PMC9399610_01
Brain diffusion-weighted magnetic resonance imaging in the present case (at the age of 76 years) (A,B) and in another NIID patient at our institution with typical imaging findings of corticomedullary junction (C). No high-intensity signal is seen in the corticomedullary junctions (A) or cerebellar hemisphere (B).
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F1
Brain DWI at the age of 76 years showed no abnormalities in the cortical medullary junctions and cerebellar paravermis (Figures 1A,B) as seen in another NIID patient at our institution with typical imaging findings of corticomedullary junction (Figures 1A-C).
Pathological findings of the present case. The motor cortex shows slight loss of neurons (A). Thoracic spinal cord shows myelin pallor of the lateral corticospinal tract bilaterally, more apparent on the right side (R), reflecting the left thalamic hemorrhage (B). Hematoxylin and eosin staining reveals an eosinophilic, round, neuronal intranuclear inclusion in the hippocampus (C) and anterior horn of the lumbar cord (D). Immunohistochemical evaluations reveal ubiquitin- and p62-immunopositive neuronal intranuclear inclusions in the hippocampus (E), motor cortex (F) and spinal anterior horn (G). In addition, uN2CpolyG immunoreactivity is confirmed by two specific antibodies (4C4 and 4D12) (H, I). p62-positive neuronal intranuclear inclusions are evident in the cardiac muscle cells (J), Auerbach's plexus of the stomach (K), and renal tubule epithelial cells (L). Kluver-Barrera staining (A, B); p62 (E, J-L); ubiquitin (F, G); uN2CpolyG (4C4) (H); uN2CpolyG (4D12) (I). Bars = 100 mum (A), 2 mm (B), and 10 mum (C-L).
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Histopathological evaluations revealed slight loss of neurons in the motor cortex (Figure 2A). The lateral corticospinal tracts degenerated bilaterally; however, the degeneration was more apparent on the right side (Figure 2B), reflecting left thalamic hemorrhage. While these inclusions were particularly frequent in the hippocampus, they were also noted in the motor cortex, facial and hypoglossal nuclei, and anterior horn of the spinal cord, being immunopositive for ubiquitin, p62, and uN2CpolyG (4C4 and 4D12) (Figures 2C-I). In addition, we examined the visceral organs, confirming p62-positive inclusions in the cardiac muscle cells, Auerbach's plexus of the stomach, and epithelial cells in the renal tubules (Figures 2J-L).
Double immunofluorescence analysis using the lumber spinal cord (L5). A p62 immunopositive-intranuclear inclusion (A) present with native TDP-43 (nTDP-43) (B) in the nucleus of anterior horn motor neuron. p62 (A); nTDP-43 (B); 4',6-diamidino-2-phenylindole (DAPI) (C); merged image (D). Bars = 10 mum.
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F3
We further demonstrated that native TDP-43 was present in neuronal nuclei with p62-positive intranuclear inclusions, indicating that NIID pathology and TDP-43 pathology are independent (Figures 3A-D).