Huntington's Disease (HD): Degeneration of Select Nuclei, Widespread Occurrence of Neuronal Nuclear and Axonal Inclusions in the Brainstem

Abstract

Huntington’s disease (HD) is a progressive polyglutamine disease that leads to a severe striatal and layer-specific neuronal loss in the cerebral neo-and allocortex. Since some of the clinical symptoms (e.g. oculomotor dysfunctions) suggested a degeneration of select brainstem nuclei we performed a systematic investigation of the brainstem of eight clinically diagnosed and genetically confirmed HD patients. This postmortem investigation revealed a consistent neuronal loss in the substantia nigra, pontine nuclei, reticulotegmental nucleus of the pons, superior and inferior olives, in the area of the excitatory burst neurons for horizontal saccades, raphe interpositus nucleus, and vestibular nuclei. Immunoreactive intranuclear neuronal inclusions were present in all degenerated and apparently spared brainstem nuclei, and immunoreactive axonal inclusions were observed in all brainstem fiber tracts of the HD patients. Degeneration of brainstem nuclei can account for a number of less well understood clinical HD symptoms (i.e. cerebellar, oculomotor and vestibular symptoms), while the formation of axonal aggregates may represent a crucial event in the cascades of pathological events leading to neurodegeneration in HD.

The Neuropathology of Huntington’s Disease: Classical Findings, Recent Developments and Correlation to Functional Neuroanatomy

“…9.2 ,9.3 ,9.4 ,and 9.5 ) (Goedert et al 1994 ;Rüb et al 2014a ;Shaw et al 1981 ). The AT270 antibody, directed against the neuronal cytoskeletal protein tau, was used as axonal marker, and the anti-p62 antibody served as marker for axonal protein aggregates (Figs.…”

“…The involvement of the brainstem is still not among the established degenerative features of HD Koeppen 1989 ;Lange and Aulich 1986 ;Oyanagi et al 1989 ;Rüb et al 2014a ;Vonsattel and DiFiglia 1998 ;Vonsattel et al 1985 ).…”

“…6.2 , 6.5 , and 6.6 ). 1 ) Bollen et al 1986 ;Koeppen 1989 ;Kremer et al 1992 ;Lange and Aulich 1986 ;Lange et al 1976 ;Lasker and Zee 1997 ;Leigh et al 1983Leigh et al , 1985Oyanagi et al 1989 ;Rüb et al 2009Rüb et al , 2014aVonsattel 2008 ;Vonsattel and DiFiglia 1998 ;Vonsattel et al 1985 ;Walker 2007a , b ). 1.4 ,7.1 ,7.2 ,and 7.3 ) have not been revisited or taken into account by current researchers (see Chap.…”

“…1 ) Bollen et al 1986 ;Koeppen 1989 ;Kremer et al 1992 ;Lange and Aulich 1986 ;Lange et al 1976 ;Lasker and Zee 1997 ;Leigh et al 1983Leigh et al , 1985Oyanagi et al 1989 ;Rüb et al 2009Rüb et al , 2014aVonsattel 2008 ;Vonsattel and DiFiglia 1998 ;Vonsattel et al 1985 ;Walker 2007a , b ). 8.3 ,8.4 ,and 8.5 ) (Kuusisto et al 2001(Kuusisto et al , 2008Ortega et al 2007 ;Rüb et al 2014a ;Seibenhener et al 2004 ;Seidel et al 2009Seidel et al , 2010Wooten et al 2006 ). The pathoanatomical approach with unconventional thick serial brain tissue sections complements the routine neuropathological examination of single thin brain tissue sections and allows the recognition of subtle pathological changes and reveals more detailed information with respect to the extent and severity of the pathological processes of neurodegenerative diseases than the routine neuropathological approach (Figs.…”

“…5.7 ) (Busse et al 2009 ;Dom et al 1976 ;Grimbergen et al 2008 ;Rüb et al 2004aRüb et al , 2008bRüb et al , 2009Rüb et al , 2013aRüb et al , 2014a. Therefore, the involvement of these vestibular nuclei together with that of the cerebellum and the interconnected ventrolateral thalamic nucleus suffi ciently explains why HD patients also may suffer from gait and truncal and postural instability and show a tendency to fall (Fig.…”