Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants

Saberi, Shahram; Stauffer, Jennifer E.; Schulte, Derek; Ravits, John

doi:10.1016/j.ncl.2015.07.012

Cited by 221 publications

(197 citation statements)

References 147 publications

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“…The pathology of sporadic amyotrophic lateral sclerosis (sALS) is associated with the dysregulation of the 43-kDa transactive response DNA-binding protein (TDP-43) [3, 4, 37, 49, 54, 66] that leads to the formation of proteinaceous cytoplasmic aggregates in specific cortical and subcortical projection neurons with long axons, whereas cells with short axons are spared [27, 60]. The Betz giant pyramidal cells in layer Vb of the primary neocortical motor cortex [14] and the α -motoneurons of the lower brainstem and spinal cord belong to the cell types that develop TDP-43 pathology early in the disease process [13].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the factors initiating the dysregulation of intranuclear TDP-43 are not known. Use of antibodies directed against the native protein shows that in neuronal types susceptible to sALS a reduction or absence of normal nuclear TDP-43 immunoreactivity is associated with TDP-43 mislocalization and inclusion body formation [28, 54, 66]. During its cytoplasmic phase, the protein becomes abnormally phosphorylated (pTDP-43) and possibly undergoes a conformational change [34, 41, 55, 69].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2016

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Two nerve cells types, Betz cells in layer Vb of the primary motor neocortex and α-motoneurons of the lower brainstem and spinal cord, become involved at the beginning of the pathological cascade underlying sporadic amyotrophic lateral sclerosis (sALS). In both neuronal types, the cell nuclei forfeit their normal (non-phosphorylated) expression of the 43-kDa transactive response DNA-binding protein (TDP-43). Here, we present initial evidence that in α-motoneurons the loss of normal nuclear TDP-43 expression is followed by the formation of phosphorylated TDP-43 aggregates (pTDP-43) within the cytoplasm, whereas in Betz cells, by contrast, the loss of normal nuclear TDP-43 expression remains mostly unaccompanied by the development of cytoplasmic aggregations. We discuss some implications of this phenomenon of nuclear clearing in the absence of cytoplasmic inclusions, namely, abnormal but soluble (and, thus, probably toxic) cytoplasmic TDP-43 could enter the axoplasm of Betz cells, and following its transmission to the corresponding α-motoneurons in the lower brainstem and spinal cord, possibly contribute in recipient neurons to the dysregulation of the normal nuclear protein. Because the cellular mechanisms that possibly inhibit the aggregation of TDP-43 in the cytoplasm of involved Betz cells are unknown, insight into such mechanisms could disclose a pathway by which the development of aggregates in this cell population could be accelerated, thereby opening an avenue for a causally based therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…8,9 On a pathological level, it is well established that TDP-43 is the main pathology found in most of ALS cases. [10][11][12][13] Interestingly, TDP-43 is also one of the main pathologies (~50%) of FTD, in particular in SD as it accounts for 75% of the cases. 14 Although there are different subtypes of TDP-43 depositions, the presence of a shared proteinopathy reinforces the idea of a continuum across ALS and FTD.…”

Section: Introductionmentioning

confidence: 99%

How predictive are temporal lobe changes of underlying TDP-43 pathology in the ALS-FTD continuum?

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et al. 2017

Ann Clin Neurophysiol

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Detection of underling proteinopathies is becoming increasingly important across neurodegenerative conditions due to upcoming disease intervention trials. In this review, we explored how temporal lobe changes in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) can potentially predict underlying TDP-43 pathology subtypes in FTD. To date, emphasis has been given to frontal lobe changes in the study of the cognitive and behavioural impairments in both syndromes but an increasing number of pathological, imaging and neuropsychological studies suggest how temporal lobe changes could critically affect the cognition and behaviour of these conditions. In this current article, we reviewed pathological, imaging as well as clinical/neuropsychological findings of temporal involvement in the ALS-FTD continuum, how they relate to temporal lobe changes and the underlying TDP-43 pathology in FTD. Findings across studies show that TDP-43 pathology occurs and coincides in many structures in ALS and FTD, but especially in the temporal lobes. In particular, anterior and medial temporal lobes atrophy is consistently found in ALS and FTD. In addition, memory and language impairment as well as emotional and Theory of Mind processing deficits that are characteristics of the two diseases are highly correlated to temporal lobe dysfunction. We conclude by showing that temporal lobe changes due to TDP-43 type B might be particular predictive of TDP-43 type B pathology in behavioural variant FTD, which clearly needs to be investigated further in the future.

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“…These are considered to be the pathological hallmark of ALS (Okamoto, Mizuno et al 2008), along with the accumulation of insoluble protein aggregates (Peters, Ghasemi et al , Leigh, Anderton et al 1988, Okamoto, Mizuno et al 2008. The pathological protein aggregations vary among patients and can be categorized into TAR DNA-binding protein (Tdp-43) pathology, Tdp-with C9orf72 pathology, FUS pathology, and superoxide dismutase gene (SOD1) pathology (Saberi, Stauffer et al 2015).…”

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confidence: 99%

Measuring the progression of upper motor neuron disease using diffusion MRI and its correlation with Clinical phenotype

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Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants

Cited by 221 publications

References 147 publications

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

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

How predictive are temporal lobe changes of underlying TDP-43 pathology in the ALS-FTD continuum?

Measuring the progression of upper motor neuron disease using diffusion MRI and its correlation with Clinical phenotype

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