The historical survey of the evolution of the knowledge in neuropathological HD research provided in this monograph shows that the stepwise scientific progress made during a time period of more than one century (1) has considerably changed the traditional, reductionistic pathoanatomical, and pathophysiological concepts of the polyglutamine disease HD, which were unilaterally based on the well-known degeneration of the striatum and (2) have paved the way for basic research aimed at elucidation of the pathogenic mechanisms leading to HD. The focused efforts and progress in neuropathological HD research led to the development, establishment, and international appreciation of a simple, but reliable grading system of the chronological and topographical progression and severity of the HD-related degeneration in the striatum. They form the empirical base for the implementation of the cerebral allo- and neocortex as additional main targets of the disease process of HD (Figs. 1.​4, 2.​1, 2.​2, 2.​4, 2.​5, 2.​6, 2.​7, 2.​8, 3.​1, 3.​2, and 3.​3) and favor the view that the consistent degeneration of the pallidum, select thalamic nuclei, cerebellum, and brainstem also represents inherent features of the HD brain pathology (Figs. 2.​10, 2.​11, 4.​4, 4.​5, 5.​2, 5.​3, 5.​4, 5.​5, 6.​4, and 6.​5) (see Chaps. 1, 2, and 3) (Atkin and Paulson 2014; Borrell-Pagès et al. 2006; Braak and Braak 1992a, b; Bruyn et al. 1979; De la Monte et al. 1988; Estrada-Sanchez and Rebec 2013; Fennema-Notestine et al. 2004; Ferrante et al. 1987; Finkbeiner and Mitra 2008; Hedreen et al. 1991; Heinsen et al. 1992, 1994, 1996, 1999; Heinsen and Rüb 1997; Imarisio et al. 2008; Lange 1981; Lange and Aulich 1986; Lange et al. 1976; Li and Conforti 2013; Margolis and Ross 2003; Myers et al. 1988; Rosas et al. 2003; Rüb et al. 2009, 2013a, 2014a, b; Schulte and Littleton 2011; Selemon et al. 2004; Sotrel et al. 1991; Valera et al. 2005; Vonsattel 2008; Vonsattel and DiFiglia 1998; Vonsattel et al. 1985; Walker 2007a, b).

By showing that the extent of brain degeneration has been considerably underestimated, these studies have helped to unravel the real extent of brain neurodegeneration in HD and showed (1) that brain neurodegeneration in HD is more widespread and severe than reported in previous studies, (2) that the distribution pattern of neuronal loss in the brain of HD patients goes far beyond the well-known subcortical predilection site of the underlying disease process (i.e., striatum) and its targets in the cerebral cortex, (3) and that the distribution pattern of HD brain neurodegeneration has more neuropathological similarities and displays far more overlap with the brain lesional pattern described in the related polyglutamine spinocerebellar ataxias types 1 (SCA1), 2 (SCA2), and 3 (SCA3) than previously thought (Hoche et al. 2008; Lastres-Becker et al. 2008; Riess et al. 2008; Rüb et al. 2003a, 2004a, b, 2005, 2008a, b, 2013b, 2014b; Scherzed et al. 2012; Seidel et al. 2012). Thus, the traditional reductionistic view of HD as a primary and exclusive disease of the striatum has been challenged and is outdated in the meantime: the new findings of neurodegeneration at multiple cortical and subcortical brain sites ultimately form the empirical base of the currently favored concept of the polyglutamine disease HD as a polytopic or multisystem degenerative disease of the human brain (Heinsen et al. 1994; Lange and Aulich 1986; Rüb et al. 2013a; Vonsattel 2008). Further results of postmortem studies in support of the multisystem character of HD suggested that a number of additional subcortical regions (e.g., amygdala, hypothalamus, subthalamic nucleus, claustrum), which are intimately linked with the well-known targets of the disease process of HD via fiber tracts (e.g., prefrontal cortex, entorhinal and transentorhinal regions, thalamic mediodorsal nucleus and centromedian-parafascicular complex, striatum), may also undergo neurodegeneration during HD (see Chap. 1) (Fig. 1.​4) (Lange et al. 1976; Lange and Aulich 1986; Van Wamelen et al. 2014; Vonsattel 2008; Vonsattel and DiFiglia 1998; Vonsattel et al. 1985). However, according to our current experience, the involvement of these brain grays may be difficult to be assessed, and it may also represent an inconsistent feature of HD that depends on the disease duration or is actually characterized by a subregional distribution of neurodegeneration that contradicts the current neuropathological literature. Therefore, further confirmative postmortem studies of these brain sites in HD are recommended.

In the most prevalent human synucleinopathy (i.e., Parkinson’s disease, PD), the motor and nonmotor disease symptoms have been exclusively and unilaterally explained by the well-known degeneration of the compact part of the substantia nigra for a long time. However, this traditional view has been revised during the last three decades. Since then we have learned much about the degenerative process, the different types of PD-related neuronal and glial protein aggregations, and the brain extent, distribution, and propagation of the PD-related aggregation pathology and coexistent neuronal loss. We have obtained a refined picture of the neuropathology of this neuronal and oligodendroglial synucleinopathy which led to the replacement of previous concepts by the empirically based consideration of PD as a multisystem disorder of the human brain. According to the improved neuropathological knowledge, the PD-related pathology involves not only the midbrain mesostriatal dopaminergic system but also the mesolimbic dopaminergic projection system, the cholinergic systems of the basal forebrain and midbrain, the histaminergic hypothalamus, as well as the noradrenergic and serotonergic brainstem systems. The disease process of PD ultimately results in a brain pathology that is widely distributed over interconnected gray components of the cerebral cortex, basal forebrain, diencephalon, and brainstem and characteristically leads to a severe involvement of the cortical and subcortical components of the limbic system of the brain. This improved pathoanatomical knowledge facilitated advanced and more precise clinicopathological correlations in PD and offered new and more adequate morphological explanations for a large spectrum of motor and nonmotor PD symptoms that have been previously attributed to the well-known damage to the dopaminergic substantia nigra (e.g., vestibular, ingestive, and oculomotor dysfunctions) (Braak et al. 2003a, 2003c, 2004).

Similar to the situation in the synucleinopathy PD, many disease symptoms of the polyglutamine disease HD including somatomotor, oculomotor, cognitive, and psychiatric dysfunctions have been more or less mechanically and exclusively explained by the functional consequences of the prominent neuronal loss in the striatum, the subcortical predilection site of the HD-related pathology which for a long time has been regarded as the primary and only target of the underlying disease process (Mink 1996; Walker 2007a). However, the identification and description of neurodegeneration in a number of extrastriatal brain sites of HD patients resulted in an improved pathoanatomical HD knowledge. This improved knowledge, in turn, provided new insights into the morphological basis of a large spectrum of HD-related disease symptoms and, likewise, offered for the first time appropriate explanations for disease signs that were previously associated with neostriatal damage (e.g., oculomotor dysfunctions, dysphagia, incoordination, falls, ataxia, imbalance, cognitive decline, psychiatric manifestations).

Despite progress in HD research, further pathoanatomical brain studies are required to elucidate the possible morphological counterparts of some less well-explained disease symptoms of HD patients (e.g., weight loss, dysfunctions of vertical saccades, vergence, and steady fixation). In the advanced clinical stages, most affected HD patients suffer from an unintended and severe weight loss that most commonly leads to cachexia, which represents a frequent cause of death in HD. This tremendous weight loss of HD patients for a long time has been unilaterally explained by an additional energy expenditure caused by the excessive occurrence of unwanted choreatic movements. Most recent studies, however, have shown that weight loss in HD by no means is a secondary effect of hyperkinetic symptoms or is associated with a reduced food or caloric intake. It occurs despite adequate or even increased caloric intake, is particularly marked in the final hypokinetic stages of HD, and may result from an altered intrinsic metabolic functioning which is under control of the hypothalamus (Aziz et al. 2008; Borrell-Pagès et al. 2006; Bruyn et al. 1979; Gil and Rego 2008; Kremer et al. 1992; Petersen et al. 2005; Rüb et al. 2013a, 2014a; Walker 2007a, b). Accordingly, accurate postmortem reexaminations of the pathoanatomy of the hypothalamus of patients in different clinical stages of HD and with different Vonsattel grades of striatal atrophy by means of reliable morphological methods are mandatory.

The midbrain rostral interstitial nucleus of the medial longitudinal fascicle (riMLF) represents the immediate premotor structure for the performance of vertical and torsional saccades and harbors the premotor burst neurons necessary for the generation of these eye movements (Fig. 6.​1) (Büttner-Ennever 2006; Büttner and Büttner-Ennever 2006; Büttner-Ennever and Horn 1997, 2004; Büttner-Ennever et al. 1982; Horn 2006; Horn and Büttner-Ennever 1998, 1999; Leigh and Kennard 2004; Leigh and Zee 2006; Rüb et al. 2008b, 2009). The more caudally located superior colliculus (SC) is crucial for the initiation of saccades, contributes to vergence, and is involved in the suppression of unwanted saccades during steady target fixation (Fig. 6.​1) (Büttner and Büttner-Ennever 2006; Büttner-Ennever and Horn 1997; Horn 2006; Leigh and Zee 2006; Rüb et al. 2008b, 2009). Since these two midbrain premotor oculomotor nuclei have never been subjected to accurate neuropathological investigations, studies of the riMLF and SC are necessary to improve our knowledge about the pathoanatomical base of dysfunctions of vertical saccades, as well as impairments of vergence and steady target fixation that may occur in HD patients (see Sect. 6.​6).

According to our current neuropathological knowledge and evidence-based theories, the underlying pathological process of HD apparently does not develop, propagate, or operate according to the random principle or in an arbitrary fashion. In contrast, this destructive process proceeds with a selective vulnerability; apparently targets only a subset of subcortical nuclei, as well as distinct neuronal layers of specific areas of the cerebral cortex; and ultimately leads to an interindividually constant damage to a subset of cortical and subcortical brain regions. At the present, the reasons why some brain regions are more heavily affected than others during HD are unclear, and the pathophysiological background of the evolution of the highly characteristic, disease-specific, and consistent distribution pattern of neuronal loss in HD is still enigmatic. Despite this, we and other researchers are guided by the idea that the anatomical interconnectivities between affected brain grays and intra-axonal mechanisms may play a central role in the progression of the pathological process of HD. According to this idea that takes the multisystem character of the polyglutamine disease HD into account, the underlying nonrandom disease process of HD might spread transneuronally along anatomical pathways throughout the brain and, in a stepwise manner, might sequentially propagate from the diseased brain components to the next vulnerable brain site in the neural chain as has also been proposed for the tauopathy Alzheimer’s disease (AD) and the synucleinopathy PD (Braak et al. 2003c; Brundin et al. 2010; Costanzo and Zurzolo 2013; Duyckaerts et al. 2009; Goedert et al. 2010; Itzhaki et al. 2004; Jucker and Walker 2011; Labbadia and Morimoto 2013; Lace et al. 2007; Millecamps and Julien 2013; Norrby 2011; Renner and Melki 2014). Indeed, the pattern of brain neurodegeneration in HD elaborated during the last decades apparently follows the neuronal fiber tracts described in nonhuman primates by modern tracing studies and is compatible with the pathoanatomical ideas that pointed to the possible role of intact anatomical interconnectivities for the spread of the HD-related pathology throughout the brain. The pattern of neurodegeneration suggests (1) that the degenerated cortical and subcortical brain areas are directly anatomically interconnected and (2) that the pathological process of HD may use these anatomical pathways and interconnectivities for its transneuronal spread and propagation throughout the brain (Brundin et al. 2010; Costanzo and Zurzolo 2013; Goedert et al. 2010; Jucker and Walker 2011; Labbadia and Morimoto 2013; Millecamps and Julien 2013; Norrby 2011; Renner and Melki 2014; Rüb et al. 2014b). The mechanisms responsible for the targeted spread and neuron-to-neuron propagation along anatomical pathways throughout the diseased brain may include (1) physical blockade of axonal trafficking by intra-axonal protein aggregates and swellings, (2) inhibition of synaptic functions by impairments of anterograde axonal transport mechanisms, and (3) transsynaptic and interneuronal spread and propagation of the disease process in a prion-like manner. Although the widespread occurrence of intra-axonal immunoreactive protein aggregations in brain fiber tracts of HD patients conforms to the idea that HD in fact may represent a chronically progredient prion-like protein misfolding disease, further studies are required to prove the suggested prion–like nature of the disease process of HD (see Sects. 3.​5, 4.​1, and 10.​2) (Brundin et al. 2010; Costanzo and Zurzolo 2013; Goedert et al. 2010; Jucker and Walker 2011; Labbadia and Morimoto 2013; Millecamps and Julien 2013; Norrby 2011; Renner and Melki 2014).

In both, the human tauopathy AD and the human synucleinopathy PD, neuropathological staging procedures have been proposed that capture the different developmental stages of the disease-related pathologies, their proposed possible brain induction sites, as well as their final brain distribution pattern and extent (Braak and Braak 1991; Braak et al. 2003a, 2003c, 2004, 2006; Goedert et al. 2010; Jucker and Walker 2011; Seidel et al. 2015). It would be a seminal task to extend and complement the description of the spatially and chronologically spread of neurodegeneration within the striatum according to the Vonsattel grading system by the results of further cross-sectional studies of HD brains and to develop an extended HD staging procedure that takes all aspects of the brain pathology into consideration (see Chap. 2) (Figs. 2.​1, 2.​2, 2.​4, and 2.​5) (Vonsattel 2008; Vonsattel and DiFiglia 1998; Vonsattel et al. 1985).

Despite the fact that multiple efforts are under way to change this situation, unfortunately, no established causative treatment or effective disease–modifying therapy exists for HD patients which would be able to delay the onset or prevent and reverse the progression of the disease. To date, only symptomatic treatments of chorea, dystonia, other movement disorders, and nonmotor aspects of HD can be offered which may have favorable effects on disease symptoms and quality of life of affected patients. The spectrum of symptomatic pharmacological treatment strategies is complemented by a number of non-pharmacological interventions, such as surgical procedures; adjunctive, alternative, and complementary therapies (e.g., physical therapy, speech therapy, occupational therapy, exercise therapy, music therapy, dance, or video game playing); behavioral plans; and cognitive interventions, which also may play a role in addressing the symptoms of HD and need also to be considered when choosing medications (Borrell-Pagès et al. 2006; Finkbeiner and Mitra 2008; Imarisio et al. 2008; Labbadia and Morimoto 2013; Ortega et al. 2007; Schapira et al. 2014; Walker 2007a, b).