Neuroimaging in Huntington’s disease

Poster 12: Self-Efficacy in Health Behaviors: Is There a Difference in Huntington vs Parkinson Disease?

Huntington disease (HD) is a fatal genetic disorder that affects the movement and cognition of affected individuals. It is inherited in an autosomal dominant manner, meaning that each child of a parent with HD has a 50% chance of inheriting the mutated gene. The mutation involves an expansion of a trinucleotide repeat (CAG) in the HD gene, which is located on the short arm of chromosome 4p16.3. The HD gene encodes a protein called huntingtin, which has an unknown function. The number of CAG repeats determines the severity and onset of the disease. Normal individuals have 26 or fewer repeats, while HD patients have 40 or more repeats. Individuals with 27 to 35 repeats do not develop HD, but they can pass on the mutation to their offspring, especially if the mutation is inherited from the father. Individuals with 36 to 39 repeats may or may not develop HD, depending on other factors. The more CAG repeats, the earlier the symptoms appear. HD is the most extensively studied neurodegenerative disorder with a genetic cause. There are genetic tests available to diagnose HD and to predict the risk of developing HD in asymptomatic individuals. There are also prenatal and preimplantation tests to prevent the transmission of HD to the next generation. HD is characterized by involuntary movements called chorea, which affect all muscles and impair all psychomotor functions. HD patients also suffer from cognitive decline and psychiatric symptoms, such as mood disorders and social changes. These symptoms are chronic and progressive, leading to complete dependence and death. Chorea can also be caused by other conditions, such as metabolic disorders or drug-induced side effects. Neuroimaging techniques, such as MR imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), MR spectroscopy, and diffusion tensor imaging, can help to diagnose HD and monitor its progression. The pathophysiology of HD involves the loss of neurons and the dysfunction of neurotransmitter systems, especially the dopaminergic system. There is no cure for HD, but there are treatments to manage the symptoms and to improve the quality of life of HD patients. These include pharmacological interventions, such as dopamine receptor antagonists or depleters, and non-pharmacological interventions, such as psychological and social support. HD is a devastating disease that poses many challenges for patients, families, and healthcare providers. There is hope that gene-targeted therapies will be developed in the near future to stop or slow down the disease process.

Huntington's disease (HD) is an inherited and fatal polyglutamine neurodegenerative disorder caused by an expansion of the CAG triplet repeat coding region within the HD gene. Progressive dysfunction and loss of striatal GABAergic medium spiny neurons (MSNs) may account for some of the characteristic symptoms in HD patients. Interestingly, in HD, MSNs expressing neuropeptide Y (NPY) are spared and their numbers is even up-regulated in HD patients. Consistent with this, we report here on increased immuno-linked NPY (IL-NPY) levels in human cerebrospinal fluid (hCSF) from HD patients (Control n = 10; early HD n = 9; mid HD n = 11). As this antibody-based detection of NPY may provide false positive differences as a result of the antibody-based detections of only fragments of NPY, the initial finding was validated by investigating the proteolytic stability of NPY in hCSF using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and selective inhibitors. A comparison between resulting NPY-fragments and detailed epitope analysis verified significant differences in IL-NPY1-36/3-36 and NPY1-30 levels between HD patients and control subjects with no significant differences between early vs mid HD cases. Ex vivo degradomics analysis demonstrated that NPY is initially degraded to NPY1-30 by cathepsin D in both HD patients and control subjects. Yet, NPY1-30 is then further differentially hydrolyzed by thimet oligopeptidase (TOP) in HD patients and by neprilysin (NEP) in control subjects. Furthermore, altered hCSF TOP-inhibitor Dynorphin A1-13 (Dyn-A1-13 ) and TOP-substrate Dyn-A1-8 levels indicate an impaired Dyn-A-TOP network in HD patients. Thus, we conclude that elevated IL-NPY-levels in conjunction with TOP-/NEP-activity/protein as well as Dyn-A1-13 -peptide levels may serve as a potential biomarker in human CSF of HD. Huntington's disease (HD) patients' cerebrospinal fluid (CSF) exhibits higher neuropeptide Y (NPY) levels. Further degradomics studies show that CSF-NPY is initially degraded to NPY1-30 by Cathepsin D. The NPY1-30 fragment is then differentially degraded in HD vs control involving Neprilysin (NEP), Thimet Oligopeptidase (TOP), and TOP-Dynorphin-A network. Together, these findings may help in search for HD biomarkers.

Back to table of contents Previous article Next article Communications and UpdatesFull AccessEating Disorder as a Psychiatric Onset of Juvenile Huntington's DiseaseSara Marconi, M.D., Giovanni Rizzo, M.D., Ph.D., Sabina Capellari, M.D., Ph.D., Cesa Scaglione, M.D., Ph.D., Pietro Cortelli, M.D., Ph.D., Paolo Martinelli, M.D., Ph.D., and Sara Bonazza, M.D.Sara MarconiBologna, ItalySearch for more papers by this author, M.D., Giovanni RizzoBologna, ItalySearch for more papers by this author, M.D., Ph.D., Sabina CapellariBologna, ItalySearch for more papers by this author, M.D., Ph.D., Cesa ScaglioneBologna, ItalySearch for more papers by this author, M.D., Ph.D., Pietro CortelliBologna, ItalySearch for more papers by this author, M.D., Ph.D., Paolo MartinelliBologna, ItalySearch for more papers by this author, M.D., Ph.D., and Sara BonazzaBologna, ItalySearch for more papers by this author, M.D.Published Online:1 Oct 2011https://doi.org/10.1176/appi.ajp.2011.11020312AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Huntington's disease is an autosomal-dominant disorder with onset in midlife caused by an excess of CAG nucleotide repeats in the IT15 gene, codifying for huntingtin protein, and is classically characterized by motor, cognitive, and psychiatric disturbances. Juvenile forms of Huntington's disease may have an atypical presentation with different motor signs including parkinsonism and ataxia and, commonly, with nonspecific psychiatric features. Among the broad spectrum of psychiatric symptoms, little attention has been paid to the possible association between Huntington's disease and eating disorders. We describe the case of a young woman with Huntington's disease that developed with an eating disorder.Case ReportThe patient's family history was unknown because she had been adopted at birth. After a family bereavement when she was 16 years old, the girl developed an eating disorder that was characterized by fear of weight gain, frequent binge eating, compensatory behaviors, and an abnormally low body weight without amenorrhea. An eating disorder not otherwise specified was diagnosed, and she was treated with cognitive-behavioral therapy. At age 22 she began to complain of instability and disequilibrium. She experienced progressively worsening falls until age 26, when she came to our attention. Neurological examination revealed moderately depressed mood and partial cooperation; mild choreic movements in the extremities, trunk, and face; rare distal myoclonus; reduced eye-head coordination; bilateral brisk reflexes; limb hypotonia and dysmetria; and ataxic gait and balance. Neuropsychological testing revealed a low IQ (WAIS score=52). A blood examination and MRI failed to show clear abnormalities. Genetic testing revealed a CAG expansion (large/short allele: 55/17 triplets) in the IT15 gene. Treatment with pimozide, 2 mg/day, moderately improved her mood.Over the next 4 years, the patient's motor and cognitive profile progressively deteriorated, and frequent binge eating episodes reappeared.DiscussionIn our juvenile Huntington's disease patient, the eating disorder at onset preceded motor symptoms by 6 years. Although the two diseases may be a casual finding in our patient, there could be a link. Involvement of frontostriatal circuits and the hypothalamus has been reported in both diseases (1). Recent studies have focused on hypothalamic dysfunction in Huntington's disease, and hypothalamic atrophy was found in Huntington's disease patients by neuropathological analysis (2). MRI, positron emission tomography, and clinical data support a hypothalamic involvement in early Huntington's disease patients and premanifest Huntington's disease gene carriers (3). In addition, the hypothalamus plays a critical role in regulation of feeding and appetite. An alteration of hypothalamic-pituitary-adrenal axis function is known in eating disorders, and a recent functional MRI study disclosed an aberrant hypothalamic activation in eating disorder patients with binge-purge behaviors (1). Hypothalamic dysfunction could be related to the onset of eating disorders in our patient and to the reappearance of abnormal eating behavior.Bologna, ItalyThe authors report no financial relationships with commercial interests.Accepted for publication in May 2011.

The performances of patients with dementia of the Alzheimer type (DAT), patients with Huntington's disease (HD), and demented and nondemented patients with Parkinson's disease (PD) were compared on 2 tests of implicit memory that do not require the conscious recollection of prior study episodes: (1) a pursuit-rotor motor learning task and (2) a lexical priming test. The HD patients were found to be impaired on the motor learning but not the lexical priming task, whereas the DAT patients evidenced the opposite relationship on these tasks. The demented, but not the nondemented, PD patients were found to be impaired on both tests of implicit memory. For both the HD and PD patients, deficits on the motor learning task correlated significantly with severity of dementia but not with level of primary motor dysfunction. The noted double dissociation between HD and DAT patients indicates that different forms of implicit memory, all of which are intact in amnesia, are dependent upon distinct neuroanatomic systems. Motor skill learning may be mediated by a corticostriatal system, whereas verbal priming may depend upon the integrity of the neocortical association areas involved in the storage of semantic knowledge. The results for the PD patients suggest that the demented PD patients have endured damage to the neurologic systems subserving both motor learning and lexical priming.

<h3>Background</h3> Recent diffusion tensor imaging (DTI) studies suggest that abnormalities in Huntington9s disease (HD) extend to white matter (WM) tracts in early HD and even in presymptomatic (PreHD) stages. However, DTI tractography, which allows precise localisation of WM abnormalities has not yet been used to investigate changes associated with HD. <h3>Aims</h3> The purpose of this study was to investigate whether the corpus callosum (CC) of PreHD subjects exhibit a measurable difference compared to healthy controls and HD patients in the Forceps Major (posterior projections) and Minor (frontal projections). <h3>Methods</h3> All T1 and DTI data were acquired on a 3T Allegra MRI system (Siemens) for 33 healthy controls (22M/11F; age: 43.88±11.69), 19 PreHD subjects (13M/6F; age: 38.11±7.75) and 23 HD patients (13M/10F; age: 48.30±13.79). DTI scans were acquired with 30 directions and three acquisitions. The Forceps Major and Minor were delineated using predefined ROI9s in TrackVis. The general linear model was used to compare tract volume with sex, age and CC volume included in the model. <h3>Results</h3> Mean track volume for the FMajor: Controls=18.28±5.07, PreHD= 15.23±4.16, HD=13.98±4.16, and FMinor: Controls=14.90±4.21, PreHD=16.18±4.12, HD=11.60±4.08). Controls had a significantly larger FMajor compared to PreHD F[1,51]=6.534, p&lt;0.02 and PreHD subjects had a significantly larger FMajor compared to HD patients F[1,42]=4.44, p &lt;0.045. PreHD subjects had a significantly larger FMinor than HD Patients F[1,42]=13.261, p&lt;002. <h3>Conclusion</h3> The results suggest there is a significant difference in posterior and frontal CC projections between PreHD subjects and HD patients indicating a volume reduction associated with disease progression. Furthermore, PreHD subjects exhibit significantly smaller posterior projections compared to healthy controls but no significant difference in frontal projections, signalling a posterior-to-anterior direction in disease progression.

Verbal recall and recognition were examined in Huntington's disease (HD) and Alzheimer's disease (AD) patients. Subgroups of HD and AD patients were matched for overall severity of dementia. Subjects were administered the Hopkins Verbal Learning Test, a list-learning task with three free-recall trials followed immediately by one yes/no recognition trial with semantically related and unrelated distractors. The matched AD and HD groups did not differ in the number of words recalled, although the HD patients showed slightly greater improvement over trials. Recognition performance was evaluated with measures of accuracy and response bias that are independent of each other. The matched groups did not differ in overall recognition accuracy, but the AD patients tended to have a more liberal ("yea-saying") response bias than did the HD patients. In addition, only the AD patients were differentially enticed to false-positive responding by semantically related distractors. The results suggest that the rule for making decisions when uncertain, rather than memory strength per se, distinguishes the recognition memory performance of AD and HD patients.

Manuel B. Cossio abordaba en su aula del Museo Pedagogico la linea de una nueva pedagogia, una de cuyas notas distintivas fue la valoracion de la educacion fisica.-- En la practica, las ideas pedagogicas de Cossio pueden identificarse con las de la Institucion Libre de Ensenanza. En ellas, el muy amplio concepto de educacion fisica hay que entenderlo desde el de educacion integral, y este desde su conceptualizacion del hombre dentro de la Weltanschauung krausista.-- La filosofia krausista proporcionaba la mas solida base para la valoracion de los aspectos corporales en educacion.-- La Institucion sostuvo una actitud de vanguardia en la evolucion de las ideas sobre educacion fisica en Europa.

The objective of this study was to report bladder dysfunction and cystometric findings in a systematically studied cohort of Huntington's disease (HD) patients. In HD patients and asymptomatic HD gene carriers a urinary function questionnaire, neurologic assessment using the Unified Huntington's Disease Rating Scale, and postvoid residual volume measurement were applied. All patients were also invited to cystometric studies. Urinary function data were compared to control men and women. The most common symptoms in 54 HD patients (24 men) were those of bladder overactivity (men/women 54%/40%), followed by urinary incontinence (29%/43%) and symptoms of disturbed bladder emptying (25%/40%). Using urinary function questionnaires severe bladder dysfunction was found in 4%/0%, moderate in 21%/23%, and mild in 25%/30% of HD men/women. Urinary symptoms interfered with daily life in 21%/37% and sexual life in 21%/33% of sexually active HD men/women. In 5 HD men and 1 woman, increased postvoid residual volume (>100 ml) was found. Compared to 49/55 control men/women urinary incontinence, and urgency were more common in HD men, but not in HD women (urinary incontinence reported 10%/38% of control men/women). Cystometry, performed in 12 HD patients and 1 of 10 asymptomatic HD gene carriers, demonstrated detrusor-sphincter dyssynergia in 5 (42%), detrusor overactivity in 2 (17%), and reduced detrusor capacity in 2 (17%) HD patients. Our study demonstrated significant urinary symptoms in HD patients, which reduced their quality of life. Physicians helping HD patients should also consider this largely neglected aspect of the disease.

Inositol pyrophosphate diphosphoinositol pentakisphosphate is ubiquitously present in mammalian cells and contains highly energetic pyrophosphate bonds. We have previously reported that inositol hexakisphosphate kinase type 2 (InsP(6)K2), which converts inositol hexakisphosphate to inositol pyrophosphate diphosphoinositol pentakisphosphate, mediates apoptotic cell death via its translocation from the nucleus to the cytoplasm. Here, we report that InsP(6)K2 is localized mainly in the cytoplasm of lymphoblast cells from patients with Huntington disease (HD), whereas this enzyme is localized in the nucleus in control lymphoblast cells. The large number of autophagosomes detected in HD lymphoblast cells is consistent with the down-regulation of Akt in response to InsP(6)K2 activation. Consistent with these observations, the overexpression of InsP(6)Ks leads to the depletion of Akt phosphorylation and the induction of cell death. These results suggest that InsP(6)K2 activation is associated with the pathogenesis of HD.

Huntington disease (HD) is a neurodegenerative disorder caused by an expansion of polyglutamines in the first exon of huntingtin (HTT), which confers aggregation-promoting properties to amino-terminal fragments of the protein (N-HTT). Mutant N-HTT aggregates are enriched for ubiquitin and contain ubiquitin E3 ligases, thus suggesting a role for ubiquitination in aggregate formation. Here, we report that tumor necrosis factor receptor-associated factor 6 (TRAF6) binds to WT and polyQ-expanded N-HTT in vitro as well as to endogenous full-length proteins in mouse and human brain in vivo. Endogenous TRAF6 is recruited to cellular inclusions formed by mutant N-HTT. Transient overexpression of TRAF6 promotes WT and mutant N-HTT atypical ubiquitination with Lys6, Lys27, and Lys29 linkage formation. Both interaction and ubiquitination seem to be independent from polyQ length. In cultured cells, TRAF6 enhances mutant N-HTT aggregate formation, whereas it has no effect on WT N-HTT protein localization. Mutant N-HTT inclusions are enriched for ubiquitin staining only when TRAF6 and Lys6, Lys27, and Lys29 ubiquitin mutants are expressed. Finally, we show that TRAF6 is up-regulated in post-mortem brains from HD patients where it is found in the insoluble fraction. These results suggest that TRAF6 atypical ubiquitination warrants investigation in HD pathogenesis.

Huntington's disease (HD) is a hereditary neurodegenerative disorder for which biological indicators of disease progression, or disease stage, would be especially important for therapeutic trials. 24S-hydroxycholesterol (24OHC) is a brain-generated cholesterol metabolite which has been associated with neurodegeneration, and alterations of cholesterol metabolism in murine HD models and patients' tissues have been recently identified. On these grounds, and with the aim of identifying putative biomarkers in HD, we studied cholesterol metabolism through the analysis in vivo of plasma 24OHC and cholesterol in two independent cohorts of controls and patients of Italian and British origin. We analysed a total of 62 controls, 96 HD symptomatic patients at different disease stages (stage 1-3), and 33 HD gene-positive pre-manifest subjects [pre-manifest HD (pre-HD)]. Cholesterol and 24OHC plasma levels were comparable in both the British and Italian subjects, and were not influenced by fasting or post-meal status. Cholesterol levels did not show differences between controls, pre-HD subjects and HD patients. In contrast, the plasma levels of 24OHC were significantly higher in controls than in HD patients at all disease stages (P < 0.001). Interestingly, in pre-HD subjects plasma 24OHC concentrations were similar to those of controls, and thus significantly greater than those of HD patients at any disease stage (P < 0.001). As expected, significant differences in caudate volumes between stage 1-2 HD patients and pre-HD subjects, and pre-HD subjects and controls were found. The pre-HD cohort of subjects was heterogeneous as to 24OHC levels, since subjects closer to predicted development of motor signs of disease had lower 24OHC levels than those far from onset. Our data indicate that the brain-generated cholesterol metabolite 24OHC measured in plasma was significantly depleted in HD patients at any disease stage, and it could discriminate pre-manifest subjects from patients with overt motor disease. However, 24OHC levels failed to mark further disease progression in patients with manifest HD. Overall, we demonstrate that 24OHC levels parallel the large decrease in caudate volumes observed in gene-positive subjects from pre-manifest to HD stage 1, thus reflecting a critical phase characterized by neuronal loss. We conclude that that 24OHC levels complement MRI morphometry as a valuable tool to follow neurodegenerative changes in the early stages of Huntington disease.

In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient choosing to continue treatment over the 18-month follow-up period). The treatment regimen was well tolerated. No significant differences on neuropsychological parameters before and after treatment were detected; but the patient who continued treatment did not deteriorate at 18 months' reevaluation, whereas the three patients who had stopped treatment after 3 to 4 months had minor progression in all cognitive domains on re-evaluation 12 months after the end of treatment.

Motor memory and the preselection effect in Huntington's and Parkinson's disease

Dispelling the stigma of Huntington's disease