Brent P. Forester - US grants

ABSTRACT Alzheimer's dementia (AD), the most prevalent neurodegenerative disease of aging, affects cognition, emotion, and behavior. Agitation is a common behavioral syndrome that frequently emerges during middle to late stage AD and is characterized by psychomotor hyperactivity, aggression, irritability, yelling, resistance to care, and insomnia. The untoward consequences of agitation and related behavioral disturbances are considerable and include impaired quality of life, accelerated cognitive decline, heightened risk of institutionalization, and increased morbidity and mortality. Agitation also increases caregiver burden, including stress and deleterious health consequences. However, despite the damaging impact of agitation on the patient and caregiver, current treatments have only modest efficacy. Behavior management strategies are widely employed, but effective only in mild cases. Antipsychotics, the most commonly used class of medication for agitation and psychosis in dementia, have demonstrated mixed results in controlled studies and are associated with elevated morbidity and mortality. Thus, there is a clear need for improved interventions, particularly for severe agitation in AD. Electroconvulsive Therapy (ECT) is a safe and effective intervention for severe mood disorders in later life, including depression complicated by psychosis, mania or catatonia. Concerns regarding adverse cognitive effects of ECT, however, have limited ECT's clinical use in treating dementia with agitation. Both retrospective and prospective studies conducted by our group support the safety and efficacy of ECT in patients with AD and severe agitation. ECT, therefore, may represent an effective treatment of severe agitation in AD. We propose a five-site, randomized, single-blind, controlled clinical trial to determine the safety and efficacy of ECT plus usual care compared with Simulated ECT (S-ECT) plus usual care in 200 hospitalized individuals with moderate to severe stage AD , probable Alzheimer's type (based on NIA-AA criteria), complicated by severe agitation. Subjects will be randomized to either (1) ECT for three weeks (up to 9 ECT treatments) plus usual care (UC), defined as standard behavioral therapy and pharmacotherapy or (2) Simulated ECT (S-ECT) plus UC. Primary efficacy will be measured with the Cohen-Mansfield Agitation Inventory (CMAI). Safety parameters include daily assessment of delirium (Confusion Assessment Method, CAM), cognition (Severe Impairment Battery, SIB-8) and serious adverse events. A 12-week follow-up includes monthly assessments to explore stability of agitation reduction.

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disease of aging, affecting ~5.4 million individuals in the United States with a predicted increase to 13.8 million by 2050. This would be a substantial burden on healthcare systems. Thus, developing new and effective treatment strategies is imperative. In this vein, changes in metabolism and mitochondrial dysfunction have been identified as hallmarks of the aging process. The brain consumes ~20% of the body's glucose, of which ~80% is metabolized in mitochondria to generate ATP and support brain function. Mitochondrial dysfunction results in decreased ATP production and release of free radicals with elevated oxidative stress during aging. Mitochondrial function is mediated, in part, by nicotinamide adenine dinucleotide (NAD, including oxidizing and reducing forms, i.e. NAD+ and NADH). Unfortunately, decreases in NAD+ levels, and consequently the redox ratio (NAD+/NADH), are associated with normal aging, especially after age 45, and also with numerous diseases such as AD. Accumulating evidence suggests that nicotinamide riboside (NR), an orally bioavailable precursor of NAD+, can enhance mitochondrial function and help slow or reverse these age-related abnormalities. Currently, 30+ clinical trials, including two AD studies, are registered on clinicaltrials.gov using NR and related compounds. However, no studies to date have investigated in vivo metabolic and bioenergetic changes associated with NR supplementation because of the challenges in measuring NAD+/NADH, namely low concentration (<1mM) and overlapping resonances with other metabolites. Such measurement requires dedicated, state-of-the-art imaging approaches. To that end, we have developed novel neuroimaging approaches to measure in vivo NAD+ and NADH, as well as other markers of mitochondrial function, including creatine kinase (CK)/ATPase activity and the antioxidant glutathione (GSH)? a molecule essential for cellular repair that has functional ties to NAD. These technical achievements undergird our current proposal, which aims to investigate the neurobiological mechanisms and clinical effects of NR in patients with mild cognitive impairment (MCI)/mild AD using in vivo neuroimaging techniques. We propose a 12- week, open-label, proof of concept study to measure the effects of oral NR (1g/day) on brain energy metabolism, oxidative stress, and cognitive functioning in MCI/mild AD patients. This study may provide crucial information about NAD-related molecular mechanisms in MCI/AD, and facilitate the development and refinement of this promising treatment approach. In summary, our innovative theoretical framework, driven by our pilot data and published literature, includes three conceptual prongs: first, MCI/mild AD is associated with excessive redox dysregulation, oxidative stress and deficient mitochondrial function; second, these abnormalities could be remediated by NR; and third, the downstream effects of NR would accelerate CK/ATPase activities, thereby increasing GSH levels and, in turn, improving cognitive function. Thus, identifying the precise molecular mechanisms involved in MCI/AD-related bioenergetic dysfunction will provide important therapeutic targets.