Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.

Background and Purpose: The feasibility, safety, and efficacy of a high-intensity multimodal exercise program (aerobic, strengthening, and balance training) have not been well vetted in persons with Parkinson disease (PD). Thus, the primary aim was to determine whether a high-intensity multimodal exercise boot camp (HIBC) was both feasible and safe in persons with PD. The secondary aim was to determine whether the program would produce greater benefit than a usual care, low-intensity exercise program (UC). An exploratory aim was to determine whether these programs affected putative disease-modifying mechanisms. Methods: Twenty-seven participants (19 men and 8 women) were randomized into 8 weeks of either the HIBC or UC supervised by physical therapists. For feasibility, participation, and meeting, Centers for Disease Control and Prevention (CDC) exercise guidelines were assessed. For safety, adverse events were monitored. For efficacy, the following outcome domains were assessed before and after participation: balance, motor activity, endurance and fatigue, strength, mental health, and quality of life. For disease-modifying mechanisms, circulating brain-derived neurotrophic factor (BDNF) and its genotype, superoxide dismutase, and cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-10) were monitored. Results: The HIBC was better at attaining CDC guidelines (P = 0.013) and spent more minutes in higher-intensity exercise per week (P < 0.001). There were no differences in adverse events (P = 0.419). The HIBC experienced significant improvements in 7/31 outcomes versus 3/31 in the UC arm. BDNF improved significantly for both groups from pre- to posttests (Ps ≤ 0.041) and an improved anti-inflammatory was observed for both groups. Discussion and Conclusions: A high-intensity multimodal exercise boot camp was feasible and safe in persons with PD. Compared with usual care, there were no differences in adverse events. Moreover, the high-intensity multimodal exercise program produced more improvement across more domains than usual care. Our results also suggest a possible link between improvement in outcomes and an improved anti-inflammatory milieu. Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A244).

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Alterations in N-methyl-d-aspartate (NMDA) receptor function have been linked to numerous behavioral deficits and neurochemical alterations. Recent investigations have begun to explore the role of NMDA receptor function on principally inhibitory neurons and their role in network function. One of the prevailing models of schizophrenia proposes a reduction in NMDA receptor function on inhibitory interneurons and the resulting disinhibition may give rise to aspects of the disorder. Studies using NMDA receptor antagonists such as PCP and ketamine have induced schizophrenia-like behavioral deficits in animal model systems as well as changes in inhibitory circuits. The current study investigated whether the administration of a subanesthetic dose of ketamine (8 mg/kg subcutaneously), that disrupts sensorimotor gating, also produces impairments in a Pavlovian emotional learning and memory task. We utilized both standard delay and trace cued and contextual fear conditioning (CCF) paradigms to examine if ketamine produces differential effects when the task is more difficult and relies on connectivity between specific brain regions. Rats administered ketamine displayed no significant deficits in cued or contextual fear following the delay conditioning protocol. However, ketamine did produce a significant impairment in the more difficult trace conditioning protocol. Analyses of tissue from the hippocampus and amygdala indicated that the administration of ketamine produced an alteration in GABA receptor protein levels differentially depending on the task. These data indicate that 8 mg/kg of ketamine impairs learning in the more difficult emotional classical conditioning task and may be related to altered signaling in GABAergic systems.