Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile. Areas covered: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I-III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD. Expert opinion: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.
Alzheimer's disease is the most common major neurocognitive disorder with substantial social and economic impacts. This article is an update on current pharmacotherapy, advancements in biomarker use, and drugs in the pipeline for this disease. To date, no new drug has qualified to be added to the current therapeutic arsenal comprising cholinesterase inhibitors and the NMDA receptor antagonist memantine. Drugs in the pipeline include symptomatic therapies that are neurotransmitter-based, but mostly disease-modifying therapies. The latter have yielded disappointing results by focusing mainly on the two pathophysiological hallmarks of Alzheimer's disease: Aβ amyloid deposits and tau protein aggregates forming neurofibrillary tangles. These unsuccessful trials may have resulted from studying these drugs 'too late' relative to Alzheimer's disease onset, in addition to focusing only on the amyloid cascade. In fact, Alzheimer's disease is a complex multifactorial disease. Combining different biomarkers might enhance our ability to identify those patients most at risk of developing the disease, and better predict their conversion rates. Furthermore, adopting an integrative treatment approach by targeting additional pathophysiological pathways in Alzheimer's disease such as inflammation and oxidative stress could be the key to better outcomes in Alzheimer's disease pharmacotherapy research.
The physiological effects of vitamin D on calcium/phosphorus metabolism have been well studied since its discovery in the early 20th century. With recent advances in cellular and molecular biology, its role in maintaining normal brain functions and the protection of neurons via maintenance of cellular homeostasis, immune regulation, modulation of synaptic structure and function are more clearly known. Recently, its deficiency is increasingly implicated in major neurocognitive disorders including Alzheimer’s disease, Parkinson’s disease, and vascular dementia. Older adults are particularly vulnerable not only because vitamin D deficiency becomes more prevalent with aging, but they also are often complicated with other comorbid illnesses. This article reviews the role of vitamin D in maintaining normal brain functions, and implications for vitamin D deficiency in cognitive disorders.
Keratoconus is a progressive disorder affecting the cornea, which causes the cornea to become weakened and conical in appearance. The resultant decrease in structural integrity of the cornea predisposes affected individuals to acute corneal hydrops, a break in Descemet’s membrane, the deepest layer of the cornea, resulting in pain and acute vision loss. We present here a case of this little-known cause of acute vision loss, and an example of Munson’s sign, which is a v-shaped protrusion of the lower eyelid on downward gaze that is characteristic of advanced keratoconus. We hope to highlight Munson’s sign as a simple identifier of keratoconus in an otherwise undiagnosed individual suspected of having acute corneal hydrops.
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