Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP43 proteinopathy

Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer's Disease Core Center, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA.
Acta Neuropathologica (Impact Factor: 10.76). 04/2011; 121(4):509-517. DOI: 10.1007/s00401-011-0797-z


Motor neuron disease (MND) may present as an isolated lower motor neuron (LMN) disorder. Although the significance of pathological
43 kDa transactive responsive sequence DNA binding protein (TDP-43) for amyotrophic lateral sclerosis (ALS) was appreciated
only recently, the topographical distribution of TDP-43 pathology in MND clinically isolated to the LMN versus normal controls
(COs) is only incompletely described. Therefore, we performed longitudinal clinical evaluation and retrospective chart review
of autopsied patients diagnosed with isolated LMN disease. Cases with a disease duration over 4 years were designated as progressive
muscular atrophy (PMA), and those with a more rapid course as MND/LMN. Immunohistochemistry was employed to identify neuronal
and glial TDP-43 pathology in the central nervous system (CNS) in patients and COs. We examined 19 subjects including six
patients (i.e., four with MND/LMN and two with PMA) and 13 COs. All patients showed significant TDP-43 linked degeneration
of LMNs, and five cases showed a lesser degree of motor cortex degeneration. Additional brain areas were affected in varying
degrees, ranging from predominantly brainstem pathology to significant involvement of the whole CNS including neocortical
and limbic areas. Pathological TDP-43 was present only rarely in the CO group. We conclude that MND limited to the LMN and
PMA is part of a disease continuum that includes ALS and FTLD-TDP, all of which are characterized by widespread TDP-43 pathology.
Hence, we suggest that the next revision of the El Escorial criteria for the diagnosis of ALS include MND patients with disease
clinically limited to the LMN and PMA as variants of ALS, which like classical ALS, are TDP-43 proteinopathies.

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    • "Abnormalities of cortical excitability, including an increase in MEP amplitude along with reduction of SICI and RMTs, have been reported in the flail-arm variant of ALS, underscoring the utility of TMS in detecting subclinical UMN dysfunction.42 Of further relevance, subclinical UMN dysfunction has been reported in progressive muscular atrophy (PMA),101–103 suggesting that PMA may be a phenotype of ALS. While corticomotoneuronal integrity was recently reported to be intact in PMA using a β-band intermuscular coherence technique,104 assessment of cortical function with TMS techniques may be of diagnostic utility, especially in light of presence of subclinical UMN pathology in PMA.102 103 "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS.
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    No preview · Article · Aug 2011 · Journal of Neuropathology and Experimental Neurology
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    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.
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