executive oculomotor performance across all clusters. Clusters B and C showed intermediate results regarding parameter values. Discussion In a multimodal dataset of technical assessments of brain structure and function in ALS, an artificial intelligence‐based cluster analysis showed high congruence of DTI, executive oculomotor function, and neuropsychological performance for mapping in vivo correlates of neuropathological spreading.

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Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal α-motoneurons in sporadic amyotrophic lateral sclerosis

Cited by 71 publications

References 73 publications

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Kinnier Wilson’s puzzling features of amyotrophic lateral sclerosis

Multimodal in vivo staging in amyotrophic lateral sclerosis using artificial intelligence

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