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

Abstract

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

Degeneration of the Mid-Cingulate Cortex in Amyotrophic Lateral Sclerosis Detected In Vivo with MR Spectroscopy

“…The spatial distribution of TDP-43 was reported to include the anterior cingulate and the thalamus in 1 study. 41 The widespread finding of TDP-43 outside the pyramidal motor system substantiates the neuroimaging abnormalities found in these regions and the behavioral and cognitive impairments present in some patients with ALS.…”

Frontotemporal Cortical Thinning in Amyotrophic Lateral Sclerosis

“…[6][7][8][9][10] In vivo, independent of the structural neuroimaging approach used (VBM or SBM), the most commonly affected extramotor cortical areas were identified in the frontal and temporal lobes. [11][12][13][14][15][16][17][18][19][20][26][27][28] However, significant correlations between cortical involvement and disease progression 18,26,27 or cognitive impairment 2,14,15,20,28 were reported only in a few studies.…”

“…5,7 From the histochemical and genetic points of view, recent findings suggest that ALS may belong to a broader clinicopathologic spectrum, known as transactivating responsive sequence DNAbinding protein 43-kDa (TDP-43) proteinopathy, which also includes FTD. [8][9][10] Structural and functional MR imaging studies have corroborated the theory of a relevant frontotemporal impairment in ALS with approximately half of the patients displaying at least mild abnormalities. [11][12][13][14][15][16][17][18][19][20] The development of advanced automated imaging analysis techniques, on the basis of construction of statistical parametric maps, has allowed detailed anatomic studies of brain morphometry.…”

Sympathetic Hyperactivity and Sympathovagal Imbalance in Amyotrophic Lateral Sclerosis

“…Source: reproduced with permission from Benarroch, 1993. 46 sporadic ALS revealed a wide distribution of the protein aggregates in the central nervous system, 48 including the limbic system, also called the 'central autonomic network' (see Figure 2). 46 In addition, the limbic motor and bulbo-respiratory motor systems are anatomically and physiologically linked to each other.…”