Neuropathology and Applied Neurobiology (2015), 41, 843–848
doi: 10.1111/nan.12236
Scientific correspondence
Selective loss of oxytocin and vasopressin in the hypothalamus in early Huntington disease: a case study Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene [1]. The neuropathology is most striking in the striatum of the basal ganglia where atrophy and cell death are used to classify the severity of the disease according to the five-step grading system developed by Vonsattel and colleagues [2]. The striatal pathology correlates well with the severity of motor symptoms used for the clinical diagnosis of the disease. Non-motor aspects such as psychiatric symptoms, sleep disturbances and metabolic dysfunction are also common and they typically precede the motor symptoms of the disease [3,4]. The non-motor symptoms and signs indicate pathologic processes outside of the basal ganglia, such as the hypothalamus [5]. Previous neuropathological studies of the hypothalamus in brains with prevalent striatal pathology (that is, Vonsattel grades 2–4) showed loss of the neuropeptides oxytocin, vasopressin and orexin (hypocretin) in HD [6–8]. Whether hypothalamic changes occur prior to frank neurodegeneration of the striatum (that is, Vonsattel grade 0) is at present unknown. Here we report the first neuropathological analysis of the hypothalamus of an HD case graded as Vonsattel 0, which suggests that specific pathological changes appear in this region at an early stage of HD. The study was approved by the regional ethical review board, Lund University, Sweden (reference number 2014/ 466). Written informed consent was obtained from the patient’s relative for the publication of this case report. The patient was a 52-year-old man who was referred to a neurologist with a suspicion of HD, as he had a history of HD in his family. The man had suffered from anxiety as well as sleep disturbances during the last year. His spouse had noticed subtle alterations in his movements. The neurological examination revealed mild hyperkinetic movements but an otherwise normal status. Upon questioning, the man reported that he did not notice the slight hyperkinetic movements himself. No medication was given at 1
These authors contributed equally.
© 2015 British Neuropathological Society
this time. The neurologist considered early HD as the possible cause for the described movements, but was not certain. It was decided that a genetic test for the HD gene should be taken before the appointment. Seven months later, before the date of the next visit, the man suffered a cardiac arrest and was found pulseless by a relative. Despite cardiopulmonary resuscitation, which lasted 1 h, he passed away. By that time, the patient had symptoms of disease that were slightly more pronounced, yet still relatively mild. Autopsy was performed 4 days after death. The cause of death was an acute myocardial infarction. Genetic testing revealed the presence of an expanded CAG repeat of 43 in one allele and 19 (within normal range) in the other. The brain weighed 1282 g. Gross examination of the brain, coronally cut in 1–1.5-cm-thick slices according to standard clinical diagnostic procedures, did not reveal any overt pathology, in particular no general or focal atrophy (Figure 1A). There was a normal curvature of the caudate nucleus, no atrophy of the caudate nucleus or the putamen, and no enlargement of the ventricles. Gross examination of paraffin-embedded sections coronally cut at 6 μm at the level of the striatum stained with hematoxylin and eosin showed no overt pathology. Microscopic evaluation of the sections revealed an overall preservation of neurones and no gliosis in the caudate nucleus. However, there were some discrete foci of neuronal shrinkage and minor neuronal loss with slight microvacuolization visible in a small 1–1.5-mm-wide band of the medial subependymal region along the anterior and medial part of the caudate nucleus (Figure 1B). Immunohistochemistry for neurofilament light protein revealed slightly reduced staining intensity in this medial area of the caudate nucleus (Figure 1C). Immunohistochemistry for glial fibrillary acidic protein did not indicate any increased gliosis beyond baseline levels (Figure 1D). Immunohistochemistry for p62 LCK LIGAND (p62) showed rare immunopositive inclusions in
doi: 10.1111/nan.12236
Scientific correspondence
Selective loss of oxytocin and vasopressin in the hypothalamus in early Huntington disease: a case study Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene [1]. The neuropathology is most striking in the striatum of the basal ganglia where atrophy and cell death are used to classify the severity of the disease according to the five-step grading system developed by Vonsattel and colleagues [2]. The striatal pathology correlates well with the severity of motor symptoms used for the clinical diagnosis of the disease. Non-motor aspects such as psychiatric symptoms, sleep disturbances and metabolic dysfunction are also common and they typically precede the motor symptoms of the disease [3,4]. The non-motor symptoms and signs indicate pathologic processes outside of the basal ganglia, such as the hypothalamus [5]. Previous neuropathological studies of the hypothalamus in brains with prevalent striatal pathology (that is, Vonsattel grades 2–4) showed loss of the neuropeptides oxytocin, vasopressin and orexin (hypocretin) in HD [6–8]. Whether hypothalamic changes occur prior to frank neurodegeneration of the striatum (that is, Vonsattel grade 0) is at present unknown. Here we report the first neuropathological analysis of the hypothalamus of an HD case graded as Vonsattel 0, which suggests that specific pathological changes appear in this region at an early stage of HD. The study was approved by the regional ethical review board, Lund University, Sweden (reference number 2014/ 466). Written informed consent was obtained from the patient’s relative for the publication of this case report. The patient was a 52-year-old man who was referred to a neurologist with a suspicion of HD, as he had a history of HD in his family. The man had suffered from anxiety as well as sleep disturbances during the last year. His spouse had noticed subtle alterations in his movements. The neurological examination revealed mild hyperkinetic movements but an otherwise normal status. Upon questioning, the man reported that he did not notice the slight hyperkinetic movements himself. No medication was given at 1
These authors contributed equally.
© 2015 British Neuropathological Society
this time. The neurologist considered early HD as the possible cause for the described movements, but was not certain. It was decided that a genetic test for the HD gene should be taken before the appointment. Seven months later, before the date of the next visit, the man suffered a cardiac arrest and was found pulseless by a relative. Despite cardiopulmonary resuscitation, which lasted 1 h, he passed away. By that time, the patient had symptoms of disease that were slightly more pronounced, yet still relatively mild. Autopsy was performed 4 days after death. The cause of death was an acute myocardial infarction. Genetic testing revealed the presence of an expanded CAG repeat of 43 in one allele and 19 (within normal range) in the other. The brain weighed 1282 g. Gross examination of the brain, coronally cut in 1–1.5-cm-thick slices according to standard clinical diagnostic procedures, did not reveal any overt pathology, in particular no general or focal atrophy (Figure 1A). There was a normal curvature of the caudate nucleus, no atrophy of the caudate nucleus or the putamen, and no enlargement of the ventricles. Gross examination of paraffin-embedded sections coronally cut at 6 μm at the level of the striatum stained with hematoxylin and eosin showed no overt pathology. Microscopic evaluation of the sections revealed an overall preservation of neurones and no gliosis in the caudate nucleus. However, there were some discrete foci of neuronal shrinkage and minor neuronal loss with slight microvacuolization visible in a small 1–1.5-mm-wide band of the medial subependymal region along the anterior and medial part of the caudate nucleus (Figure 1B). Immunohistochemistry for neurofilament light protein revealed slightly reduced staining intensity in this medial area of the caudate nucleus (Figure 1C). Immunohistochemistry for glial fibrillary acidic protein did not indicate any increased gliosis beyond baseline levels (Figure 1D). Immunohistochemistry for p62 LCK LIGAND (p62) showed rare immunopositive inclusions in
