Thomas J. Montine

Extended results of the Alzheimer’s disease anti-inflammatory prevention trial

Epidemiologic evidence suggests that nonsteroidal anti‐inflammatory drugs (NSAIDs) delay onset of Alzheimers dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimers Disease Anti‐inflammatory Prevention Trial (ADAPT) randomized 2528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID‐assigned groups.

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

IntroductionCurcumin 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 Alzheimers 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.MethodsWe 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 Alzheimers Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimers Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, 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.ResultsMean 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).ConclusionsCurcumin 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 registrationClinicalTrials.gov Identifier: NCT00099710.

Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease

The hypothesis that inflammation and beta amyloid deposition are causally linked in Alzheimers disease (AD) was tested in a transgenic mouse model. Untreated beta amyloid plaque-bearing Tg2576 mice did not differ from wild type animals in brain levels of most inflammatory mediators. Indomethacin treatment suppressed brain levels of prostaglandins by 90%, but reduced hippocampal beta amyloid by only 20%, with no effect on cortical beta amyloid. The discordant effects on beta amyloid and cyclooxygenase (COX) suggest that these effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are not causally linked. Further evidence against a causal relationship is seen in an unexpected trend to lower levels of beta amyloid after an inflammatory stimulus [lipopolysaccharide (LPS)].

A patient with Huntington’s disease and long-surviving fetal neural transplants that developed mass lesions

Transplantation of human fetal neural tissue into adult neostriatum is an experimental therapy for Huntington’s disease (HD). Here we describe a patient with HD who received ten intrastriatal human fetal neural transplants and, at one site, an autologous sural nerve co-graft. Although initially clinically stable, she developed worsening asymmetric upper motor neuron symptoms in addition to progression of HD, and ultimately died 121xa0months post transplantation. Eight neural transplants, up to 2.9xa0cm, and three ependymal cysts, up to 2.0xa0cm, were identified. The autologous sural nerve co-graft was found adjacent to the largest mass lesion, which, along with the ependymal cyst, exhibited pronounced mass effect on the internal capsules bilaterally. Grafts were composed of neurons and glia embedded in disorganized neuropil; robust Y chromosome labeling was present in a subset of grafts and cysts. The graft–host border was discrete, and there was no evidence of graft rejection or HD pathologic changes within donor neurons. This report, for the first time, highlights the potential for graft overgrowth in a patient receiving fetal neural transplantation.

Phytochemicals in Alzheimer Disease: The Development of Clinical Trials

Polyphenolics and other phytochemicals may have a role in the prevention or treatment of Alzheimer disease. Targets of therapy in Alzheimer disease include neurotransmitter deficits, beta amyloid neurotoxicity, oxidative damage, and inflammation, to name a few. Challenges to the development of phytochemical and other neuroprotectant therapy in Alzheimer disease include the inability to measure pathology in living patients and the challenge of detecting modification of an indolent disease course. These challenges are partially surmounted by the use of animal models and of biomarkers of disease. This review describes currently available animal models and biomarkers and surveys clinical trials of phytochemical therapies that are recently completed or currently under way. Both animal studies and clinical trials of Ginkgo biloba are described, as well as a trial of Uncaria tomentosa that has not been previously reported.

Flow Cytometric Evaluation of Crude Synaptosome Preparation as a Way to Study Synaptic Alteration in Neurodegenerative Diseases

Neurodegenerative diseases, the most common among them Alzheimers disease (AD) and Lewy body disease (LBD), are a group of progressive incurable illnesses. In both AD and LBD, abundant evidence points to the synapse as the critical and early focus of pathological changes. Here we present a method for the isolation and flow cytometric analysis of synaptosomes prepared from postmortem human brain tissue, which we also applied to animal models, including mice and nonhuman primates. The use of flow cytometry for analysis allows for relatively fast and efficient examination of thousands of synaptosome particles in a matter of minutes, and also makes it possible to use crude, rather than purified, synaptosomal preparation, thus conserving tissue resources. We have applied this method to study synaptic alteration in several brain regions in human research participants and animal models.