Huntington disease is caused by a dominantly transmitted CAG repeat expansion mutation that is III, Homozygotes, ± (3)+, , ± (3)+, Huntington's disease (HD) is a prototypical neurodegenerative disease in which .. Pyruvate. Using a quinolinic acid striatal lesion model of HD, treatment . EUROPEAN HUNTINGTON'S DISEASE NETWORK Limitations in Functional Activities. 21 . Figure 1: The pre-manifest stage in Huntington's disease 1.
disease 3.2.3. Huntington’s
In the grey matter, the most frequent is ramified form, which express protein Iba1 ionized calcium-binding adapter molecule 1 also known as AIF-1 allograft inflammatory factor 1. The density of this marker significantly increases with activation of cells. It is obvious that the activation of microglia is a basic mechanism in the defence of the CNS, also in relation to neurodegenerative processes e.
Although the role of microglia in neurodegeneration is still controversial, it is evident that in human brain they are activated in early stages of NDP of different phenotype, primarily in HD e. It is possible that microglia transform to phagocytes and target neurons as the disease progresses but appear to be dysfunctional with increasing amounts of ingested debris [ 48 ].
It is commonly known that the neurodegenerative process of HD phenotype is a chronic process, morphologically characterized by the progressive degeneration of neurons, principally in the striatum, but gradually affecting almost all parts of the brain.
This results in a reduction of grey matter and brain atrophy with compensatory enlargement of the lateral brain ventricles. Nevertheless, also as the second component of the brain parenchyma, the glial cells play an irreplaceable role in this process. The reaction of astrocytes to any damage of the CNS parenchyma in a sense of their conversion into the reactive intensely GFAP-positive subset is well known already for long time.
Although the participation of other types of glial cells, particularly of microglia and NG2 glia, in neurodegenerative process has been studied in last two decades, the histopathological interrelations among all above-mentioned cell types have not been well described yet. Moreover, the validation of existing transgenic rat model of HD51 from this point of view is still lacking. The clinical features of HD described in autopsy records were characteristic for the given stages in all three patients.
However, detailed neurological records or results of genetic testing were not available because old archival material was used. The severity of striatal histopathological changes was graded grades 0—4 according to Vonsattel and coauthors [ 2 ]. Paraffin blocks of brain tissue from autopsies were taken from the neostriatum the caudate nucleus and putamen at the level of the globus pallidus and at the level of the nucleus accumbens. The transcardial perfusion with fixative solution under deep anaesthesia followed by postfixation for 3 days or 2 hours, resp.
After postfixation, the brain hemispheres were separated and processed separately. Histological processing was the same for both the experimental material and autopsies. Findings obtained by immunofluorescent detections double-labelling were mostly confirmed by a single antibody detection using peroxidase-antiperoxidase PAP immunohistochemistry on parallel paraffin sections.
For immunohistochemical detection, deparaffinized and rehydrated sections were used. Sections were then washed and incubated with the appropriate biotinylated secondary antibody Jackson ImmunoResearch Lab. The sequential technique for immunofluorescent double-labelling of antibodies Ab was same for both types of sections.
The negative control, omitting the primary antibody, was made in each labelling. In order to characterize the progression of NDP in the striatum of tgHD51 rats, we used the quantitative analysis of the median diameter of neuronal nuclei as a marker of proposed significant process in a course of neurodegeneration in tgHD rats; it means the shrinkage of striatal neurons. We would like also to determine the onset of significant neuronal degeneration in the striatum of tgHD51 rats and the possible participation of age-related changes.
Selected sections were labelled with NeuN antibody, which marks selectively the nuclei of mature neurons, using the PAP immunohistochemical detection. The number of analysed sections was the following: Neuronal nucleus median diameter was obtained from 50 independent measurements in the central area of the striatum on each analysed section.
Due to possible distortions of the shape of neuronal nucleus in the section, the largest size of the nucleus was considered the nucleus diameter. Each group of rats of the same age was represented by the set of all medians in given group. Statistical analyses of the differences between groups were performed using MS Excel Microsoft Corp. Surprisingly, the most distinct changes in striatal grey matter develop by the end of the first year of age probably between 9 and 12 months.
The end of the first year represents the turn in the development of morphological changes related to the progression of NDP within the striatum of tgHD51 rats. These findings correspond to the course of HD in human brain, where the motor and behavioural changes precede the loss of striatal neurons [ 20 ]. We demonstrate possible parallels between the HD progression in humans and the above-described transgenic rat model and prove the validity of our findings for human HD pathology.
The cases demonstrated here represent the sequence of 3 stages grades , grade 3, and grade 4 of the progression of HD in human brain. It is almost impossible to dissociate the alterations referring to neurons and glia in a course of NDP because of very close relationship and mutual influence of both main components of striatal parenchyma. However, we would like to stress some features specific for each of them in a course of the development of NDP within the striatum of both rat and human brains.
For that reason, we described their involvement in progression of NDP separately. When we compare the brains of 2- and 3-month-old, young adult wild-type and tgHD rats, there is no difference in morphology of the striatum. Also lateral brain ventricles are narrow, of the same shape in both mentioned groups Figure 1 a. Only in month-old tgHD51 rats appears the identifiable enlargement of lateral ventricles, which documents developing striatal atrophy.
The process gradually progresses resulting in prominent widening of lateral ventricles Figure 1 b , with concave medial outline of the striatum in the oldest 22—month-old tgHD rats, which is fully comparable with the progression of HD in human brain. However, with the progression of HD in humans, gradual decrease in number of neurons is significant, particularly in advanced stages of HD grade 3—Figure 4 b and grade 4—Figure 4 c.
Nuclei of striatal neurons are very characteristic, especially due to their large size and fine loosely arranged chromatin in comparison with significantly smaller nuclei with more densely arranged chromatin of glial cell. Despite the fact that striatal neurons become gradually smaller in course of HD progression compare Figures 3 a and 3 b , such specific features of neuronal and glia nuclei always enable their distinguishing. Our immunohistochemical analysis of neuronal nuclei by NeuN shows slow but already significant progression of neuronal degeneration in the striatum from 12 to 24 months of age of tgHD rats Figure 3 b when compared with age-matched controls Figure 3 a and younger tgHD rats.
The most typical for NDP in tgHD51 rats is a gradual decrease in size of neuronal bodies and nuclei with maintenance of nucleo-cytoplasmic rate , which results in the disintegration and disappearance of affected neurons Figures 2 d — 2 f , ultimately scavenged by microglia Figures 12 b and 12 c.
In the human HD brain, grades with approximately 2-year clinical manifestation , the degeneration and loss of neurons were only random; therefore, the loosening of the neuropil has not been apparent yet.
On the other hand, in grade 3 approximately 8-year clinical history , neuronal degeneration was already obvious Figure 4 b. Depletion of neurons particularly in the CN and putamen Pu accompanied with rarefaction of the neuropil resulted in a reduction of striatal volume and noticeable enlargement of the lateral ventricles.
In grade 4 with approximately year clinical diagnosis the entire corpus striatum CN, Pu, and globus pallidus was affected by degeneration of neurons and neuropil resulting in severe striatal atrophy and therefore the concomitant astrogliosis here prevailed Figures 4 c , 10 b , and 10 c. The remaining striatal neurons marked by their prominent nuclei gradually became smaller with the progression of NDP, like in the brain of tgHD rats.
Additionally, we confirmed that, alike in human HD brain, neuronal degeneration is selective, that is, affecting primarily certain groups of neurons in the striatum of investigated senescent tgHD rats and moreover that age-related changes contribute to final extent of NDP. In order to precisely characterize the progression of NDP within the striatum of tgHD51 rats, our morphological findings were supplemented by quantitative analysis of the diameter of neuronal nuclei labelled with NeuN.
Also the proportion of age-related changes in this process was assessed. The progression in decrease of the median diameter of neuronal nuclei with age of rats in both wt and tgHD groups of rats is documented by Progress Chart Figure 5 a. In the first two groups of rats, that is, , and 6-month survivors, no differences in the median diameter of NeuN-positive nuclei were detected when compared within the individual group or among the groups.
Surprisingly, further progression in decrease of the median diameter of neuronal nuclei was not so rapid; however, finally the reduction reached Statistical characteristic of the groups of rats using Box Plot Figure 5 b enables the multiple comparison of the median diameter of neuronal nuclei of the following groups of rats: Differences among three remaining groups are statistically insignificant.
Moreover, it is potentiated with age-related changes particularly in the oldest animals. Unexpectedly, the transitional amelioration of the process up to slight improvement appeared in both groups wt and tgHD of month survivors. Neuronal degeneration in wt rats can be attributed only to the debit of the aging process; the decrease in size of nuclei was slow and the difference between month-old rats and month-old ones was only 8.
Striatal atrophy, in the case of HD, is primarily caused by the degeneration of striatal neurons. Of course, the most prominent feature, seen on histological preparations, is a gradual reduction of neuronal bodies marked by the nuclei. Indeed, the reduction in a volume of neuropil is at least of the same importance.
Although the rarefaction of neuropil is not based only on the degeneration of this network of neuronal processes and synapses, it demonstrates the progression of such process in both human and rat brains Figures 8 a — 8 d.
In addition, we also proved the alterations in a character of synapses. In control brains of both rats and humans, synaptophysin-positive synapses are very fine, of uniform size and shape, and plentiful Figures 6 a and 7 a. With the progression of NDP, most of synapses become coarser, more prominent, but of variable size, and some of them are intensely labelled for synaptophysin; consequently, their number gradually decreases Figures 6 b and 7 b.
Despite different size of synapses in rat Figures 6 a and 6 b and human Figures 7 a and 7 b , the mentioned alterations are of the same character. Since the severity of the striatal damage is also influenced by duration of NDP, the changes in morphology of synapses, and particularly the loosening of neuropil, are certainly more prominent in advanced stages of HD in human brain Figure 7 b than in terminal stage of NDP in tgHD rats Figures 6 b and 8 d.
Additionally, the alterations in glial component and the ageing-associated changes see Section 3. Indeed, the pattern of such process in this basic aspect is the same for both tgHD rats and HD patients. Detection of polyglutamine deposits using polyQ-huntingtin provides interesting findings, which give a complete histopathological picture of HD progression.
In wt rats, polyQ detects a normal polyglutamine domain huntingtin encoded by lower number about 35 or less of consecutive glutamine repeats; therefore, only fine polyQ deposits are spread in the nuclei of striatal neurons Figure 8 a. In contrast, the pathogenic alleles usually contain 39 or more glutamine repeats, which results in production of mhtt and increased density of intranuclear polyQ expression in relation to the progression of NDP of HD phenotype Figures 8 b — 8 d.
Surprisingly, using polyQ-huntingtin antibody, neither typical large intranuclear nor neuropil aggregates were seen. Moreover, neurons in adjacent cortex also exhibit intranuclear but more cytoplasmic polyQ deposits; therefore, they are more densely stained in comparison with striatal neurons, particularly in tgHD rats Figures 8 e — 8 g. On the contrary, only few cortical glial cells express polyQ, which corresponds to the absence of typical reactive gliosis in this region.
It is evident that the developments of changes in glial cell morphology, and certainly also in their function, are conditioned by the intensity and rate of neuronal degeneration in the context of the neuron-glia relationship. Protoplasmic astrocytes are the most numerous component of the striatal parenchyma. The shape of astrocytes changes during the progression of NDP; however specific prominent alterations occur only in human HD brains, where the astrogliosis gradually develops Figures 10 b and 10 c.
Due to only slow development of neuronal degeneration in the striatum of tgHD rats, the subsequent astrogliosis progresses also slowly—with insignificant onset after 6 months of age of tgHD rats—and becomes more distinct just in 18—month-old animals Figure 9 c. Age-related changes not only are seen in old wt rats, but also participate in progression of reactive gliosis in tgHD rats. Less in wt rats or more in tgHD rats developed striatal atrophy is manifested in senescent rats by denser accumulation of smaller nuclei of neurons and glia compare Figures 2 a — 2 c.
First of all, in both HD patients and tgHD rats, generation of reactive astrocytes proceeds gradually and slowly, unlike the almost immediate appearance of reactive astrocytes after the acute brain damage.
Indeed, their bodies are not significantly enlarged hypertrophic ; contrariwise, a part of them also undergoes the degeneration and they are scavenged by microglia Figures 12 c , 13 c , and 13 d. On the contrary, we never found the reexpression of intermediate filaments nestin and vimentin, which is considerable feature of hypertrophic reactive astrocytes after the acute brain damage.
Although less prominent, expression is also in fine astrocytic processes. In tgHD rats, the coexpression is slightly enhanced in end-feet Figures 10 b and 10 c , unlike significant coexpression in both the cytoplasm of cell bodies and end-feet in human HD brains Figures 10 b and 10 c.
During an EEG, an instrument records electrical activity of the brain. In August , the Food and Drug Administration FDA approved tetrabenazine Xenazine for the treatment of the repetitive, involuntary movements chorea.
The drug has been available in Europe for several years. Other treatment for Huntington's disease is symptomatic and supportive. There are some treatments that may alleviate various symptoms temporarily. Neuroleptic medication such as haloperidon can partially suppress the involuntary movement, especially in the early stages.
Other medication can often help depression and other emotional symptoms. Special high calorie food preparations may help an affected individual maintain weight and avoid choking during the later stages of Huntington's disease. Genetic counseling will be of benefit for affected individuals and their families.
Family members of affected individuals should also receive clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Huntington's disease.
Information on current clinical trials is posted on the Internet at www. All studies receiving U. In , the U. It also appeared to elevate brain levels of creatine.
HD is produced by Avicena. For information, contact the company at:. The one in the U. For information, call the Huntington Study Group at or go to www. This study was launched in The report details studies with animals, but studies involving rapamycin and humans now are planned. Researchers are studying mice with the HD gene and the use of a type of bile acid called TUDCA in possibly preventing the death of brain neurons.
However, more research is needed before this approach can be tested in humans. This trial is being conducted at the Massachusetts General Hospital in Boston.
The principal investigator is Merit E. More information may be obtained by contacting:. Additional study is needed to determine the safety and effectiveness of this treatment for Huntington disease. In , the FDA granted ethyl eicosapentaenoate orphan drug status for the treatment of Huntington disease.
Information about current clinical trials related to Huntington disease may be accessed through the Huntington Study Group, a non-profit organization of physicians and other healthcare providers in the United States, Europe, Canada, and Australian. Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Merck Research Laboratories; The Merck Manual-Home Edition. Mayo Clinic Family Health Book. William Morrow and Company, Inc; Choreas, Athetosis, and Ballism. Bennett JC, Plum F. Cecil Textbook of Medicine.
Rosenblatt A, et al, eds. Looking backward to move forward: Curr Neurol Neurosci Rep. Ostenfeld T, Svendsen CN. Recent advances in stem neurobiology. Adv Tech Stand Neurosurg. Three studies on clinically manifest HD found impairments for various negative emotions but all investigated very small samples Sprengelmeyer et al. Furthermore, Milders et al. The manifest HD group in the study of Henley et al. Impaired recognition of each emotion was associated with striatal volume loss.
The results of Johnson et al. In contrast to emotion identification the elicitation of feelings by the presentation of emotion-relevant scenes has hardly been studied in HD. The only study by Hayes et al. Similar to disgust recognition it has been suggested that the experience of disgust feelings recruits the insula. In an fMRI investigation by Stark et al.
However, other studies did not observe a specific involvement of a basal ganglia-insular circuit in the central representation of disgust experience e. In summary, findings on affective processing dysfunctions in HD are inconsistent. One reason for this concerns small sample sizes in most studies, which limits the power to detect more subtle group differences and enhances the possibility of sample-dependent results.
Furthermore, severity of symptoms, influenced by CAG length and disease duration, differed between studies. Unspecific symptoms can precede motor symptoms, which are commonly used as markers of clinical manifestation Langbehn et al. Specificity of emotion recognition deficits might vary with disease progression, starting with impaired disgust perception in asymptomatic gene-carriers, as revealed in two studies Gray et al.
Adequate emotional experience and understanding other persons' emotional behaviour are important for social functioning and quality of life.
HD results in a complex symptomatology especially during progressed stages, including impairment of voluntary motor functions, cognition, language and mental functions. HD is related to multiple psychosocial problems in the afflicted persons and their families. Abnormal emotional processing has negative implications for patients' daily lives, especially for social interactions.
Findings of previous studies already demonstrated that the psychosocial well-being of patients with HD is strongly affected e. The primary objective of this study was to determine whether the impairment of facial disgust recognition in symptomatic HD extends to the experience of visually induced disgust.
We asked the participants to rate facial expressions according to the displayed emotion intensities for all basic emotions graded choice. This allowed the analysis of quantitative intensity as well as qualitative classification accuracy emotion processing deficits in HD. The same approach was applied for the analysis of emotions elicited by affective scenes. Further, we were interested whether HD patients show a disproportionately severe impairment in disgust recognition or a more general deficit that extends to other basic emotions.
Socio-economic status was based on the highest educational level completed. Mean years of education were Twelve of the patients Symptom onset had occurred 0. Handedness was taken as the hand used to write with. All patients with exception of one woman were right-handed. A conducted analysis of variance with the factors medication medicated vs.
We further tested 28 mentally healthy subjects, 17 men and 11 women, matched for sex, age and socio-economic status. They had been recruited by advertisements in a local newspaper. Sixteen subjects of the control group Mean education level was Controls were right-handed with the exception of one man and one woman. The presence of neurological disorders for controls and of other neurological disorders besides HD for patients was also an exclusion criterion.
All participants gave informed written consent to the study. This scale ranges between 0 and 50 points and allows the detection of early signs of cognitive impairment. A score lower than 35 indicates a tentative dementia diagnosis exclusion criterion.
The Cronbach's alpha is 0. The UHDRS Huntington Study Group, , only used for the patient group, is a standardized clinical rating scale for assessing motor, cognitive, behavioural, and functional capacity symptoms of Huntington's disease. The TFC Shoulson and Fahn, is a standard measure of functional capacity consisting of five items assessing engagement in occupation, capacity to handle financial affairs, capacity to manage domestic responsibilities, capacity to perform activities of daily living and the type of residential care provided.
Scores range from 0 to 13, with higher scores indicative of higher functioning and greater independence. The Cronbach's alpha of this scale is 0. Habitual emotional reactivity was assessed by self-report inventories:. Before starting the experiment participants were asked for their understanding of basic emotions by a short verbal description.
The stimulus material had been matched for item difficulty, complexity, brightness and colour. Since the IAPS does not include pictures which reliably induce anger, sadness and surprise these categories were omitted. It is known that IAPS scenes which should induce sadness or anger usually produce mixed emotions e. Affective neutral stimuli were included as a control reference condition. Pre-tests had displayed that this time was reported as sufficient for identifying the pictures also by HD patients.
The presentation could be terminated early by pressing a button on a three-button device, which had been developed for the experiment. For the scenes, subjects rated how intense the six basic emotions were induced by a particular picture e. For each facial expression subjects rated how intense the depicted person experienced the six basic emotions e.
To avoid position effects, the order of the two picture perception tasks recognition vs. We computed mean emotion intensity ratings for affective scenes and facial expressions for each emotional condition and all six basic emotions. Alpha level significance was set at 0. Effect sizes were calculated by Cohen's d. Groups did not differ in depressive symptoms BDI; patients: We also found no group effects for trait anxiety STAI; patients: Group comparison of the mean scores standard errors for intensity ratings of target emotions.
Left panel refers to affective facial expressions and right panel to affective scenes. Group comparison of the mean scores standard errors for classification accuracy difference between rated target emotion intensity and mean sum of non-target intensity ratings for affective facial expressions.
Higher scores mean better classification performance. Group comparison of the Mean scores standard deviations for intensity ratings in neutral stimuli for emotion perception tasks. In this study we investigated emotion recognition and emotion experience in symptomatic HD. The participants had been asked to judge the intensity of affective facial expressions as well as the intensity of emotional experiences elicited by affective scenes using graded choice over six basic emotions. The analysis of the recognition task revealed lower intensity ratings of target emotions for angry, disgusted and surprised faces in HD patients compared to controls.
This points to a quantitative recognition deficit in HD patients.
Rare Disease Database
Neuron. May;14(5) Widespread expression of Huntington's disease gene (IT15) protein product. Sharp AH(1), Loev SJ, Schilling G, Li SH, Li XJ. Findings on affective processing deficits in Huntington's disease (HD) have been .. Correlative analyses. a). Controlling for confounding variables: For. Calculating something as simple as the prevalence of Huntington's disease (HD) is problematic and . using the meta package in R RESULTS. Figure 1.