Motor neuron disease with dementia combined with degeneration of striatonigral and pallidoluysian systems

Background: Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described. Objective:To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS.Design: Performance of an immunohistochemical wholecentral nervous system scan for evidence of pathological TDP-43 in ALS patients.Setting: An academic medical center. Participants:We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants. Main Outcome Measures:Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology.Results: In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls.Conclusions: These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy. Neurol. 2008;65(5):636-641 Arch

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Evidence of Multisystem Disorder in Whole-Brain Map of Pathological TDP-43 in Amyotrophic Lateral Sclerosis

Geser¹,

Brandmeir²,

Kwong³

et al. 2008

Arch Neurol

260

223

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Amyotrophic Lateral Sclerosis with Pallidonigroluysian Degeneration: A Clinicopathological Study

Itô

Shimizu

Ohta

et al. 2019

Annals of Neurology

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ObjectiveThe pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype.MethodsFrom a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA‐binding protein (TDP‐43) inclusions, we selected those with PNLD and analyzed their clinicopathological features.ResultsEleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP‐43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneiderʼs staging or Nishihiraʼs typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP‐43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP‐43 aggregates from the cerebral cortex to the substantia nigra.InterpretationThe PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP‐43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302–312

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Parkinsonism and motor neuron diseases: Twenty‐seven patients with diverse overlap syndromes

et al. 2010

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It has long been recognized that signs of motor neuron disease (MND) may accompany clinical evidence of parkinsonism in different neurodegenerative conditions. By using the Columbia University Division of Movement Disorders database, we reviewed data from 5,500 cases of parkinsonism and recorded the presence of upper motor neuron (UMN) dysfunction, lower motor neuron (LMN) dysfunction, or both. Among the 27 patients so identified, we counted those with autonomic dysfunction, cerebellar dysfunction, or dementia. Among the 27 cases, seven had UMN signs and LMN signs as well as parkinsonism and were diagnosed with amyotrophic lateral sclerosis (ALS)-parkinsonism (Brait-Fahn disease). Three of the seven had dementia that was not deemed to be frontotemporal dementia (FTD). Six other patients had no LMN signs but had UMN signs and parkinsonism and were classified as having primary lateral sclerosis (PLS)-parkinsonism. Four patients had both UMN and LMN signs with parkinsonism as well as the characteristic dementia of FTD; they were diagnosed with FTD-parkinsonism-ALS. Seven patients had MND, parkinsonism, and autonomic or cerebellar dysfunction, a combination compatible with multiple system atrophy (MSA). Three patients had syndromes compatible with hereditary spastic paraplegia (HSP). In sum, we found that MND occurs in association with diverse parkinsonian syndromes; some are heritable, others sporadic and causes are uncertain. Having MND may be a risk factor for parkinsonism. A prospective study may elucidate this possibility.

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Motor neuron disease with dementia combined with degeneration of striatonigral and pallidoluysian systems

Cited by 21 publications

References 25 publications

Evidence of Multisystem Disorder in Whole-Brain Map of Pathological TDP-43 in Amyotrophic Lateral Sclerosis

Evidence of Multisystem Disorder in Whole-Brain Map of Pathological TDP-43 in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis with Pallidonigroluysian Degeneration: A Clinicopathological Study

Parkinsonism and motor neuron diseases: Twenty‐seven patients with diverse overlap syndromes

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