Abstract
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0335-2) contains supplementary material, which is available to authorized users.
Highlights
Amyotrophic lateral sclerosis (ALS), an adult-onset, fatal neurodegenerative disorder, is the most common type of motor neuron disease (MND)
One of the above studies demonstrated that 7 of 10 cases that were sporadic and exhibited MND in addition to dementia had cortical ubiquitin pathology characterized by a mixture of numerous neuronal cytoplasmic inclusion (NCI) and frequent small dystrophic neurite (DN) [22], corresponding to Type A of the new classification system mentioned above [23]; this finding suggested that the cortical ubiquitin pathology in ALS-D and/or Frontotemporal lobar degeneration (FTLD)-MND could be heterogeneous
Using a phosphorylation-independent anti-TDP-43 antibody, we have previously demonstrated that immunopositive NCIs and glial cytoplasmic inclusions (GCIs) can occur in many brain regions in ALS, and that cases can be classified into two types – type 1 and type 2–based on the distribution pattern of NCIs in the CNS and hierarchical cluster analysis of the pattern [17]
Summary
Amyotrophic lateral sclerosis (ALS), an adult-onset, fatal neurodegenerative disorder, is the most common type of motor neuron disease (MND). After confirmation that the majority of FTLD-U cases represent FTLD-TDP, these two classification systems were integrated into a ‘harmonized classification system’ that included four types (Types A, B, C and D) of FTLD-TDP pathology [23], the new Type D being associated with mutations of the VCP (valosin-containing protein) gene [24, 25] In this new classification system, MND with FTD (so-called ALS-D) was regarded as a common phenotype of Type B, being characterized by moderate numbers of NCIs and very few DNs throughout all cortical layers. One of the above studies demonstrated that 7 of 10 cases that were sporadic and exhibited MND in addition to dementia had cortical ubiquitin pathology characterized by a mixture of numerous NCIs and frequent small DNs [22], corresponding to Type A of the new classification system mentioned above [23]; this finding suggested that the cortical ubiquitin pathology in ALS-D and/or FTLD-MND could be heterogeneous
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