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Background
Huntington's disease (HD) is a progressive, fatal, autosomal dominant neuro-degenerative disease caused by increased CAG repeats in the huntington gene. It is characterized by chorea and imbalance as well as deterioration in cognitive and neuropsychiatric function. Primary pathological changes are found in the caudate-putamen (striatum), where gabaminergic neurons undergo degenerative changes. There is also evidence that HD is a multi-system degeneration. A recent study reported that cortical degeneration is present in early stages of HD and may explain at least some of the clinical symptoms (Rosas et al, 2002).
Sturrock et al (2010) evaluated in-vivo brain metabolite differences in control subjects, individuals with pre-manifest HD (pre-HD), and individuals with early HD using ¹H magnetic resonance spectroscopy (MRS) and assessed their relationship with motor performance. A total of 85 subjects (30 controls, 25 pre-HD, and 30 early HD) were recruited as part of the TRACK-HD study; 84 were scanned at 3T with single-voxel spectroscopy in the left putamen. Disease burden score was greater than 220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment including Unified Huntington's Disease Rating Scale (UHDRS) motor scoring and a novel quantitative motor battery. Statistical analyses included linear regression and 1-way analysis of variance. Total N-acetylaspartate (tNAA), a neuronal integrity marker, was lower in early HD (approximately 15 %) versus controls (p < 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (approximately 8 %) and early HD (approximately 17 %) versus controls (p < 0.05). The glial cell marker, myo-inositol (mI), was 50 % higher in early HD versus pre-HD (p < 0.01). In early HD, mI correlated with UHDRS motor score (R² = 0.23, p < 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R² = 0.30, p < 0.0001) and with disease burden score (R² = 0.17, p < 0.005). The authors demonstrated that lower putaminal tNAA in early HD compared to controls in a cross-section of subjects. A novel biomarker role for mI in early HD was also identified. These findings resolve disagreement in the literature about the role of MRS as an HD biomarker. The authors concluded that putaminal MRS measurements of NAA and mI are promising potential biomarkers of HD onset and progression.
In a multi-center, double-blind, randomized, placebo-controlled trial, Kieburtz K et al (2010) evaluated the safety and tolerability of latrepirdine in HD and explored its effects on cognition, behavior, and motor symptoms. A total of 91 patients with mild to moderate HD enrolled at 17 United States and United Kingdom centers from July 18, 2007, through July 16, 2008. Subjects received latrepirdine, 20 mg thrice-daily (n = 46), or matching placebo (n = 45) for a 90-day treatment period. The primary outcome variable was tolerability, defined as the ability to complete the study at the assigned drug dosage. Secondary outcome variables included score changes from baseline to day 90 on the UHDRS, the Mini-Mental State Examination (MMSE), and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Latrepirdine was well-tolerated (87 % of the patients given latrepirdine completed the study versus 82 % in the placebo group), and adverse event rates were comparable in the 2 groups (70 % in the latrepirdine group and 80 % in the placebo group). Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95 % confidence interval [CI]: 0.10 to 1.85; p = 0.03). No significant treatment effects were seen on the UHDRS or the ADAS-cog. The authors concluded that short-term administration of latrepirdine is well-tolerated in patients with HD and may have a beneficial effect on cognition. They stated that further investigation of latrepirdine is warranted in this population with HD.
In a randomized, double-blind, placebo-controlled, 4-week trial, Lundin et al (2010) evaluated the safety and effectiveness of the dopaminergic stabilizer pridopidine (ACR16) in patients with HD. Subjects received pridopidine (50 mg/day, n = 28) or placebo (n = 30). The primary outcome measure was the change from baseline in weighted cognitive score, assessed by cognitive tests (Symbol Digit Modalities, verbal fluency, and Stroop tests). Secondary outcome measures included changes in the UHDRS, Hospital Anxiety and Depression Scale, Leeds Sleep Evaluation Questionnaire, Reitan Trail-Making Test A, and Clinical Global Impression of Change. Safety assessments were also performed. There was no significant difference between pridopidine and placebo in the change from baseline of the weighted cognitive score. However, secondary measures such as affective symptoms showed trends toward improvement, and there was significant improvement in voluntary motor symptoms compared with placebo (p < 0.05). Pridopidine was well- tolerated, with a safety profile similar to placebo. The author concluded that pridopidine shows promise as a treatment for some of the symptoms of HD. In this small-scale study, the most notable effect was improvement in voluntary motor symptoms. The authors stated that larger, longer-term trials are needed.
Fetal neural transplantation has been demonstrated to be a feasible treatment for patients with Parkinson's disease (PD). Embryonic mesencephalic tissue containing dopaminergic cells is implanted into the patient's striatum to modify motor disability of patients with advanced PD. However, the effectiveness of fetal neural transplantation for the treatment of PD has yet to be established.
Recently, fetal neural transplantation has also been performed as a potential treatment for HD. While it is clear that the techniques of neural transplantation is feasible for various neurodegenerative diseases, significant problems remain in the availability of suitable donor tissues and defining the optimal conditions for reliable survival of the implanted cells. There is insufficient data on the "progress" of HD patients following fetal striatal transplantation. Furthermore, a recent study on the use of bilateral fetal striatal transplantation for the treatment of HD found that patients with moderately advanced HD are at risk for subdural hemorrhages following transplantation surgery (Hauser et al, 2002). Thus, the safety and effectiveness of fetal striatal transplantation for the treatment of HD has yet to be established.
In an article on the safety and tolerability of intrastriatal neural allografts in patients with HD, Bachoud-Levi and colleagues (2000) called for caution regarding the involvement of HD patients in experimental surgical protocols. In an editorial on fetal striatal transplantation for the treatment of HD published in the Neurology, Greenamyer and Shoulson (2002) stated that the benefits (of this procedure) -- even the theoretical benefits -- are unclear. Rosser and Dunnett (2003) noted that a small number of studies have demonstrated the feasibility and safety of transplantation in HD, but it will require several more years before the effectiveness of the procedure can be confidently established.
In a long-term follow-up study, Bachoud-Levi and colleagues (2006) stated that although they have shown in 3 out of 5 patients with HD that motor and cognitive improvements 2 years after intra-cerebral fetal neural grafts are correlated with recovery of brain metabolic activity in grafted striatal areas and connected regions of the cerebral cortex, neural grafts are not known to have protective effects on the host brain per se. These investigators undertook long-term follow-up of previously reported patients with the disease to ascertain the nature and extent of any secondary decline after grafting. Five patients with HD from the authors’ pilot study were assessed annually with the UHDRS, neuropsychological tests, and MRI, for up to 6 years after neural grafting. Resting cerebral activity was recorded at 2 and 6 years. Clinical improvement reached a plateau after 2 years and then faded off variably 4 to 6 years following surgery. Dystonia deteriorated consistently, whereas chorea did not. Cognitive performance remained stable on non-timed tests, whereas progression of motor disability was shown by deterioration on timed tests. Hypo-metabolism also affected the brain heterogeneously, sparing the benefits in the frontal cortex and at the precise location of the grafts, but showing a progressive deterioration in other areas. Two patients who had no benefit from grafting at 2 years continued to decline in the same way as non-grafted patients. These researchers noted that neuronal transplantation in HD provides a period of several years of improvement and stability, but not a permanent cure for the disease. Improvement of the surgical procedure as well as in patient selection could improve the therapeutic value, but neuroprotective treatment seems to be unavoidable in the disease.
Keene et al (2007) reported the pathological findings in 2 patients with HD who died 74 and 79 months after transplantation. Neostriatum from both patients showed typical neuropathological changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in host striatum than graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intra-nuclear inclusions were identified in graft neurons, although these were prevalent in host cells. The authors concluded that these 2 autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate viability of neurons from fetal transplants in human neostriatum for more than 6 years. Despite prolonged survival, these grafts had poor integration with host striatum that is likely responsible for lack of clear clinical improvement in these patients.
In an editorial that accompanied the article by Keen et al, Frank and Biglan (2007) stated that "more work is needed in the design of trials, clinical and pathologic follow-up, and methods of transplantation of various cells. There are cell-based therapies that are commercially available, mostly outside the United States. Rather than referring patients to centers that will infuse or implant cells, these procedures should only be done in the setting of a rigorous research trial using established criteria".
Clelland et al (2008) stated that a major impetus for research into the treatment of HD has centered on cell therapy strategies to protect vulnerable neuronal cell populations or to replace dysfunctional or dying cells. The work underlying 3 approaches to HD cell therapy includes (i) the potential for self-repair through the manipulation of endogenous stem cells and/or neurogenesis, (ii) the use of fetal or stem cell transplantation as a cell replacement strategy, and (iii) the administration of neurotrophic factors to protect susceptible neuronal populations. These approaches have shown some promising results in animal models of HD. Although striatal transplantation of fetal-derived cells has undergone clinical assessment since the 1990s, many cell therapy strategies have yet to be applied in the clinic environment. A more thorough understanding of the pathophysiology underlying HD as well as the response of both endogenous and exogenous cells to the degenerating brain will inform their merit as potential therapeutic agents and enhance the framework by which the success of such therapies are ascertained.
Reuter et al (2008) reported the findings of 2 patients with moderate HD who received bilateral fetal striatal allografts. One patient demonstrated, for the first time, increased striatal D2 receptor binding, evident with 11C-raclopride positron emission tomography, and prolonged clinical improvement over 5 years, suggesting long-term survival and efficacy of the graft. The other patient did not improve clinically or radiologically. The authors stated that these results indicated that striatal transplantation in HD may be beneficial but further studies are needed to confirm this.
Gallina and colleagues (2010) reported the findings of 4 HD patients who underwent bilateral transplantation with human fetal striatal tissues (9 to 12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean of 24.7 months). Surgery was uneventful. Starting from the 4th month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in 1 case, with the ventral striatum, was also observed. The new tissue growth halted after the 9th month post-transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provided the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain following neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. The authors stated that further studies are needed to evaluate the clinical effectiveness of human fetal striatal transplantation for the treatment of HD.
Sadan et al (2012) stated that excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. These researchers developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF(+) cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. These investigators examined the effectiveness of NTF(+) cells using the quinolinic acid (QA) rat model for excitotoxicity. They showed that NTF(+) cells transplanted into rat brains after QA injection survive transplantation (19 % after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF(+) cells exhibit improved behavior; namely, perform 80 % fewer apomorphine- induced rotations than phosphate-buffered saline (PBS)-treated QA-injected rats. More importantly, these researchers found that MSCs derived from HD patients can be induced to become NTF(+) cells and exert efficacious effects similarly to NTF(+) cells derived from healthy donors. To the authors' knowledge, this is the first study to take adult bone marrow derived MSCs from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI the authors demonstrated in-vivo that PBS-treated QA-injected striatae exhibit increasing T(2) values over time in lesioned regions, whereas T(2) values decrease in equivalent regions of QA-injected rats treated with NTF(+) cells. The authors concluded that NTF cellular treatment could serve as a novel therapy for managing HD.
Mestre and Ferreira (2012) noted that HD is a neuro-degenerative disease with diverse symptoms for which there is no curative or disease-modifying treatment available. Currently, tetrabenazine is the only drug approved for HD by a regulatory agency, and only for the treatment of chorea. These researchers presented updated results from recent clinical trials and ongoing clinical research efforts to find safe and effective treatments for HD motor, and neuropsychiatric and cognitive symptoms. They used a systematic review approach that included data from well-designed randomized controlled trials. The authors concluded that there is weak evidence to support most of the treatment decisions in HD and thus clinicians may be guided only by expert opinion-based therapeutic recommendations.
On behalf of the American Academy of Neurology, Armstrong and Miyasaki (2013) developed an evidence-based guideline assessing pharmacologic options for treating HD chorea. These investigators evaluated available evidence from a structured literature review performed through February 2011. If HD chorea requires treatment, clinicians should prescribe tetrabenazine (up to 100 mg/day), amantadine (300 to 400 mg/day), or riluzole (200 mg/day) (Level B) for varying degrees of expected benefit. Occurrence of adverse events should be discussed and monitored, particularly depression/suicidality and parkinsonism with tetrabenazine and elevated liver enzymes with riluzole. Clinicians may also prescribe nabilone for modest decreases (1- to less than 2-point changes on the UHDRS chorea score) in HD chorea (Level C), but information is insufficient to recommend long-term use, particularly given abuse potential concerns (Level U). Clinicians should not prescribe riluzole 100 mg/day for moderate (2- to less than 3-point UHDRS chorea change) short-term benefits (Level B) or for any long-term (3-year) HD anti-choreic goals (Level B). Clinicians may choose not to prescribe ethyl-EPA (Level B), minocycline (Level B), or creatine (Level C) for very important improvements (greater than 3-point UHDRS chorea change) in HD chorea. Clinicians may choose not to prescribe coenzyme Q10 (Level B) for moderate improvements in HD chorea. Data are insufficient to make recommendations regarding the use of neuroleptics or donepezil for HD chorea treatment (Level U).
Gonzalez et al (2014) noted that experience of globus pallidus internus (GPi) deep brain stimulation (DBS) in the treatment of HD has been limited to a small number of case reports. These researchers analyzed long-term motor outcome of a cohort of HD patients treated with GPi DBS. A total of 7 patients with pharmacologically resistant chorea and functional impairment were included in a prospective open-label study from 2008 to 2011. The main outcome measure was the motor section of the UHDRS. The primary end-point was reduction of chorea. Patients underwent MRI-guided bilateral GPi implantation. The median duration of follow-up was 3 years. A significant reduction of chorea was observed in all patients, with sustained therapeutic effect; the mean improvement on the chorea subscore was 58.34 % at the 12-month follow-up visit (p = 0.018) and 59.8 % at the 3-year visit (p = 0.040). Bradykinesia and dystonia showed a non-significant trend toward progressive worsening related to disease evolution and partly to DBS. The frequency of stimulation was 130 Hz for all patients. Deep brain stimulation-induced bradykinesia was managed by pulse-width reduction or bipolar settings. Levodopa mildly improved bradykinesia in 4 patients. Regular off-stimulation tests confirmed a persistent therapeutic effect of DBS on chorea. The authors concluded that GPi DBS may provide sustained chorea improvement in selected HD patients with pharmacologically resistant chorea, with transient benefit in physical aspects of quality of life before progression of behavioral and cognitive disorders. Moreover, DBS therapy did not improve dystonia or bradykinesia. They stated that further studies including quality of life (QoL) measures are needed to evaluate the impact of DBS in the long-term outcome of HD.
Gruber et al (2014) stated that recent case reports suggested beneficial effect of GPi-DBS in selected patients suffering from HD with marked disabling chorea. These investigators present a 41-year old man with genetically confirmed HD following quadruple GPi- and sub-thalamic nucleus (STN)-DBS. Motor function was assessed by Abnormal Involuntary Movement Scale (AIMS) and by UHDRS pre-surgery and post-surgery for up to 4 years. Furthermore, cognitive, neuropsychiatric state and QoL including life satisfaction (QLS) were annually evaluated. Chorea assessed by AIMS and UHDRS subscores improved by 52 and 55 %, 45 and 60 %, 35 and 45 % and 55 to 66 % at 1 to 4 years, respectively, compared to pre-surgical state following GPi-STN-DBS. During these time periods bradykinesia did not increase following separate STN- and combined GPi-STN-DBS compared to pre-surgical state. Mood, QoL and QLS were ameliorated. However, dysexecutive symptoms increased at 4 years post-surgery. The present case report suggested that bilateral GPi- and STN-DBS may represent a new treatment avenue in selected HD patients. Clinically, GPi-DBS attenuated chorea and was associated with a larger effect-adverse effect window compared to STN-DBS. However, GPi-DBS-induced bradykinesia may emerge as one main limitation of GPi-DBS in HD. The authors concluded that quadruple GPi-STN-DBS may be indicated, if separate GPi-DBS does not result in sufficient control of motor symptoms. Moreover, they stated that future controlled studies are needed to confirm if the present anecdotal observation of additive beneficial effects of GPi- and STN-DBS in a HD patient with severe generalized chorea and relatively intact cognitive and affective functions indeed represents a new therapeutic option.
Furthermore, an UpToDate review on “Huntington disease: Management” (Suchowersky, 2014) states that “Neurotrophic factors -- Increasing the presence of neurotrophic factors (e.g., brain-derived neurotrophic factor [BDNF], ciliary neurotrophic factor [CNTF], glial cell line-derived neurotrophic factor [GDNF]) in the striatum is a possible approach to prolong the survival of native neurons in patients with HD. A number of studies have shown benefit in animal models, but clinical evidence is limited. A preliminary human study used encapsulated CNTF-releasing cells in the ventricle of patients over two years with no clear benefit. The technical difficulties were significant and remain an obstacle to this technology”. In this review, neurotrophic factors are listed among several investigational therapies (including DBS) for HD. The review states that “The utility of deep brain stimulation in HD is unknown. Data are limited to case studies, which suggest some benefit in chorea”.
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