Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease.

The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.

Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease.

Recent evidence provides support for involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that a pro-inflammatory intestinal milieu, due to intestinal hyper-permeability and/or microbial dysbiosis, initiates or exacerbates PD pathogenesis. One factor that can cause intestinal hyper-permeability and dysbiosis is chronic stress which has been shown to accelerate neuronal degeneration and motor deficits in Parkinsonism rodent models. We hypothesized that stress-induced intestinal barrier dysfunction and microbial dysbiosis lead to a pro-inflammatory milieu that exacerbates the PD phenotype in the low-dose oral rotenone PD mice model. To test this hypothesis, mice received unpredictable restraint stress (RS) for 12 weeks, and during the last six weeks mice also received a daily administration of low-dose rotenone (10 mg/kg/day) orally. The initial six weeks of RS caused significantly higher urinary cortisol, intestinal hyperpermeability, and decreased abundance of putative "anti-inflammatory" bacteria (Lactobacillus) compared to non-stressed mice. Rotenone alone (i.e., without RS) disrupted the colonic expression of the tight junction protein ZO-1, increased oxidative stress (N-tyrosine), increased myenteric plexus enteric glial cell GFAP expression and increased α-synuclein (α-syn) protein levels in the colon compared to controls. Restraint stress exacerbated these rotenone-induced changes. Specifically, RS potentiated rotenone-induced effects in the colon including: 1) intestinal hyper-permeability, 2) disruption of tight junction proteins (ZO-1, Occludin, Claudin1), 3) oxidative stress (N-tyrosine), 4) inflammation in glial cells (GFAP + enteric glia cells), 5) α-syn, 6) increased relative abundance of fecal Akkermansia (mucin-degrading Gram-negative bacteria), and 7) endotoxemia. In addition, RS promoted a number of rotenone-induced effects in the brain including: 1) reduced number of resting microglia and a higher number of dystrophic/phagocytic microglia as well as (FJ-C+) dying cells in the substantia nigra (SN), 2) increased lipopolysaccharide (LPS) reactivity in the SN, and 3) reduced dopamine (DA) and DA metabolites (DOPAC, HVA) in the striatum compared to control mice. Our findings support a model in which chronic stress-induced, gut-derived, pro-inflammatory milieu exacerbates the PD phenotype via a dysfunctional microbiota-gut-brain axis.

Role of TLR4 in the gut-brain axis in Parkinson's disease: a translational study from men to mice.

OBJECTIVE: Recent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given the prominence of dysbiosis and colonic dysfunction in patients with Parkinson's disease (PD), we propose that toll-like receptor 4 (TLR4)-mediated intestinal dysfunction could contribute to intestinal and central inflammation in PD-related neurodegeneration. DESIGN: To test this hypothesis we performed studies in both human tissue and a murine model of PD. Inflammation, immune activation and microbiota composition were measured in colonic samples from subjects with PD and healthy controls subjects and rotenone or vehicle-treated mice. To further assess the role of the TLR4 signalling in PD-induced neuroinflammation, we used TLR4-knockout (KO) mice in conjunction with oral rotenone administration to model PD. RESULTS: Patients with PD have intestinal barrier disruption, enhanced markers of microbial translocation and higher pro-inflammatory gene profiles in the colonic biopsy samples compared with controls. In this regard, we found increased expression of the bacterial endotoxin-specific ligand TLR4, CD3+ T cells, cytokine expression in colonic biopsies, dysbiosis characterised by a decrease abundance of SCFA-producing colonic bacteria in subjects with PD. Rotenone treatment in TLR4-KO mice revealed less intestinal inflammation, intestinal and motor dysfunction, neuroinflammation and neurodegeneration, relative to rotenone-treated wild-type animals despite the presence of dysbiotic microbiota in TLR4-KO mice. CONCLUSION: Taken together, these studies suggest that TLR4-mediated inflammation plays an important role in intestinal and/or brain inflammation, which may be one of the key factors leading to neurodegeneration in PD.

Similar α-Synuclein staining in the colon mucosa in patients with Parkinson's disease and controls.

BACKGROUND: The gut is proposed as a starting point of idiopathic IPD, but the presence of α-synuclein in the IPD colon mucosa is debated. OBJECTIVES: The objective of this study was to evaluate if α-synuclein in the colon mucosa can serve as a biomarker of IPD. METHODS: Immunohistochemistry was used to locate and quantify in a blinded approach α-synuclein in the mucosa from biopsies of the right and left colon in 19 IPD patients and 8 controls. RESULTS: Total α-synuclein was present in all but 1 IPD patients and in all controls; phosphorylated α-synuclein was present in all subjects. There was no intensity difference depending on disease status. Staining of total α-synuclein was stronger in the right colon (p = .04). CONCLUSIONS: Conventional immunohistochemistry α-synuclein staining in colon mucosal biopsies cannot serve as a biomarker of idiopathic PD. These findings do not contradict the assumption of disease starting in the colon, and a colon segment-specific risk for disease initiation can still be hypothesized. © 2016 International Parkinson and Movement Disorder Society.

Therapeutic advances in Huntington's Disease.

Huntington's disease is a rare hereditary degenerative disease with a wide variety of symptoms that encompass movement, cognition, and behavior. The genetic mutation that causes the disease has been known for more than 20 y, and animal models have illuminated a host of intracellular derangements that occur downstream of protein translation. A number of clinical trials targeting these metabolic consequences have failed to produce a single effective therapy, although clinical trials continue. New strategies targeting the protein at the level of transcription, translation, and posttranslational modification and aggregation engender new hope that a successful strategy will emerge, but there is much work ahead. Some of the clinical manifestations of the illness, particularly chorea, affective symptoms, and irritability, are amenable to palliative strategies, but physicians have a poor evidence base on which to select the best agents. Clinical trials since 2013 have dashed hopes that coenzyme Q10 or creatine might have disease-modifying properties but suggested other agents were safe or hinted at efficacy (cysteamine, selisistat, hydroxyquinoline) and could proceed into later-stage disease modification trials. The hunt for effective symptom relief suggested that pridopidine might be shown effective given the right outcome measure. This review summarizes recent progress in HD and highlights promising new strategies for slowing disease progression and relieving suffering in HD.

Colonic bacterial composition in Parkinson's disease.

INTRODUCTION: We showed that Parkinson's disease (PD) patients have alpha-synuclein (α-Syn) aggregation in their colon with evidence of colonic inflammation. If PD patients have altered colonic microbiota, dysbiosis might be the mechanism of neuroinflammation that leads to α-Syn misfolding and PD pathology. METHODS: Sixty-six sigmoid mucosal biopsies and 65 fecal samples were collected from 38 PD patients and 34 healthy controls. Mucosal-associated and feces microbiota compositions were characterized using high-throughput ribosomal RNA gene amplicon sequencing. Data were correlated with clinical measures of PD, and a predictive assessment of microbial community functional potential was used to identify microbial functions. RESULTS: The mucosal and fecal microbial community of PD patients was significantly different than control subjects, with the fecal samples showing more marked differences than the sigmoid mucosa. At the taxonomic level of genus, putative, "anti-inflammatory" butyrate-producing bacteria from the genera Blautia, Coprococcus, and Roseburia were significantly more abundant in feces of controls than PD patients. Bacteria from the genus Faecalibacterium were significantly more abundant in the mucosa of controls than PD. Putative, "proinflammatory" Proteobacteria of the genus Ralstonia were significantly more abundant in mucosa of PD than controls. Predictive metagenomics indicated that a large number of genes involved in metabolism were significantly lower in the PD fecal microbiome, whereas genes involved in lipopolysaccharide biosynthesis and type III bacterial secretion systems were significantly higher in PD patients. CONCLUSION: This report provides evidence that proinflammatory dysbiosis is present in PD patients and could trigger inflammation-induced misfolding of α-Syn and development of PD pathology.

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

IMPORTANCE: There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE: To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS: The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS: Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES: The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS: The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE: Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00449865.

Gut feelings about smoking and coffee in Parkinson's disease.

Strong epidemiologic evidence suggests that smokers and coffee drinkers have a lower risk of Parkinson's disease (PD). The explanation for this finding is still unknown, and the discussion has focused on two main hypotheses. The first suggests that PD patients have premorbid personality traits associated with dislike for coffee-drinking and smoking. The second posits that caffeine and nicotine are neuroprotective. We propose an alternative third hypothesis, in which both cigarette and coffee consumption change the composition of the microbiota in the gut in a way that mitigates intestinal inflammation. This, in turn, would lead to less misfolding of the protein alpha-synuclein in enteric nerves, reducing the risk of PD by minimizing propagation of the protein aggregates to the central nervous system, where they otherwise can induce neurodegeneration.

Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a multifocal degenerative disorder for which there is no cure. The majority of cases are sporadic with unknown etiology. Recent data indicate that untreated patients with de novo PD have increased colonic permeability and that both de novo and premotor patients have pathological expression of α-synuclein (α-syn) in their colon. Both endpoints potentially can serve as disease biomarkers and even may initiate PD events through gut-derived, lipopolysaccharide (LPS)-induced neuronal injury. Animal models could be ideal for interrogating the potential role of the intestines in the pathogenesis of PD; however, few current animal models of PD encompass these nonmotor features. We sought to establish a progressive model of PD that includes the gastrointestinal (GI) dysfunction present in human patients. C57/BL6 mice were systemically administered one dose of either LPS (2.5 mg/kg) or saline and were sacrificed in monthly intervals (n = 5 mice for 5 months) to create a time-course. Small and large intestinal permeability was assessed by analyzing the urinary output of orally ingested sugar probes through capillary column gas chromatography. α-Syn expression was assessed by counting the number of mildly, moderately, and severely affected myenteric ganglia neurons throughout the GI tract, and the counts were validated by quantitative optical density measurements. Nigrostriatal integrity was assessed by tyrosine hydroxylase immunohistochemistry stereology and densitometry. LPS caused an immediate and progressive increase in α-syn expression in the large intestine but not in the small intestine. Intestinal permeability of the whole gut (large and small intestines) progressively increased between months 2 and 4 after LPS administration but returned to baseline levels at month 5. Selective measurements demonstrated that intestinal permeability in the small intestine remained largely intact, suggesting that gut leakiness was predominately in the large intestine. Phosphorylated serine 129-α-syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α-syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α-syn immunoreactivity, intestinal permeability, and pathological α-syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease-modifying therapies, including intestinal-directed therapies to fortify intestinal barrier integrity.

Diffusion tensor imaging of Parkinson's disease, atypical parkinsonism, and essential tremor.

Diffusion tensor imaging could be useful in characterizing movement disorders because it noninvasively examines multiple brain regions simultaneously. We report a multitarget imaging approach focused on the basal ganglia and cerebellum in Parkinson's disease, parkinsonian variant of multiple system atrophy, progressive supranuclear palsy, and essential tremor and in healthy controls. Seventy-two subjects were studied with a diffusion tensor imaging protocol at 3 Tesla. Receiver operating characteristic analysis was performed to directly compare groups. Sensitivity and specificity values were quantified for control versus movement disorder (92% sensitivity, 88% specificity), control versus parkinsonism (93% sensitivity, 91% specificity), Parkinson's disease versus atypical parkinsonism (90% sensitivity, 100% specificity), Parkinson's disease versus multiple system atrophy (94% sensitivity, 100% specificity), Parkinson's disease versus progressive supranuclear palsy (87% sensitivity, 100% specificity), multiple system atrophy versus progressive supranuclear palsy (90% sensitivity, 100% specificity), and Parkinson's disease versus essential tremor (92% sensitivity, 87% specificity). The brain targets varied for each comparison, but the substantia nigra, putamen, caudate, and middle cerebellar peduncle were the most frequently selected brain regions across classifications. These results indicate that using diffusion tensor imaging of the basal ganglia and cerebellum accurately classifies subjects diagnosed with Parkinson's disease, atypical parkinsonism, and essential tremor and clearly distinguishes them from control subjects.

Is alpha-synuclein in the colon a biomarker for premotor Parkinson's disease? Evidence from 3 cases.

BACKGROUND: Despite clinicopathological evidence that Parkinson's disease (PD) may begin in peripheral tissues, identification of premotor Parkinson's disease is not yet possible. Alpha-synuclein aggregation underlies Parkinson's disease pathology, and its presence in peripheral tissues may be a reliable disease biomarker. OBJECTIVE: We sought evidence of alpha-synuclein pathology in colonic tissues before the development of characteristic Parkinson's disease motor symptoms. METHODS: Old colon biopsy samples were available for three subjects with PD. Biopsies were obtained 2-5 years before PD onset. We performed immunohistochemistry studies for the presence of alpha-synuclein and Substance P in these samples. RESULTS: All subjects showed immunostaining for alpha-synuclein (two, five and two years before first motor Parkinson's disease symptom). No similar alpha-synuclein immunostaining was seen in 23 healthy controls. Staining of samples for substance P suggested colocalization of alpha-synuclein and substance P in perikarya and neurites. CONCLUSIONS: This is the first demonstration of alpha-synuclein in colon tissue prior to onset of PD. Additional study is required to determine whether colonic mucosal biopsy may be a biomarker of premotor PD.

Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease.

The diagnosis of Parkinson's disease rests on motor signs of advanced central dopamine deficiency. There is an urgent need for disease biomarkers. Clinicopathological evidence suggests that α-synuclein aggregation, the pathological signature of Parkinson's disease, can be detected in gastrointestinal tract neurons in Parkinson's disease. We studied whether we could demonstrate α-synuclein pathology in specimens from unprepped flexible sigmoidoscopy of the distal sigmoid colon in early subjects with Parkinson's disease. We also looked for 3-nitrotyrosine, a marker of oxidative stress. Ten subjects with early Parkinson's disease not treated with dopaminergic agents (7 men; median age, 58.5 years; median disease duration, 1.5 years) underwent unprepped flexible sigmoidoscopy with biopsy of the distal sigmoid colon. Immunohistochemistry studies for α-synuclein and 3-nitrotyrosine were performed on biopsy specimens and control specimens from a tissue repository (23 healthy subjects and 23 subjects with inflammatory bowel disease). Nine of 10 Parkinson's disease samples were adequate for study. All showed staining for α-synuclein in nerve fibers in colonic submucosa. No control sample showed this pattern. A few showed light α-synuclein staining in round cells. 3-Nitrotyrosine staining was seen in 87% of Parkinson's disease cases but was not specific for Parkinson's disease. This study suggests a pattern of α-synuclein staining in Parkinson's disease that was distinct from healthy subjects and those with inflammatory bowel disease. The absence of this pattern in subjects with inflammatory bowel disease suggests it is not a sequel of inflammation or oxidative stress. 3-Nitrotyrosine immunostaining was common in all groups studied, suggesting oxidative stress in the colonic submucosa.

Infections and Changes in Commensal Bacteria and the Pathogenesis of Parkinson's Disease.

The cause of Parkinson's disease (PD) is unknown, but environmental factors are purported to influence risk. Interest in PD as a sequel of infection dates back to reports of parkinsonism arising from encephalitis lethargica. The objective of this paper is to review the literature as it relates to infections and changes in microbiome and the genesis of PD. There is evidence to support prior infection with Helicobacter pylori, hepatitis C virus, Malassezia, and Strep pneumonia in association with PD. A large number of studies support an association between changes in commensal bacteria, especially gut bacteria, and PD. Extant literature supports a role for some infections and changes in commensal bacteria in the genesis of PD. Studies support an inflammatory mechanism for this association, but additional research is required for translation of these findings to therapeutic options.

Gut-Derived Sterile Inflammation and Parkinson's Disease.

The etiology of Parkinson's disease (PD) is unknown, but evidence is increasing that there is a prominent inflammatory component to the illness. Epidemiological, genetic, and preclinical evidence support a role for gut-derived sterile inflammation. Pro-inflammatory bacteria are over-represented in the PD gut microbiota. There is evidence for decreased gut barrier function and leak of bacterial antigen across the gut epithelium with sub-mucosal inflammation and systemic exposure to the bacterial endotoxin lipopolysaccharide. Preclinical evidence supports these clinical findings and suggests that systemic inflammation can affect the CNS through vagal pathways or the systemic circulation. We will review recent preclinical and clinical evidence to support this mechanism and suggest possible treatments directed at the gut-brain axis.

Suicidal ideation in Huntington disease: the role of comorbidity.

Huntington disease (HD) is a neurodegenerative condition characterized by cognitive impairments, motor abnormalities, and psychiatric disturbance. An increased risk for suicide has been documented. The majority of HD research has focused on cognitive and motor features of HD; the implications of psychiatric manifestations have received less consideration. Recent studies have sought to identify the stages of HD in which patients are at increased risk to experience suicidal ideation, though no study has examined possible risk factors for suicidality. The current study examines the presence of psychiatric comorbidity and its involvement in suicidal ideation. Suicidal ideation was examined in 1941 HD patients enrolled in the Huntington Study Group. Of those, 19% (N=369) endorsed current suicidal ideation. Logistic regression analyses indicated that depression/anxiety and aggression/irritability are significant predictors of suicidal ideation. In a subsample with the greatest suicidal ideation, alcohol and drug abuse were also predictive. It is recommended that all individuals with HD (specifically those with features of depression, aggression, substance abuse) have routine suicide assessment; further research is needed to understand the high rate of suicide in HD.

Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology.

BACKGROUND: The etiology of sporadic Parkinson's disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. METHODS: We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)-an inhibitor of nuclear factor kappa B (NFκB)-to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. RESULTS: High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. CONCLUSIONS: This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice.

The Montreal Cognitive Assessment as a screening tool for cognitive dysfunction in Huntington's disease.

Cognitive dysfunction is one of the hallmarks of Huntington's disease (HD) and may precede the onset of motor symptoms. The Montreal Cognitive Assessment (MoCA), a brief cognitive screening instrument with high specificity and sensitivity for detecting early cognitive impairments, has not been studied in the HD population. In this study, we compare the MoCA with the mini-mental state examination (MMSE) as a screening tool for cognitive dysfunction among 53 patients with HD. The mean MMSE score was 26 +/- 2.4, and mean MoCA score was 21 +/- 4.4. Twenty-one patients (81%) of those who scored >or=26 on the MMSE had the MoCA score <26. Thirty-two patients (78%) of those who scored >or=24 on the MMSE had the MoCA score <24. The MoCA may be a more sensitive screening tool for cognitive impairments in HD relative to the MMSE.

Recent Advances in the Treatment of Huntington's Disease: Targeting DNA and RNA.

Huntington's disease is a dominantly inherited neurodegenerative disease caused by an unstable expanded trinucleotide repeat at the short end of the fourth chromosome. Central nervous system pathology begins in the striatum, eventually affecting the entire brain and occurs consequent to multiple intracellular derangements. The proximate cause is a mutant protein with an elongated polyglutamine tract. Pharmacological approaches targeting multiple domains of intracellular functions have universally been disappointing. However, recent developments in gene therapy, including antisense oligonucleotides, small interfering RNAs, and gene editing are bringing new hope to the Huntington's community. This review discusses the promises and challenges of these new potential treatments.

The current clinical management of Huntington's disease.

Huntington's disease is a neurodegenerative condition, characterized by movement disorders, cognitive decline, and psychiatric disturbance. We review the pharmacological management of the various movement disorders associated with the disease, the cognitive decline and the commonly encountered behavioral disturbances. We discuss the nonclassical features of the disease, important in the management of these patients. Nonpharmacological support including genetic counseling and therapy and the importance of palliative care are also addressed. Finally, experimental approaches that may soon impact upon clinical practice are discussed.

Long-term outcome in Parkinson disease: no advantage to initiating therapy with dopamine agonists.

This Practice Point commentary discusses long-term follow-up of a treatment intervention study on Parkinson disease (PD). Katzenschlager et al. report on 166 of 302 survivors of a randomized open-label study that compared initial therapy with levodopa, with levodopa plus selegiline, or with bromocriptine, in early untreated PD. The primary study publication, from 1993, suggested that bromocriptine-treated participants were less likely than levodopa-treated participants to develop motor complications during the subsequent 4 years, although levodopa was more effective at relieving symptoms of parkinsonism. The current publication presents data after a median follow-up of 14 years and suggests that protection from motor complications does not persist over the long term. Furthermore, participants who were randomly allocated to initial treatment with levodopa showed better relief of disability and better quality of life over the long term. More than 60% of the original PD cohort had died over the 14-year time interval, underscoring the continued poor prognosis of late-stage PD. The Katzenschlager studies and other recent publications underscore the need to develop newer treatment strategies that consider the multisystem nature of the illness and expand treatment horizons beyond the single neurotransmitter dopamine.