The Role of Combined Treatment with Citicoline in Alzheimer’s Disease

28 February 2021

Comment on the article “A retrospective study on the benefits of combined citicoline, memantine and acetylcholinesterase inhibitor treatments in older patients affected with Alzheimer’s disease.”

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. [1], 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) [4], AChEIs (the Citicholinage Study) [5], and memantine (the CITIMEM study) [6].

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) [7]. 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 [1] 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) [7]. 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 [1], 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) [8]. 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 [9]. 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 [14].

Eventually we would like to focus on three further main aspects related to citicoline administration:

  1. 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 [15]. It also protects cells from post-ischemic damage;
  2. Citicoline’s metabolism; indeed, CDP-choline is hydrolyzed into cytidine and choline [16]. Choline itself is in turn converted into betaine, which leads to the synthesis of S-adenosyl-L-methionine (SAME) [16], that is a serotonin precursor. This explains why patients taking citicoline could have an improvement in mood [6] 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 [17];
  3. It increases the activity of blood serum acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and neprilysin (NEP) [18]. NEP is a metalloprotease able to degrade amyloid-β and it is regulated by the protein nicastrin, which is part of γ-secretase enzyme [19].

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: pietro.gareri@alice.it; 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: geriatrix1@libero.it; ORCID ID 0000-0002-0393-0540

REFERENCES
[1] Castagna A, Fabbo A, Manzo C, Lacava R, Ruberto C, Ruotolo G (2021) A retrospective study on the benefits of combined citicoline, memantine, and acetylcholinesterase inhibitor treatments in older patients affected with Alzheimer's disease. J Alzheimers Dis 79, 1509-1515.
[2] Cotroneo AM, Castagna A, Putignano S, Lacava R, Fantò F, Monteleone F, Rocca F, Malara A, Gareri P (2013) Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clin Interv Aging 8, 131–137.
[3] Putignano S, Gareri P, Castagna A, Cerqua G, Cervera P, Cotroneo AM, Fiorillo F, Grella R, Lacava R, Maddonni A, Marino S, Pluderi A, Putignano D, Rocca F (2012) Retrospective and observational study to assess the efficacy of citicoline in elderly patients suffering from stupor related to complex geriatric syndrome. Clin Interv Aging 7, 113-118.
[4] Castagna A, Cotroneo AM, Ruotolo G, Gareri P (2016) The CITIRIVAD Study: CITIcoline plus RIVAstigmine in elderly patients affected with Dementia Study. Clin Drug Invest 36, 1059-1065.
[5] Gareri P, Castagna A, Cotroneo AM, Putignano D, Conforti R, Santamaria F, Marino S, Putignano S (2017) The Citicholinage Study: citicoline plus cholinesterase inhibitors in aged patients affected with Alzheimer's disease study. J Alzheimers Dis 56, 557–565.
[6] Gareri P, Cotroneo AM, Orsitto G, Putignano S (2020) The CitiMem Study: a pilot study. Optimizing pharmacological treatment in dementia. Arch Gerontol Geriatr 89, 104073.
[7] Gareri P, Cotroneo AM, Orsitto G, Putignano S (2020) The CITIDEMAGE Study: Stressing the cholinergic hypothesis for the best outcomes in dementia patients. Alzheimers Dement 16 (Suppl 9), e038178.
[8] Gareri P, Castagna A, Cotroneo AM, Putignano S, De Sarro G, Bruni AC (2015) The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages and doubts for an old drug with new perspectives. Clin Interv Aging 10, 1421-1429.
[9] Cook S (2018) The unique benefits of Citicoline: an emerging nootropic and brain health nutrient. Natural Medicine Journal; IMPACT Health Media, Inc.
[10] Secades JJ, Frontera G (1995) CDP-choline: pharmacological and clinical review. Methods Find Exp Clin Pharmacol 17 (Suppl B), 1–54.
[11] Hurtado O, Lizasoain I, Moro MÁ (2011) Neuroprotection and recovery: recent data at the bench on citicoline. Stroke 42 (Suppl 1), S33–S35.
[12] Hurtado O, Moro MA, Cardenas A, Sánchez V, Fernández-Tomé P, Leza JC, Lorenzo P, Secades JJ, Lozano R, Dávalos A, Castillo J, Lizasoain I (2005) Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: Effects on glutamate transport. Neurobiol Dis 18, 336–345.
[13] Gutierrez-Fernandez M, Rodriguez-Frutos B, Fuentes B, Vallejo-Cremades MT, Alvarez-Grech J, Expósito-Alcaide M, Díez-Tejedor E (2012) CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke. Neurochem Int 60, 310–317.
[14] García-Cobos R, Frank-García A, Gutiérrez-Fernández M, EDíez-Tejedor E (2010) Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci 299, 188-192.
[15] Zhang F, Wang S, Gan L, Vosler PS, Gao Y, Zigmond MJ, Chen J (2011) Protective effects and mechanisms of sirtuins in the nervous system. Prog Neurobiol 95, 373–395.
[16] Adibhatla RM, Hatcher JF, Dempsey RJ (2001) Effects of citicoline on phospholipid and glutathione levels in transient cerebral ischemia. Stroke 32, 2376-2381.
[17] Synoradzki K, Grieb P (2019) Citicoline: a superior form of choline? Nutrients 11, 1569.
[18] Zhuravin IA, Nalivaeva NN, Kozlova DI, Kochkina EG, Fedorova YB, Gavrilova SI (2015) The activity of blood serum cholinesterases and neprilysin as potential biomarkers of mild-cognitive impairment and Alzheimer’s disease. Zh Nevrol Psikhiatr 11, 77-85.
[19] Pardossi-Piquard R, Dunys J, Yu G, George-Hyslop P, Alves da Costa C, Checler F (2006) Neprilysin activity and expression are controlled by nicastrin. J Neurochem 97, 1052–1056.

Comments

Dear Editors,

We thank Dr. Gareri and Dr. Cotroneo for their interest in our retrospective study, recently published in JAD [1].

It is a fact that several retrospective studies focused the role of citicoline, alone and in combined treatment, in older patients affected with cognitive impairment. As Gareri and Cotroneo well know, two of the authors (AC and RL) of our study participated in the vast majority of the studies they mentioned in the initial part of their letter [2-5]. We are therefore wondering what is the usefulness for the reader and the logic of such clarifications.

Additionally, what is the usefulness of listing other, and in some cases only experimental, mechanisms of action of citicoline [6], if the final result does not change in a clinical practice? Indeed, there is no doubt that successful use of citicoline depends on its chronic administration, as our study also confirmed. Moreover, the information the authors cited in their letter is well known to our research group, and already discussed in our article. Are repetitions useful for the reader?

We acknowledge that the statements related to the Citicholinage and the CitiMem studies were not correctly reported in our article. This was due to a printing error. We are grateful to the authors for pointing this out. Nevertheless, we are convinced that this did not distract the reader from the central theme and results of our article.

Finally, we want to clearly address the part of the letter in which the two authors wrote that “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…This was the CITIDEMAGE study…”. This is not correct. On December 7, 2020, Alzheimer’s and Dementia published in a supplement a poster entitled “The CITIDEMAGE Study: Stressing the cholinergic hypothesis for the best outcomes in dementia patients” [7]. As reported, the enrolled patients were visited between 2016 and 2018. On the other hand, our study enrolled patients since January 1, 2014 (please see Materials and Methods, line 102). On December 1, 2020 our study was published (in early view) as a research article, after a long review process involving three reviewers and a handling associate editor (Prof. Patrizia Mecocci).

We read with great attention and interest the poster presented by Gareri et al., and we are grateful to them for this contribution. Their preliminary report confirms efficacy and safety of a combined therapy with citicoline, memantine, and an AChEI in older patients with AD, and reinforces scientific soundness of our article. Obviously, we wait to read the full-text article, if and when published after the review process.

Alberto Castagna1, Andrea Fabbo2, Ciro Manzo3, Roberto Lacava1, Carmen Ruberto1, Giovanni Ruotolo4

1Azienda Sanitaria Provinciale Catanzaro, Primary Care Departiment, Center for Cognitive Disorders and Dementia, Catanzaro, Italy; E-mail: albertocastagna@tiscali.it
2Health Authority and Services (AUSL) of Modena, Geriatric Service, Cognitive Disorders and Dementia Unit, Modena, Italy
3 Azienda Sanitaria Locale Napoli 3 sud, Internal and Geriatric Medicine department, Center for Cognitive Disorders and Dementia, health district no.51, Pomigliano d’Arco, Naples, Italy
4Azienda Ospedaliera Pugliese-Ciaccio di Catanzaro, Medical Department, Geriatric Unit, Catanzaro, Italy

REFERENCES
[1] Castagna A, Fabbo A, Manzo C, Lacava R, Ruberto C, Ruotolo G (2021) A retrospective study on the benefits of combined citicoline, memantine, and acetylcholinesterase inhibitor treatments in older patients affected with Alzheimer's disease. J Alzheimers Dis 79, 1509-1515.
[2] Cotroneo AM, Castagna A, Putignano S, Lacava R, Fantò F, Monteleone F, Rocca F, Malara A, Gareri P (2013) Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clin Interv Aging 8, 131–137.
[3] Putignano S, Gareri P, Castagna A, Cerqua G, Cervera P, Cotroneo AM, Fiorillo F, Grella R, Lacava R, Maddonni A, Marino S, Pluderi A, Putignano D, Rocca F (2012) Retrospective and observational study to assess the efficacy of citicoline in elderly patients suffering from stupor related to complex geriatric syndrome. Clin Interv Aging 7, 113-118.
[4] Castagna A, Cotroneo AM, Ruotolo G, Gareri P (2016) The CITIRIVAD Study: CITIcoline plus RIVAstigmine in elderly patients affected with Dementia Study. Clin Drug Invest 36, 1059-1065.
[5] Gareri P, Castagna A, Cotroneo AM, Putignano D, Conforti R, Santamaria F, Marino S, Putignano S (2017) The Citicholinage Study: citicoline plus cholinesterase inhibitors in aged patients affected with Alzheimer's disease study. J Alzheimers Dis 56, 557–565.
[6] Hurtado O, Hernandez-Jimenez M, Zarruk JG, Cuartero MI, Ballesteros I, Camarero G, Moraga A, Pradillo JM, Moro MA, Lizasoain I (2013) Citicoline (CDPcholine) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke. J Neurochem 126, 816-819.
[7] Gareri P, Cotroneo AM, Orsitto G, Putignano S (2020) The CITIDEMAGE study: stressing the cholinergic hypothesis for the best outcomes in dementia patients. Alzheimers Dement 16, e038178.

The answer is not very elegant, because it is in turn the harsh and resentful comment to a different opinion, without leaving room for a serene dialectical and scientific comment.

It is quite astonishing that eminent researchers do not take into account the remarkable role of experimental studies, which are crucial and somewhat propaedeutic for understanding the possible clinical role. Few clinical studies were conducted on citicoline, but the starting point was just its relevant role at a biochemical and cellular level.

The roles on SIRT 1, glutamate, synaptogenesis, cell membranes, mitochondria are crucial for understanding why it works! Missing these aspects means misunderstanding why citicoline should be used instead of other cholinergic precursors marketed up to now. Furthermore, it does not sound respectful towards all the past studies that opened the route towards possible clinical outcomes [1 - 9].

Last point, the poster you have mentioned on the role of the triple therapy (citicoline + memantine + AchEIs - Alzheimer’s and Dementia, 2020 ) was submitted more than one year ago and presented online at the AAIC first, on July 24, 2020, and at the Italian Congress of Psychogeriatrics on mid-- September. Maybe it will not be published, but the idea of the triple association was conceived some years ago. That’s all for those who want to understand!

 

References

[1]     Secades JJ, Frontera G (1995) CDP-choline: a pharmacological and clinical review. Methods Find Exp Clin Pharmacol 17(suppl B), 1–54.

[2]     Hurtado O, Lizasoain I, Moro MÁ (2011) Neuroprotection and recovery: recent data at the bench on citicoline. Stroke 42(suppl1), S33–S35.

[3]     Hurtado O, Moro MA, Cardenas A, Sánchez V, Fernández-Tomé P, Leza JC, Lorenzo P, Secades JJ, Lozano R, Dávalos A, Castillo J, Lizasoain I (2005) Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: Effects on glutamate transport. Neurobiol Dis 18, 336–45.

[4]     Gutierrez-Fernandez M, Rodriguez-Frutos B, Fuentes B, Vallejo-Cremades MTAlvarez-Grech JExpósito-Alcaide MDíez-Tejedor E (2012) CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke. Neurochem Int 60, 310–7.

[5]     Pardossi-Piquard R, Dunys J, Yu G, George-Hyslop PAlves da Costa CChecler F(2006) Neprilysin activity and expression are controlled by nicastrin. In: J Neurochem 97, 4, 1052–6.

[6]     Secades JJ. Citicoline: pharmacological and clinical review, 2010 update (2011) Rev Neurol 52 (suppl 2), S1–S62.

[7]     Hurtado O, Hernández-Jiménez M, Zarruk JG, Cuartero MIBallesteros ICamarero GMoraga A Pradillo JMMoro MALizasoain I (2013) Citicoline (CDPcholine) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke. J Neurochem 126, 816–819.

[8]     Krupinski J, Slevin M, Badimon L (2005) Citicoline inhibits MAP kinase signaling pathways after focal cerebral ischemia. Neurochem Res 30 (8), 1067–1073.

[9]     Álvarez-Sabín J and Román GC (2013) The Role of Citicoline in Neuroprotection and Neurorepair in Ischemic Stroke. Brain Sci 3, 1395-1414; doi:10.3390/brainsci3031395

 

 

Pietro Gareri, MD, PhD - Center for Cognitive Disorders and Dementia – Catanzaro Lido, ASP Catanzaro; Catanzaro, Italy; Antonino Maria Cotroneo, MD - Director Department of Geriatrics – Maria Vittoria Hospital ASL City of Turin, Italy.