Clinicopathological characteristics of FTLD-TDP showing corticospinal tract degeneration but lacking lower motor neuron loss

Kobayashi, Zen; Tsuchiya, Kuniaki; Arai, Tetsuaki; Yokota, Osamu; Yoshida, Mari; Shimomura, Yoko; Kondo, Hiromi; Haga, Chie; Asaoka, Toshiyasu; Onaya, Mitsumoto; Ishizu, Hideki; Akiyama, Haruhiko; Mizusawa, Hidehiro

doi:10.1016/j.jns.2010.08.013

Cited by 32 publications

(32 citation statements)

References 30 publications

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“…The Type A is reported to be a common phenotype in behavioural variants of frontotemporal dementia and progressive non‐fluent aphasia, and in association with the presence of GRN (progranulin gene) mutations 28 . It is noteworthy that FTLD‐MND (including ALS‐D) 38 is usually subclassified as Type B 28 (Type 3, 34 Type 2 35 ), 39–43 in which the cortical TDP‐43 pathology is characterized by moderate NCIs and few DNs (/NTs) 28 . We also confirmed a classification of Type B in clinicopathologically proven cases of FTLD‐MND 44 .…”

Section: Discussionsupporting

confidence: 81%

“…We also confirmed a classification of Type B in clinicopathologically proven cases of FTLD‐MND 44 . Thus, the overall pTDP‐43 pathology was also distinguishable from that seen in typical ALS, 36,45 ALS of long duration, 46 ALS‐D or FTLD‐MND, 39–44 or MND clinically limited to the lower motor neuron system; 47 the clinicopathology of the present cases appears to add a new variant, “PLS: upper‐motor‐predominant ALS with FTLD‐TDP ( Type A ) 28 ”, to the single major TDP‐43 proteinopathy spectrum involving ALS and FTLD 48–50 …”

Section: Discussionmentioning

confidence: 59%

“…However, it is apparent that in their two cases, cognitive impairment was an initial and cardinal clinical feature; taking this clinical aspect into account, we consider that our case in question is not an example of FTLD‐PLS, but rather one of PLS‐FTLD. In a recent article dealing with FTLD‐TDP, in most cases designated FTLD‐PLS, the clinical diagnosis was a tauopathy, Pick's disease 42 …”

Section: Discussionmentioning

confidence: 99%

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Primary lateral sclerosis: Upper‐motor‐predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration – immunohistochemical and biochemical analyses of TDP‐43

Kosaka¹,

Fu²,

Shiga³

et al. 2011

Neuropathology

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Primary lateral sclerosis (PLS) is clinically defined as a disorder selectively affecting the upper motor neuron (UMN) system. However, recently it has also been considered that PLS is heterogeneous in its clinical presentation. To elucidate the association of PLS, or disorders mimicking PLS, with 43-kDa TAR DNA-binding protein (TDP-43) abnormality, we examined two adult patients with motor neuron disease, which clinically was limited almost entirely to the UMN system, and was followed by progressive frontotemporal atrophy. In the present study, the distribution and severity, and biochemical profile of phosphorylated TDP-43 (pTDP-43) in the brains and spinal cords were examined immunohistochemically and biochemically. Pathologically, in both cases, frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) was evident, with the most severe degeneration in the motor cortex. An important feature in both cases was the presence of Bunina bodies and/or ubiquitin inclusions, albeit very rarely, in the well preserved lower motor neurons. The amygdala and neostriatum were also affected. pTDP-43 immunohistochemistry revealed the presence of many positively stained neuronal cytoplamic inclusions (NCIs) and dystrophic neurites/neuropil threads in the affected frontotemporal cortex and subcortical gray matter. By contrast, such pTDP-43 lesions, including NCIs, were observed in only a few lower motor neurons. pTDP-43 immunoblotting revealed that fragments of ∼25-kDa were present in the cortices, but not in the spinal cord in both cases. Genetically, neither of the patients had any mutation in the TDP-43 gene. In conclusion, we consider that although PLS may be a clinically significant disease entity, at autopsy, the majority of such clinical cases would present as upper-motor-predominant amyotrophic lateral sclerosis with FTLD-TDP.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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Primary lateral sclerosis: Upper‐motor‐predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration – immunohistochemical and biochemical analyses of TDP‐43

Kosaka¹,

Fu²,

Shiga³

et al. 2011

Neuropathology

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“…Distinct pathological change is identified in the motor and extramotor areas of the brains as well as the spinal cords of patients whose disease was clinically limited to the LMN and these changes seem independent of progression rate (57). PLS neuropathology shows changes in the LMN and these changes are of the same molecular pattern as is seen in typical disease (58,59). …”

Section: Molecular Neuropathologysupporting

confidence: 52%

Deciphering amyotrophic lateral sclerosis: What phenotype, neuropathology and genetics are telling us about pathogenesis

Ravits¹,

Appel²,

Baloh³

et al. 2013

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

153

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Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS – and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease – a goal that seems increasingly achievable.

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“…There is overlap in TDP-43 pathology in ALS with that found in FTLD-TDP suggesting that they form a disease spectrum [18, 33]. While most patients with mutations in TARDBP present with ALS, there are some with FTD with or without motor neuron disease [21, 34].…”

Section: Introductionmentioning

confidence: 99%

Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72

et al. 2011

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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.

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Clinicopathological characteristics of FTLD-TDP showing corticospinal tract degeneration but lacking lower motor neuron loss

Cited by 32 publications

References 30 publications

Primary lateral sclerosis: Upper‐motor‐predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration – immunohistochemical and biochemical analyses of TDP‐43

Primary lateral sclerosis: Upper‐motor‐predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration – immunohistochemical and biochemical analyses of TDP‐43

Deciphering amyotrophic lateral sclerosis: What phenotype, neuropathology and genetics are telling us about pathogenesis

Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72

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