Choline-containing phospholipids and treatment of adult-onset dementia disorders

The observation of a loss of cholinergic function in the neocortex and hippocampus in Alzheimer's disease (AD) has led to the hypothesis that a replacement of the cholinergic function may be of benefit in the treatment of AD patients. The different approaches proposed or tested included intervention with acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or nicotinic receptor agonists, and acetylcholinesterase (AChE) or cholinesterase (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE inhibitors and precursor loading using choline-containing phospholipids were the treatments more fully investigated in clinical trials. Among the numerous compounds proposed for the treatment of AD, AChE and ChE inhibitors, together with the NMDA receptor antagonist memantine, are those with regulatory indication for treatment of mild to moderate or moderate to severe stages of AD. The first cholinergic attempts in the treatment of AD were based on the idea that cholinergic precursors may enhance deficient cholinergic neurotransmission, but clinical trials did not confirm the clinical utility of this class of compounds. The cholinergic precursors most used in the early studies, such as choline and phosphatidylcholine (lecithin), were probably not effective at enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic pathways, such as CDP–choline (citicoline), choline alphoscerate, and phosphatidylserine, which are different from phosphatidylcholine, enhanced ACh bioavailability or release and induced an improved cognitive function in patients with AD. In terms of activity, the more pronounced effects were obtained with choline alphoscerate. The present chapter discusses the main evidence for the role of choline-containing phospholipids in the treatment of adult-onset dementia disorders. Based on the available results, choline-containing phospholipids, if properly used, could still have a place in the pharmacotherapy of dementia disorders. Among molecules more extensively investigated in clinical studies, choline alphoscerate provided interesting effects and partly countered the atrophy occurring in the brain areas of AD patients involved in learning and memory. These observations suggest that this molecule would merit further evaluation in larger clinical trials.