Feasibility study for detection of retinal amyloid in clinical trials: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial.

INTRODUCTION: The retina and brain exhibit similar pathologies in patients diagnosed with neurodegenerative diseases. The ability to access the retina through imaging techniques opens the possibility for non-invasive evaluation of Alzheimer's disease (AD) pathology. While retinal amyloid deposits are detected in individuals clinically diagnosed with AD, studies including preclinical individuals are lacking, limiting assessment of the feasibility of retinal imaging as a biomarker for early-stage AD risk detection. METHODS: In this small cross-sectional study we compare retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin-positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline. RESULTS: The four participants from the A4 trial showed a greater number of retinal spots compared to the four participants from the LEARN study. We observed a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr). DISCUSSION: The results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample size will be necessary to fully ascertain the relationship between amyloid PET and retinal amyloid both cross-sectionally and longitudinally.

Clinical trials: new opportunities.

Human cognitive aging has been too long neglected and underappreciated for its critical importance to quality of life in old age. The articles in this session present novel approaches to improving cognitive function in normal aging persons with drugs and interventions that are based on findings in epidemiology, studies in aged animals, and in vitro research. In addition, since aging is the primary risk factor for Alzheimer's disease, these studies also have implications as interventions for prevention and treatment. As a field of research, new knowledge regarding the causes and mechanisms of cognitive aging are ripe for translation into human studies, with the application of this knowledge leading the development of interventions and therapeutics for the prevention of cognitive decline in old age and Alzheimer's disease.

Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial.

CONTEXT: Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology. OBJECTIVE: To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer's Disease Cooperative Study. INTERVENTION: Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months. MAIN OUTCOME MEASURES: Change in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102). RESULTS: A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51-9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72-9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44-3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44-3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm(3) (95% CI, 21.4-28.0 cm(3)) during 18 months and a 1.32% (95% CI, 1.14%-1.50%) volume decline per year compared with 24.0 cm(3) (95% CI, 20-28 cm(3)) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%-1.51%) volume decline per year (P = .79). CONCLUSION: Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00440050.

High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial.

CONTEXT: Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B(6) and B(12). Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline. OBJECTIVE: To determine the efficacy and safety of B vitamin supplementation in the treatment of AD. DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, double-blind controlled clinical trial of high-dose folate, vitamin B(6), and vitamin B(12) supplementation in 409 (of 601 screened) individuals with mild to moderate AD (Mini-Mental State Examination scores between 14 and 26, inclusive) and normal folic acid, vitamin B(12), and homocysteine levels. The study was conducted between February 20, 2003, and December 15, 2006, at clinical research sites of the Alzheimer Disease Cooperative Study located throughout the United States. INTERVENTION: Participants were randomly assigned to 2 groups of unequal size to increase enrollment (60% treated with high-dose supplements [5 mg/d of folate, 25 mg/d of vitamin B(6), 1 mg/d of vitamin B(12)] and 40% treated with identical placebo); duration of treatment was 18 months. MAIN OUTCOME MEASURE: Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). RESULTS: A total of 340 participants (202 in active treatment group and 138 in placebo group) completed the trial while taking study medication. Although the vitamin supplement regimen was effective in reducing homocysteine levels (mean [SD], -2.42 [3.35] in active treatment group vs -0.86 [2.59] in placebo group; P < .001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-cog score during 18 months (0.372 points per month for placebo group vs 0.401 points per month for active treatment group, P = .52; 95% confidence interval of rate difference, -0.06 to 0.12; based on the intention-to-treat generalized estimating equations model), or on any secondary measures. A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements. CONCLUSION: This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00056225.

[123I]5-IA-85380 SPECT imaging of beta2-nicotinic acetylcholine receptor availability in the aging human brain.

Human postmortem studies have reported decreases with age in high-affinity nicotine binding in brain. We have been investigating in vivo the availability of the beta(2)-containing nicotinic acetylcholine receptor (beta(2)-nAChR) in healthy nonsmokers (18-85 years of age) using [(123)I]5-IA-85380 SPECT imaging. Age and regional beta(2)-nAChR availability (V(T)(,)) have been observed to be inversely correlated in all brain regions analyzed, with decline ranging from 21% (cerebellum) to 36% (thalamus), or by up to 5% per decade of life. Preliminary results have confirmed postmortem reports of age-related decline in high-affinity nicotine binding with age and may elucidate the role of beta(2)-nAChRs in the cognitive decline associated with aging.