Clinical and Pathological Continuum of Multisystem TDP-43 Proteinopathies

Abstract

To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa ) pathology in the central nervous system of patients with clinically and autopsyconfirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.Design: Performance of immunohistochemical wholecentral nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.Setting: An academic medical center.Participants: We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment.Main Outcome Measure: Neuronal and glial TDP-43 pathology.Results: We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology. Conclusion:These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.

Widespread Microstructural White Matter Involvement in Amyotrophic Lateral Sclerosis: A Whole-Brain DTI Study

“…49 The correlations between the disease-progression rate and FA in WM bilaterally underneath the middle temporal gyrus and the left inferior frontal gyrus and between the diseaseprogression rate and RD and MD bilaterally within the hippocampus, the left insula, and the left inferior longitudinal and uncinate fasciculi might provide further structural evidence of the progressive development in ALS of a multisystem disorder. Furthermore, the highly distributed and widespread pattern of our results is in agreement with the recent findings that in ALS, the cerebral expression of a new neuropathologic marker of disease, the transactivating responsive sequence DNA-binding protein inclusions, involves the nigrostriatal system, the neocortical and allocortical areas, and the cerebellum, more often in case of ALS dementia than in ALS without cognitive dysfunction (eg, Geser et al 13 ).…”

“…8,9 Significant correlations of diffusion parameters with duration, progression, and severity of the disease also have been reported in some previous studies. 2,[9][10][11][12] Even if the clinical signs of ALS consist of motor impairments, recent evidence suggests that ALS is not an isolated motor neuron disorder 13 and that the variability in the location and extension of FA reduction in patients with ALS is such that relying on a priori ROIs to assess DTI changes may not give a consistent and complete picture of ALS neurodegeneration. Therefore, a novel approach based on whole-brain DTI analysis may result in improved accuracy in detecting subclinical microstructural disease-related WM changes.…”

Mesial Prefrontal Cortex Degeneration in Amyotrophic Lateral Sclerosis: A High-Field Proton MR Spectroscopy Study

“…The differences in NAA and mIns did not reach statistical significance; however, the trends were in the expected direction as decreased NAA and elevated mIns are consistent with the histologic features of neuronal loss and gliosis present in this region. 7,8,31 These trends are also similar to the pattern and magnitude of change reported in the motor cortex in ALS wherein NAA/mIns was reduced 22%, NAA/Cr was reduced 10%, and mIns/Cr was increased 18%. 19 The more pronounced abnormalities in the motor cortex would suggest a greater burden of pathology compared with the frontal lobe, consistent with the pattern of pathologic changes including the distribution of TDP-43 pathology.…”

“…5,6 Neuronal inclusions in FTLD associated with motor neuron disease are ubiquitinimmunoreactive and -and ␣-synuclein negative. Such inclusions are present in both cognitively intact and cognitively impaired patients; however, the changes are more widespread in cognitively impaired patients, 7 with the greatest abnormalities in the cingulate gyrus 5 where there is also neuronal loss. 8 TDP-43 is present within ubiquinated inclusions in cases of FTLD without motor neuron disease as well as in sporadic ALS with or without cognitive impairment.…”

Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials

“…In the concept of a "continuum" of TDP-43 proteinopathies (Geser et al, 2009), ALS is classified together with fronto-temporal dementia (Giordana et al, 2011;Lillo & Hodges, 2009;Nakano, 2000;Woolley & Jonathan, 2008;Yoshida, 2004;Zago et al, 2011). This has also been shown on the morphological level (Tsujimoto et al, 2011).…”