28 February 2021
We have read with great interest the recent study on combined citicoline, memantine, and acetylcholinesterase inhibitors (AChEIs) in Alzheimer’s disease (AD) patients, by Castagna et al. , which suggests the beneficial effects of the triple approach (cholinergic therapies + memantine) versus AChEIs + memantine alone in terms of cognitive performances.
The role of citicoline, alone and in combined treatment, has been the focus of many previous studies. The IDEALE and the VITA Studies were sort of trailblazers [2, 3], showing the efficacy of citicoline in mild vascular cognitive impairment and soon after sub-acute ischemic cerebrovascular disease respectively. Then, we have tried to focus on its possible role in combined treatment in AD and even mixed dementia (MD) patients. We have shown the efficacy of oral 1 g citicoline in delaying cognitive loss in combination treatment with rivastigmine (the CITIRIVAD study) , AChEIs (the Citicholinage Study) , and memantine (the CITIMEM study) .
However, with the pure aim to avoid possible confounding of the reader, we would like to clarify that, unlike the statements of Castagna and coworkers in their research study (page 5, line 257), the CITICHOLINAGE study was performed on patients treated with citicoline plus an AChEI and not memantine, and the CITIMEM study was performed on patients treated with citicoline + memantine and not with an AChEI (page 5, line 267).
Furthermore, the first evidence of efficacy of the triple therapy (citicoline 1 g plus memantine and AChEIs at the maximum tolerated dosage) was shown some months ago (see the study presented at the Alzheimer’s Association International Conference 2020 and published in Alzheimer’s and Dementia) . This was the CITIDEMAGE study, a retrospective multicenter case-control study on 169 over 65-year-old patients, 84 treated with the triple therapy (citicoline + memantine + AChEIs) versus 81 patients treated with memantine + AChEIs (approved by the Ethic Committee, Calabria Region, Italy - registered protocol on June 21, 2018, well before the study by Castagna et al.). Patients on triple therapy showed a mild increase in MMSE score at 6 and 12 months, but the difference in MMSE was significant when comparing the two groups, both at T1 (p=0.003) and T2 (p=0.011). Another difference from the study from Castagna and coworkers  is that we also found a significant improvement in the Geriatric Depression Scale (GDS)-short form (p=0.000) and in the Euro Quality of life (EuroQoL) scores (p=0.01) . Therefore, we confirmed the efficacy of the triple therapy in disease management and in slowing down the progression of AD.
However, some points need to be further stressed regarding the possible actions of citicoline, resulting in its successful use in combined treatment in AD. As reported in the above-mentioned study , it can work at a biochemical, cellular, and clinical level, but an essential condition is closely linked to its chronic administration (from three months on) . Citicoline is able to increase phosphatidylcholine and other cell membrane phospholipids, to enhance acetylcholine synthesis, as well as other neurotransmitters such as dopamine and noradrenaline [9, 10], to prevent the accumulation of free fatty acids and the generation of free radicals at the site of ischemia . It also inhibits apoptosis and promotes mitochondria energy metabolism by preventing the loss of cardiolipin [8, 11], thus having neuroprotective effects and promotes synaptogenesis, neurogenesis, and gliagenesis [12, 13]. Furthermore, it decreases neuronal glutamate efflux and stimulates glutathione synthesis, a powerful antioxidant [12, 13]. At a clinical level, citicoline is effective in cognitive impairment of diverse etiology, including AD, MD, vascular cognitive impairment, as well as glaucoma, ambliopia, and head trauma [8, 10], and improves the immediate and delayed recall of words and objects .
Eventually we would like to focus on three further main aspects related to citicoline administration:
- It improves the expression of SIRT-1, a neuroprotective protein able to activate the transcription of ADAM10 (“the good secretase”, the α-secretase enzyme able to process the amyloid precursor protein), thus promoting the non-amyloidogenic route . It also protects cells from post-ischemic damage;
- Citicoline’s metabolism; indeed, CDP-choline is hydrolyzed into cytidine and choline . Choline itself is in turn converted into betaine, which leads to the synthesis of S-adenosyl-L-methionine (SAME) , that is a serotonin precursor. This explains why patients taking citicoline could have an improvement in mood  and consequently, in perceived quality of life. Interestingly, choline in citicoline is less prone to conversion to trimethylamine (TMA), a gaseous metabolite oxidized in the liver to its atherogenic N-oxide TMAO ;
- It increases the activity of blood serum acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and neprilysin (NEP) . NEP is a metalloprotease able to degrade amyloid-β and it is regulated by the protein nicastrin, which is part of γ-secretase enzyme .
In conclusion, citicoline is a pleiotropic drug able to delay cognitive loss in AD patients in combined treatment, thanks to a number of remarkable mechanisms. This is the true reason why its successful use depends on chronic administration.
Pietro Gareri1, Antonino Maria Cotroneo2
1Center for Cognitive Disorders and Dementia – Catanzaro Lido, ASP Catanzaro; Catanzaro, Italy. E-mail: firstname.lastname@example.org; ORCID ID 0000-0003-4277-3426
2Department of Elderly Health Care – Birago di Vische Hospital and Botticelli Territorial Geriatrics - ASL TO 2, Turin, Italy. E-mail: email@example.com; ORCID ID 0000-0002-0393-0540
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