Sporadic amyotrophic lateral sclerosis: Widespread multisystem degeneration with TDP‐43 pathology in a patient after long‐term survival on a respirator

Abstract

It has been reported that widespread multisystem degeneration can occur in patients with sporadic amyotrophic lateral sclerosis (SALS) who have survived for long periods with artificial respiratory support (ARS). We report a case of SALS of 8 years and 8 months duration in a 71-year-old woman, who received ARS for 7 years and 8 months. In this patient, the symptoms at the early stage were those of typical ALS, and a totally locked-in state with frontal lobe atrophy appeared a few years after the start of ARS. At autopsy, marked atrophy of the frontal lobe and brainstem tegmentum was evident. Microscopically, widespread multisystem degeneration with obvious neuronal loss was a feature. Bunina bodies and ubiquitinated inclusions were observed in the remaining lower motor neurons. Of interest was that Lewy body-like hyaline inclusions (LBHIs), which were later shown to be immunnoreactive (ir) for 43-kDa TAR DNA-binding protein (TDP-43) and ubiquitin, were also detected in neurons in various regions of the nervous system, including the lower and upper motor neuron nuclei. The distributions of neurons with TDP-43-ir and ubiquitin-ir cytoplasmic inclusions were also widespread in the nervous system, and in each region, the numbers of these neurons were apparently larger than those of neurons with LBHIs. Importantly, double-labeling immunofluorescence revealed that the widespread TDP-43-ir inclusions were often ubiqutinated. In conclusion, the entire pathological picture appeared to correspond well to the patient's long-standing, progressive disease, including the TDP-43 pathology with ubiquitination. These findings further strengthen the idea that TDP-43 abnormality is closely associated with the pathogenesis of SALS.

Familial ALS with FUS P525L mutation: two Japanese sisters with multiple systems involvement

“…However, their neuroanatomical lesions are various. Although all the patients in these previous studies [8,[17][18][19][20] showed severe degeneration of the globus pallidus, substantia nigra, and subthalamic nucleus, degeneration of the striatum and the brain atrophy were not present or were mild [8,[17][18][19], except in one patient [20]. This last patient showed the marked frontal lobe atrophy and the multiple system degeneration including the striatum that were also observed in patient 1.…”

“…4A) of patient 1 appeared similar to respirator-assisted long-survival ALS patients, who progressed into a totally locked-in state [8,[17][18][19][20]. However, their neuroanatomical lesions are various.…”

“…This last patient showed the marked frontal lobe atrophy and the multiple system degeneration including the striatum that were also observed in patient 1. However, the patient from the previous study had widespread TDP-43-ir NCI [20]. Therefore, it was suggested that the degeneration of the striatum was correlated with the frontal atrophy of either FUS or TDP-43 pathology.…”

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

“…27,28 The reduction of FA in the midpart of the CC and mainly in the cranial parts of the CSTs is probably a result of the prevalent axonal loss within the motor fiber pathway, as was also demonstrated by neuropathologic evidence. 29 Moreover, because the preferential loss of water diffusion in the fiber direction (decreased FA) was not accompanied by higher diffusion perpendicular to the CC fibers (measured by RD) in the body of CC, these effects seem to reflect a wallerian degeneration (atrophy) of the axons rather than a loss of myelin integrity.…”

“…29,33 If we take these results together, our data support the hypothesis of an active and at least partially independent bilateral cortical process of degeneration with secondary damage to the CC, particularly in its midbody, known to be significantly involved in the process of axonal degeneration in ALS 34 and substantially formed by interhemispheric fibers connecting the motor cortices, as also demonstrated by diffusion tensor tractography. 35 According to previous neuropathologic findings, 27,34,36 ALS degenerative changes in the cerebral cortex mainly involve motor areas, though recent whole-brain voxel-based morphometry analyses have largely reported GM abnormalities even in extramotor regions. 12,14,15,20,31,37 Thereby, the trends of MD and RD changes, which largely overlapped in our patients in both the genu and splenium of the CC, may represent an increase in the extracellular volume secondary to axonal loss associated with injury to the myelin sheaths, as previously reported in human and animal models of demyelination and axonal degeneration.…”