Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study.

INTRODUCTION: Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD. METHODS: We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex(®) with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aß1-40 and Aß1-42 in plasma and levels of Aß1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. RESULTS: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex(®) was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). CONCLUSIONS: Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex(®) in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00099710.

Concurrent discrimination learning in Parkinson's disease.

Studies of neuropsychological patients and experimental animals have demonstrated that the striatum plays a role in implicit habit learning. Here, we examined the performance of patients with Parkinson's disease (PD) on a concurrent discrimination task that can be learned implicitly by neurologically intact individuals. Participants viewed a pair of shapes on each trial and, under a timed deadline, guessed which one concealed a smiling face. About half the control participants exhibited minimal awareness of the cue-reward relationships as assessed by a post-test evaluation. Nevertheless, these participants were able to perform the discrimination task; there was no correlation between awareness and performance on the task. In contrast, minimally aware patients with PD showed no learning, whereas those who were more aware of the relationships performed as well as control participants on the task. There was a significant correlation between awareness and performance in patients with PD. These data support the idea that the basal ganglia play a role in implicit habit learning and underscore the importance of using tests of awareness to assess the content and process of learning in humans.

Zonisamide for essential tremor: an evaluator-blinded study.

In this evaluator-blinded open-treatment trial, subjects with moderate/severe upper limb essential tremor were titrated to 300 mg/day zonisamide, or adjusted to a lesser dose if symptoms warranted, as monotherapy or as adjunct to stable antitremor medication, followed by a 12-week extension phase. The primary efficacy outcome variables were blinded rater videotaped/drawing tremor score changes at the Treatment and Extension visits compared to Baseline, based on Fahn-Tolosa-Marin and Postural Tremor Scales. Subjects also rated Functional Disabilities. Primary outcomes showed reduced tremor scores at the Treatment (P < 0.00001, n = 25) and Extension (n = 16) visits, at mean doses of 252 and 225 mg/day, respectively. Subject ratings indicated 200 mg/day was superior to 100 mg/day, whereas 300 mg/day produced no additional benefit, but instead was associated with more adverse symptoms, most commonly somnolence, poor energy, imbalance, and altered taste. Future double-blind placebo-controlled trials are warranted.

Creutzfeldt-Jakob disease presenting with alien limb sign.

Creutzfeldt-Jakob disease is a fatal spongiform encephalopathy, which typically presents with a rapidly progressing dementia and additional neurological findings that can be quite variable and diverse. Here we report the unusual case of a patient who presented with left alien limb sign without overt cognitive impairment and was ultimately diagnosed with pathologically confirmed Creutzfeldt-Jakob disease.

Backward inhibition in Parkinson's disease.

Parkinson's disease has been associated with executive dysfunction, especially task-switching deficits. One factor contributing to task-switching costs is backward inhibition, as measured by less efficient performance when switching back to a task from which one has recently switched away. This alternating-switch cost is considered to be due to persisting inhibition of elements of the previous task set after a switch. In this study, patients with mild to moderate Parkinson's disease and controls performed three tasks (A-C) in an intermixed fashion. Patients with mild to moderate Parkinson's disease and controls showed equivalent response times. However, the patients made significantly more errors during an alternating switch (i.e., ABA) than did control participants. In contrast, there was no group difference in accuracy in the comparable condition of two consecutive switches between different tasks (i.e., CBA). In addition, accuracy for the two groups was similar for trials in which the task was repeated. These data suggest that Parkinson's disease is associated with either increased backward inhibition, or a reduced ability to overcome this inhibition when reactivating a recently abandoned task set.

An implicit learning task activates medial temporal lobe in patients with Parkinson's disease.

Recent studies provide evidence for an interaction between a declarative memory system, dependent on the medial temporal lobe (MTL), and a habit memory system, dependent on the basal ganglia. Using functional MRI, the authors studied this interaction when 1 system was compromised by neurological disease. Neural activity when performing a habit-learning task was compared in normal controls and subjects with Parkinson's disease (PD). Patients with PD showed less activation in the caudate nucleus and greater activation in a region of prefrontal cortex that has been associated with explicit memory retrieval. Patients with PD also showed activation of the MTL during the weather-prediction task. These findings are consistent with an interaction between memory systems of the MTL and the striatum.

Diagnosis and treatment of Wilson's disease.

Wilson's disease (WD) is an autosomal recessive disease that causes increased copper deposition in the liver and basal ganglia with resultant hepatic and neurologic sequelae. In the past few years, dramatic new discoveries have changed our understanding of the pathophysiology of WD. Although there are potentially life-saving therapies for WD, there is much controversy surrounding the optimal treatments of patients in the various stages of the disease. Specifically, the relative roles of penicillamine, trientene, and tetrathiomolybdate in the initial treatment of the symptomatic patient with WD remain to be defined. Zinc monotherapy for maintenance treatment and in the treatment of asymptomatic patients with WD is still controversial. It is also unclear whether neurologic status alone is an indication for liver transplantation in WD. This paper reviews the pathogenesis, genetics, clinical presentation, and diagnosis, with a special emphasis on the treatment controversies that arise in the care of the WD patient.