Huntington's disease (HD): the neuropathology of a multisystem neurodegenerative disorder of the human brain

Abstract

Huntington's disease (HD) is an autosomal dominantly inherited, and currently untreatable, neuropsychiatric disorder. This progressive and ultimately fatal disease is named after the American physician George Huntington and according to the underlying molecular biological mechanisms is assigned to the human polyglutamine or CAG-repeat diseases. In the present article we give an overview of the currently known neurodegenerative hallmarks of the brains of HD patients. Subsequent to recent pathoanatomical studies the prevailing reductionistic concept of HD as a human neurodegenerative disease, which is primarily and more or less exclusively confined to the striatum (ie, caudate nucleus and putamen) has been abandoned. Many recent studies have improved our neuropathological knowledge of HD; many of the early groundbreaking findings of neuropathological HD research have been rediscovered and confirmed. The results of this investigation have led to the stepwise revision of the simplified pathoanatomical and pathophysiological HD concept and culminated in the implementation of the current concept of HD as a multisystem degenerative disease of the human brain. The multisystem character of the neuropathology of HD is emphasized by a brain distribution pattern of neurodegeneration (i) which apart from the striatum includes the cerebral neo-and allocortex, thalamus, pallidum, brainstem and cerebellum, and which (ii) therefore, shares more similarities with polyglutamine spinocerebellar ataxias than previously thought.

Keywords: brainstem; cerebellum; cerebral cortex; pathoanatomy; polyglutamine diseases; thalamus.

Figure 1

p62 immunoreactive neuronal intranuclear inclusions in well‐preserved and degenerated brainstem nuclei of Huntington's disease (HD) patients. P62 immumopositive neuronal intranuclear inclusions (NI) in spared brainstem nuclei in HD: A. locus coeruleus (LC), B. facial nucleus (VII), C. gigantocellular reticular nucleus (GI). NI in degenerated brainstem nuclei in HD: D. dopaminergic substantia nigra (SN), E. reticulotegmental nucleus of the pons (RTTG), F. superior olive (SO). Arrows point to NI. (A, D, E: HD patient with 49 CAG‐repeats in the mutated HD allele; age at HD onset: 33 years; duration of HD: 18 years; Vonsattel grade 4 of striatal atrophy—B, C: HD patient with 49 CAG‐repeats in the mutated HD allele; age at HD onset: 33 years; duration of HD: 18 years; Vonsattel grade 4 of striatal atrophy—F: HD patient with 45 CAG‐repeats in the mutated HD allele; age at HD onset: 53 years; duration of HD: 12 years; Vonsattel grade 4 of striatal atrophy) (A–F: p62 immunohistochemistry, counterstaining with aldehyde‐fuchsin Darrow red; 100 μm PEG sections).

Figure 2

p62 immunoreactive axonal neuronal inclusions in brainstem fiber tracts in Huntington's disease (HD). P62 immumopositive axonal neuronal inclusions in HD: (A, B) superior cerebellar peduncles (SCP), (C) reticular formation (RF), (D) medial lemniscus (ML), (E) pontocerebellar fibers (PC), (F) abducens nerve (VI), (G) facial nerve (VII), (H) vestibulocochlear nerve (VIII), (I) (A–H: p62/AT270 double immunohistochemistry; 100 μm PEG sections). (A, B: HD patient with 44 CAG‐repeats in the mutated HD allele; age at HD onset: 50 years; duration of HD: 20 years; Vonsattel grade 2 of striatal atrophy—C, E, G: HD patient with 49 CAG‐repeats in the mutated HD allele; age at HD onset: 33 years; duration of HD: 18 years; Vonsattel grade 4 of striatal atrophy—D: HD patient with 45 CAG‐repeats in the mutated HD allele; age at HD onset: 35 years; duration of HD: 26 years; Vonsattel grade 3 of striatal atrophy—F, H: HD patient with 45 CAG‐repeats in the mutated HD allele; age at HD onset: 53 years; duration of HD: 12 years; Vonsattel grade 4 of striatal atrophy).

Figure 3

Previous ideas and current knowledge about the distribution and severity of neuronal loss in the basal forebrain of Huntington's disease (HD) patients. Schematized frontal sections through the basal forebrain at the level of the anterior commissure (AC). (A) Previous idea regarding the selective involvement of the striatum (caudate nucleus, C and putamen, PU). (B) Current pathoanatomical HD knowledge which includes the additional severe involvement of the cerebral cortex (brain regions undergoing severe neuronal loss are highlighted with blue shading). (Abbreviations: AC, anterior commissure; C, caudate nucleus; CL, claustrum; CC, cerebral cortex; CA, corpus callosum; HD, Huntington's disease; P, pallidum; PU, putamen; OC, optic chiasm).

Figure 4

Distribution and severity of neuronal loss in select brain regions of Huntington's disease (HD) patients. Schematized frontal section through the cerebral hemispheres at the level of the red nucleus (RD) (brain regions undergoing severe neuronal loss are highlighted with blue shading and brain regions with marked loss of nerve cells with lighter blue shading). (Abbreviations: C, caudate nucleus; CC, cerebral cortex; CA, corpus callosum; CL, claustrum; HD, Huntington's disease; P, pallidum; PU, putamen; RD, red nucleus; SN, substantia nigra; STN, subthalamic nucleus; TH, thalamus).

Figure 5

Distribution and severity of neuronal loss in the regions of the brainstem and cerebellum of Huntington's disease (HD) patients. Schematized sagittal section through the midbrain (MB), pons (PN), medulla oblongata (MO) and cerebellum (CE) (brainstem and cerebellar regions undergoing severe neuronal loss are highlighted with blue shading and brain regions with marked loss of nerve cells with lighter blue shading). For the exact localization of neurodegeneration in the brainstem and cerebellum please see text. (Abbreviations: CE, cerebellum; HD, Huntington's disease; MB, midbrain; MO, medulla oblongata; PN, pons).

Figure 6

Atrophy of the cerebral lobes and subcortical regions in Huntington's disease (HD). (A) Dorsolateral aspect of the left cerebral hemisphere of a typical control individual without a medical history of neurological or psychiatric diseases. (B) Medial aspect of the left cerebral hemisphere of the same control individual. (C) Dorsolateral aspect of the left cerebral hemisphere of clinically diagnosed and genetically confirmed male Huntington's disease (HD) patient (Vonsattel grade 4 of neostriatal atrophy). Note the marked atrophy of the frontal 1, parietal 2, and temporal lobes 3 with widened sulci and narrowed gyri. Additionally, the occipital lobe of this patient is severely reduced 4. (D) Medial aspect of the left cerebral hemisphere of the same HD patient: atrophy of the frontal 1, parietal 2, and occipital lobes 3, and corpus callosum 4, head of the caudate nucleus 5 and the thalamus 6. (Abbreviations: C, caudate nucleus; CC, corpus callosum; TH, thalamus).

Figure 7

Atrophy of the striatum and white matter loss in Huntington's disease (HD). (A) Frontal section through the basal forebrain of a representative control individual at the level of the accumbens nucleus (AC) with the caudate nucleus (C) and putamen (PU). (B) Frontal section through the same basal forebrain level of a clinically diagnosed and genetically confirmed Huntington's disease (HD) patient (Vonsattel grade 3 of striatal atrophy). Along with the striatum, the corpus callosum (CC) and the temporal lobe are atrophic (asterisk). Note the widened lateral ventricle 1, reduction of the cerebral white matter 2, and flattened outline of the C. (Abbreviations: AC, accumbens nucleus; C, caudate nucleus; CC, corpus callosum; PU, putamen).

Figure 8

Neuronal loss in the caudate nucleus in Huntington's disease (HD). Frontal section through the head of the caudate nucleus (C) at the level of the rostral hypothalamus of a representative control individual. (B) Marked neuronal loss of the C of a representative Huntington's disease (HD) patient with Vonsattel grade 2 of neostriatal atrophy. Note the reduction of the IC and the fact that the convex outline of the head of the C is still discernable. (A, B: Aldehyde‐fuchsin Darrow red staining; 100 µm polyethylene glycol section). (Abbreviations: C, caudate nucleus; HD, Huntington's disease; IC, internal capsule).

Figure 9

Neuronal loss in the entorhinal cortex in Huntington's disease (HD). Frontal section through the entorhinal cortex at the mid‐rostrocaudal level of the hypothalamus of a typical control individual. (B) Reduced neuronal density of the entorhinal cortex of a representative Huntington's disease (HD) patient with Vonsattel grade 2 of neostriatal atrophy. Note the predominant neuronal loss in the pre‐beta (arrowhead) and pri‐gamma layers (asterisk) of the entorhinal cortex (A, B: Aldehyde‐fuchsin Darrow red staining; 100 µm polyethylene glycol section). (Abbreviations: Diss, lamina dissecans; HD, Huntington's disease Pre, principal external layer; Pri, principal internal layer).

Figure 10

Neuronal loss in the brainstem in Huntington's disease (HD). (A) Horizontal section through the pontomedullary junction of a typical control individual showing the medial vestibular (MV) and prepositus hypoglossal nuclei (PPH). (B) Horizontal section through the caudal portion of the medulla oblongata of a representative control individual showing the medial subnucleus of the inferior olive (IOM) and the lateral reticular nucleus (LRT). (C) Considerable neuronal loss in the MV of an HD patient burdened by Vonsattel grade 3 of striatal atrophy. (D) Marked neuron loss of the IOM of a representative Huntington's disease (HD) patient with Vonsattel grade 3 atrophy. Arrows point to reaming extraneuronal lipofuscin granules. (A–D: Aldehyde‐fuchsin Darrow red staining; 100 µm polyethylene glycol section). (Abbreviations: HD, Huntington's disease; ICP, inferior cerebellar peduncle; LRT, lateral reticular nucleus; PPH, prepositus hypoglossal nucleus; RF, reticular formation).

Figure 11

Surviving ballooned nerve cells in the affected ventrolateral thalamic nucleus of Huntington's disease (HD) patients. These remaining, morphologically altered ballooned neurons are swollen and display a massively enlarged cytoplasm with a homogenous central basophilic substance. Their Nissl substance, lipofuscin granules, and flattened nucleus are concentrated along the cytoplasmic membrane, thus mimicking central chromatolysis (arrows). (Aldehyde‐fuchsin Darrow red staining; 100 µm polyethylene glycol section). (HD patient with 45 CAG‐repeats in the mutated HD allele; age at HD onset: 35 years; duration of HD: 26 years; Vonsattel grade 3 of striatal atrophy).