Quantitative Assessment of Occipital Metabolic and Energetic Changes in Parkinson's Patients, Using In Vivo 31P MRS-Based Metabolic Imaging at 7T.

Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson's disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.

Pharmacokinetics, Safety, and Tolerability of Orally Administered Ursodeoxycholic Acid in Patients With Parkinson's Disease-A Pilot Study.

Mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease. Preliminary data have shown lower brain adenosine triphosphate (ATP) levels in Parkinson's disease versus age-matched healthy controls. Ursodeoxycholic acid (UDCA) may improve impaired mitochondrial function. Our objective was to evaluate UDCA tolerability, pharmacokinetics, and its effect on brain bioenergetics in individuals with Parkinson's disease. An open-label, prospective, multiple-ascending-dose study of oral UDCA in 5 individuals with Parkinson's disease was completed. A blood safety panel, plasma concentrations of UDCA and UDCA conjugates, and brain ATP levels were measured before and after therapy (week 1: 15 mg/kg/day; week 2: 30 mg/kg/day; and weeks 3-6: 50 mg/kg/day). UDCA and conjugates were measured using liquid chromatography-mass spectrometry. ATP levels and ATPase activity were measured using 7-Tesla 31 P magnetic resonance spectroscopy. Secondary measures included the Unified Parkinson's Disease Rating Scale and Montreal Cognitive Assessment. UDCA was generally well tolerated. The most frequent adverse event was gastrointestinal discomfort, rated by subjects as mild to moderate. Noncompartmental pharmacokinetic analysis resulted in (mean ± standard deviation) a maximum concentration of 8749 ± 2840 ng/mL and half-life of 2.1 ± 0.71 hr. Magnetic resonance spectroscopy data were obtained in 3 individuals with Parkinson's disease and showed modest increases in ATP and decreases in ATPase activity. Changes in Unified Parkinson's Disease Rating Scale (parts I-IV) and Montreal Cognitive Assessment scores (mean ± standard deviation) were -4.6 ± 6.4 and 2 ± 1.7, respectively. This is the first report of UDCA use in individuals with Parkinson's disease. Its pharmacokinetics are variable, and at high doses it appears reasonably well tolerated. Our findings warrant additional studies of its effect on brain bioenergetics.

Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress.

Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using 1 H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

Magnetic resonance imaging as a potential biomarker for Parkinson's disease.

Although a magnetic resonance imaging (MRI) biomarker for Parkinson's disease (PD) remains an unfulfilled objective, there have been numerous developments in MRI methodology and some of these have shown promise for PD. With funding from the National Institutes of Health and the Michael J Fox Foundation there will be further validation of structural, diffusion-based, and iron-focused MRI methods as possible biomarkers for PD. In this review, these methods and other strategies such as neurochemical and metabolic MRI have been covered. One of the challenges in establishing a biomarker is in the selection of individuals as PD is a heterogeneous disease with varying clinical features, different etiologies, and a range of pathologic changes. Additionally, longitudinal studies are needed of individuals with clinically diagnosed PD and cohorts of individuals who are at great risk for developing PD to validate methods. Ultimately an MRI biomarker will be useful in the diagnosis of PD, predicting the course of PD, providing a means to track its course, and provide an approach to select and monitor treatments.

N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases.

OBJECTIVE: This study aimed to determine if the antioxidant N-acetylcysteine (NAC) is able to alter peripheral and central redox capabilities in patients with Parkinson disease (PD) or Gaucher disease (GD). METHODS: The study included nondemented adult subjects: 3 with PD, 3 with GD, and 3 healthy controls. Baseline brain glutathione (GSH) concentrations were measured using 7-T magnetic resonance spectroscopy (MRS). Baseline blood reduced-to-oxidized GSH ratios were determined for each subject. Brain GSH concentrations and blood redox ratios were then determined during and at specified time points after a single, 150-mg/kg NAC infusion. RESULTS: N-acetylcysteine increased blood GSH redox ratios in those with PD and GD and healthy controls, which was followed by an increase in brain GSH concentrations in all subjects. CONCLUSIONS: This is the first demonstration that with MRS, it is possible to directly measure and monitor increases in brain GSH levels in the human brain in response to a single, intravenous administration of NAC. This work shows the potential utility of MRS monitoring, which could assist in determining dosing regimens for clinical trials of this potentially useful antioxidant therapy for PD disease, GD, and other neurodegenerative disorders.

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.

ELISA for human serum leucine-rich alpha-2-glycoprotein-1 employing cytochrome c as the capturing ligand.

Leucine-rich alpha-2-glycoprotein-1 (LRG) is a serum glycoprotein of unknown function that has shown promise based on qualitative assessments as a biomarker for certain diseases including microbial infections and cancer. However, the lack of a quantitative assay for LRG has limited its application. Here an indirect enzyme-linked immunosorbent assay (ELISA) for quantifying LRG in human serum is described in which cytochrome c is employed as the capturing ligand and a monoclonal antibody specific for LRG is used to detect the captured glycoprotein. Application of this assay in quantifying LRG in various patients' sera is demonstrated. The concentration of LRG in sera of control subjects as determined by this assay is approximately 50 microg/ml. Consistent with expectations from published reports, LRG was found to be significantly elevated in the sera of some patients with a bacterial infection (toxic shock syndrome, TSS). LRG was only slightly elevated in patients infected with the human immunodeficiency virus as compared to uninfected control subjects, while normal levels of LRG were observed in patients with non-infectious diseases (inflammatory arthritis and neurological disorders, primarily Parkinson's disease). Although LRG and C-reactive protein (CRP) are both produced by the liver and are classified as acute-phase proteins, there was no significant correlation between the levels of LRG and CRP in the sera of the patients. Thus, LRG and CRP measurements are non-redundant and indicate different physiological contexts. The ELISA described in this report should be useful to further assess serum LRG as a biomarker for clinical diagnostics.

Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005).

OBJECTIVE: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A(2A) receptor antagonist, istradefylline, shows promise for the treatment of PD. METHODS: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. RESULTS: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off" time for istradefylline was a mean (+/- standard deviation) of -10.8 +/- 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 +/- 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of -1.8 +/- 2.8 hours for istradefylline and -0.6 +/- 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. INTERPRETATION: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia.

Assessment of brain iron and neuronal integrity in patients with Parkinson's disease using novel MRI contrasts.

Postmortem demonstration of increased iron in the substantia nigra (SN) is a well-appreciated finding in Parkinson's disease (PD). Iron facilitates generation of free radicals, which are thought to play a role in dopamine neuronal loss. To date, however, magnetic resonance imaging (MRI) has failed to show significant in vivo differences in SN iron levels in subjects with PD versus control subjects. This finding may be due to the limitations in tissue contrasts achievable with conventional T(1)- and T(2)-weighted MRI sequences that have been used. With the recent development of novel rotating frame transverse (T(2rho)) and longitudinal (T(1rho)) relaxation MRI methods that appear to be sensitive to iron and neuronal loss, respectively, we embarked on a study of 8 individuals with PD (Hoehn & Yahr, Stage II) and 8 age-matched control subjects. Using these techniques with a 4T MRI magnet, we assessed iron deposits and neuronal integrity in the SN. First, T(2rho) MRI, which is reflective of iron-related dynamic dephasing mechanisms (e.g., chemical exchange and diffusion in the locally different magnetic susceptibilities), demonstrated a statistically significant difference between the PD and control group, while routine T(2) MRI did not. Second, T(1rho) measurements, which appear to reflect upon neuronal count, indicated neuronal loss in the SN in PD. We show here that sub-millimeter resolution T(1rho) and T(2rho) MRI relaxation methods can provide a noninvasive measure of iron content as well as evidence of neuronal loss in the midbrain of patients with PD.

Proton MRS of the unilateral substantia nigra in the human brain at 4 tesla: detection of high GABA concentrations.

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra (SN), the cause of which is unknown. Characterization of early SN pathology could prove beneficial in the treatment and diagnosis of PD. The present study shows that with the use of short-echo (5 ms) Stimulated-Echo Acquisition Mode (STEAM) spectroscopy and LCModel, a neurochemical profile consisting of 10 metabolites, including gamma-aminobutyric acid (GABA), glutamate (Glu), and glutathione (GSH), can be measured from the unilateral SN at 4 tesla. The neurochemical profile of the SN is unique and characterized by a fourfold higher GABA/Glu ratio compared to the cortex, in excellent agreement with established neurochemistry. The presence of elevated GABA levels in SN was validated with the use of editing, suggesting that partial volume effects were greatly reduced. These findings establish the feasibility of obtaining a neurochemical profile of the unilateral human SN by single-voxel spectroscopy in small volumes.

Weight and body mass index in Parkinson's disease patients after deep brain stimulation surgery.

A retrospective chart review characterizing changes in 17 male and 10 female Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery indicated that 6 mo before surgery, patients lost a mean of 5.1 lbs, whereas in the 6 mo after surgery, subjects gained a mean of 10.1 lbs; 22% gained more than 14 lbs. In 10 patients followed an additional 6 mo, weight gain continued. This weight gain may be associated with decreased energy expenditure due to subsidence of chronic tremor. The magnitude of gain underscores the need for proactive management of body weight in PD patients undergoing DBS.

The evaluation and management of patients with neuroleptic malignant syndrome.

NMS is a rare but fatal syndrome that needs to be considered in the perioperative period. Although many aspects remain unexplored and controversial, with greater awareness of the condition, new concepts are coming into light. Definitive treatment guidelines remain an important issue to be addressed. Efforts have been initiated in that direction and all cases can be reported on a toll-free hotline ( 1-888-667-8367) or online (www.nmsis.org).

Bilateral subthalamic nucleus stimulation for the treatment of Parkinson's disease: results of six patients.

In this study, researchers evaluated the effect of bilateral subthalamic nucleus stimulation on various measures of Parkinson's disease. Assessments were completed before and after surgery in a double-blind fashion under the following six conditions: (a) on medication, (b) off medication, (c) on medication/on stimulation, (d) on medication/off stimulation, (e) off medication/on stimulation, and (f) off medication/off stimulation. On average, improvement was noted in all areas including the Unified Parkinson's Disease Rating Scale, Schwab and England Activities of Daily Living Scale, Modified Hoehn and Yahr Staging, and timed tests: In addition, dyskinesia duration and dyskinesia disability were reduced.

Recent developments in the pharmacological treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.

Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma.

Paraneoplastic chorea is described in 16 patients: 11 with limited small-cell carcinoma, 2 with lung cancer revealed by imaging, 1 with renal cell carcinoma, and 1 with lymphoma. All had CRMP-5-IgG; 6 also had ANNA-1 (anti-Hu), including 1 without evident cancer. Chorea was the initial and most prominent symptom in 11 patients, asymmetric or unilateral in 5 patients, and part of a multifocal syndrome in 14 patients. Basal ganglia abnormalities were revealed by magnetic resonance imaging and at autopsy (as perivascular inflammation and microglial activation). Four patients improved with chemotherapy, and 2 improved with intravenous methylprednisolone.