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

Rüb, Udo, Vonsattel, Jean Paul G, Heinsen, Helmut, Korf, Horst-Werner, Udo Rüb, Jean Paul G. Vonsattel, Helmut Heinsen, Horst-Werner Korf

The deleterious action of the unstable CAG repeat expansion in the Huntington's disease (HD) gene (also called IT15) located on the short arm of chromosome 4 involves widespread areas of the brain including sites of increased vulnerability or sites that are relatively resistant, but not spared (Andrew et al. 1993; Duyao et al. 1993; Myers et al. 1991; The Huntington's disease Collaborative Research Group 1993). Therefore, the intensity of the degenerative process of HD is topographically variable. The neuropathological phenotype of adult HD can be almost cryptic or outstanding within the same nucleus, but at different sites. Indeed, the expression of the degenerative process differs not only among distinct anatomical compartments, but also within specific brain compartments (e.g., cerebral cortex, white matter, striatum, pallidum, thalamus, brainstem, cerebellum), or systems (e.g., basal ganglia, limbic system) (Fig. 1.4 ) (Braak and Braak 1992a, b; Bruyn et al. 1979; De la Monte et al. 1988; Dom et al. 1976; Dunlap, 1927; Duyao et al. 1993; Estrada-Sanchez and Rebec 2013; Fennema-Notestine et al. 2004; Ferrante et al. 1987; Hedreen et al. 1991; Heinsen et al. 1992, 1994, 1996, 1999; Heinsen and Rüb 1997; Lange 1981; Lange and Aulich 1986; Lange et al. 1976; Myers et al. 1988; Rüb et al. 2013a, 2014a, b; Selemon et al. 2004; Shoulson and Young 2011; Sotrel et al. 1991; Vogt and Vogt 1920, 1942; Vonsattel 2008; Vonsattel and DiFiglia 1998; Vonsattel et al. 1985). Furthermore, the expression of the pathological phenotypes depends on a constellation of influences driven mainly by epigenetic factors, genetic modifiers, duration of symptoms, or the idiosyncratic longevity of the patients (Hodges et al. 2006; U.S.-Venezuela Collaborative Research Project and Wexler 2004). Thus, upon postmortem examination the pathological phenotypes of HD brains are more or less obvious depending on the sites or systems that are considered and on the techniques applied for assessing the brains. The involvement and the evolution of the neurodegenerative changes in the striatum (caudate nucleus, putamen), and pallidum (paleostriatum) strikingly underscore the differential regional vulnerability occurring in HD within this discrete, relatively small subregions of the brain (Fig. 1.4 ) (Birnbaum 1941; Braak and Braak 1992a, b; Bruyn et al. 1979; De la Monte et al. 1988; Dom et al. 1976; Dunlap 1927; Estrada-Sanchez and Rebec 2013; Fennema-Notestine et al. 2004; Ferrante et al. 1987; Forno and Jose 1973; Hedreen et al. 1991; Heinsen et al. 1992, 1994, 1996, 1999; Heinsen and Rüb 1997; Hodges et al. 2006; Kiesselbach 1914; Landwehrmeyer et al. 1995; Lange 1981; Lange and Aulich 1986; Lange et al. 1976; Lewy 1923; McCaughey 1961; Myers et al. 1988; Neustaedter 1933; Roos et al. 1985; Rüb et al. 2013a, b, 2014a, b; Schroeder 1931; Selemon et al. 2004; Sotrel et al. 1991; Terplan 1924; Vonsattel 2008; Vonsattel and DiFiglia 1998; Vonsattel et al. 1985).