Abstract

Cognitive decline after stroke is more common than stroke recurrence. Stroke doubles the risk of dementia and is a major contributor to vascular cognitive impairment and vascular dementia. Neuropathological studies in most cases of dementia in the elderly reveal a large load of vascular ischemic brain lesions mixed with a lesser contribution of neurodegenerative lesions of Alzheimer disease. Nonetheless, few pharmacological studies have addressed vascular cognitive impairment and vascular dementia after stroke. Citicoline has demonstrated neuroprotective effects in acute stroke and has been shown to improve cognition in patients with chronic cerebrovascular disease and in some patients with Alzheimer disease. A recent trial lasting 6 months in patients with first-ever ischemic stroke showed that citicoline prevented cognitive decline after stroke with significant improvement of temporal orientation, attention, and executive function. Experimentally, citicoline exhibits neuroprotective effects and enhances neural repair. Citicoline appears to be a safe and promising alternative to improve stroke recovery and could be indicated in patients with vascular cognitive impairment, vascular dementia, and Alzheimer disease with significant cerebrovascular disease.

Stroke considerably increases the likelihood of dementia in the elderly. For instance, in the Framingham study, stroke doubled the risk of dementia.¹ Poststroke cognitive decline is more common than stroke recurrence. Poststroke vascular dementia (VaD) affects 30% of survivors, and the incidence of new-onset dementia increases from 7% 1 year after stroke to 48% after 25 years.² The term vascular cognitive impairment (VCI)³ refers to the effects of the vascular burden of the brain on higher mental functions; VCI reflects all cognitive effects of cerebrovascular disease on cognition⁴ and includes many types of cognitive impairment, except dementia (VCI with no dementia).⁵ Patients with dementia as a result of hemorrhagic, ischemic, or hypoperfusive brain injury are included in the VaD category,⁶ as are those with mixed vascular-degenerative forms.

VCI with no dementia is twice as common as VaD.⁷ Six months after stroke, 44% to 74% of patients present some degree of cognitive disturbance.^8–16 Half of the patients with VCI have dementia develop within 5 years.¹¹ A recent meta-analysis of 16 studies¹² shows a clear relationship between stroke and dementia. Most of the studies agree that stroke doubles the risk of dementia independently of demographic data or presence of vascular risk factors. Preexisting cognitive impairment is not a determinant factor for the development of poststroke VCI.¹⁷ The risk decreases over time after the index stroke event, but it seems to be higher in patients with the apolipoprotein E ε4 allele, suggesting a link with Alzheimer disease.

Cerebrovascular lesions, including silent lacunar strokes and white matter ischemia, are common in elderly patients with dementia, and numerous clinicopathological studies have conclusively demonstrated that most patients with dementia late in life have mixed dementia, combining cerebrovascular disease and Alzheimer disease.^13,14 For instance, the neuropathological findings in the cohort of the Baltimore Longitudinal Study of Aging¹⁵ demonstrated a clear relationship between the number of microscopic and macroscopic brain infarcts and dementia during life, without decrease in significance after adjustment for vascular risk factors. An inverse relationship exists between cerebrovascular disease and Alzheimer disease lesions whereby the density of neuritic senile plaques, focal Aβ deposition, and neurofibrillary tangles are lower when vascular lesions are present; moreover, for similar levels of clinical severity of dementia, patients with vascular lesions have fewer Alzheimer disease lesions than those without.¹⁶ Stroke patients with VCI with no dementia have an increased 5-year risk for VaD or other dementias.¹¹

Given the critical role of stroke in the dementia syndrome in the elderly, both adequate primary prevention and neuroprotective intervention after occurrence of stroke would be of major importance for the prevention of dementia.¹⁷ Despite these facts, few pharmacological studies have addressed the issue of prevention of poststroke VCI, VaD, and mixed vascular-degenerative dementias. Potential beneficial therapies should be oriented to modify the consequences of brain ischemia and to stimulate neurorepair.

Citicoline

Citicoline is an intermediate in membrane phospholipid synthesis that has been extensively assessed in acute stroke clinical trials demonstrating benefits.^18–21 Using diffusion-weighted MRI, Warach et al²¹ demonstrated significant reduction in lesion volume growth and lesion volume from week 1 to week 12 in patients with acute ischemic stroke treated with citicoline within the first 24 hours after stroke onset. A marked association was found between lesion volume reduction and improvement of NIHSS score by ≥7 points.

Citicoline, also known as cytidine-5′-diphosphate-choline, is a naturally occurring endogenous nucleoside that functions as an intermediate in 3 major metabolic pathways:²² (1) synthesis of phosphatidylcholine (lecithin), one of the major cell membrane phospholipids with an important role in the formation of lipoproteins (citicoline formation is the rate-limiting step in the synthesis of phosphatidylcholine in neuronal membranes and microsomal phospholipids); (2) citicoline provides choline for acetylcholine synthesis and could limit choline availability for membrane synthesis;²³ and (3) oxidation to betaine, a methyl donor. The main components of citicoline, choline, and cytidine are readily absorbed in the gut and cross the blood–brain barrier.²⁴ As a dietary supplement, choline is grouped with the B vitamins;²⁴ a related product, choline alphoscerate, has been used less frequently.²⁵ In animal studies, citicoline is biologically active, enhances repair of ischemic neuronal injury, and increases levels of acetylcholine and dopamine.²³ In aged animals, citicoline increased dopamine release, improving learning and memory tasks²⁶ protecting against cognitive impairment in a rat model of chronic cerebral hypoperfusion.²⁷ In an experimental stroke model, Hurtado et al²⁸ showed that citicoline can produce re-growth of dendritic spines, which correlated with functional recovery. Using phosphorus magnetic resonance spectroscopy, Silveri et al²⁹ showed in elderly human subjects that citicoline treatment for 6 weeks produced significant increases in frontal lobe (anterior cingulate cortex) phosphocreatine (+17%), β-nucleoside triphosphates (largely ATP in the brain [+14%]), and in the ratio of phosphocreatine to inorganic phosphate (+32%). Also, significant increase in membrane phospholipids was demonstrated.

Citicoline in Stroke and Cognitive Decline

Citicoline is a safe drug approved in numerous countries for the treatment of acute ischemic stroke. Oral citicoline administered within 24 hours from symptoms onset has shown evidence of efficacy, as shown in data-pooled analyses based on 1372 patients in 4 clinical trials performed in United States.³⁰ Citicoline enhances neurological and functional recovery.^31,32 Compared with placebo, citicoline-treated patients with acute ischemic stroke with NIHSS score ≥8 were more likely to have a full recovery (Barthel index ≥95): placebo, 21%; citicoline, 33% (P=0.05).¹⁹

There are few studies assessing the long-term security and efficacy of citicoline treatment in stroke patients, and its efficacy in the prevention of poststroke cognitive decline. Citicoline has been used in a number of trials in patients with Alzheimer disease and has shown consistent but moderate improvement of memory and behavior.³³ However, a placebo-controlled trial of 30 patients with VaD showed no evidence of cognitive improvement.³⁴ A Cochrane review³⁵ included 14 studies on aged individuals with symptoms ranging from memory disorders to vascular mild cognitive impairment, VaD, or senile dementia. Duration of studies ranged between 20 and 30 days, 1 study lasted 6 weeks, 4 studies lasted 2 and 3 months, and 1 study lasted 12 months. Multiple doses and different inclusion criteria and outcome measures were used. Overall results (884 patients) showed evidence of benefit of citicoline on memory and behavior, but not on attention. There was significant improvement in the global impression of change in comparison with the placebo group. The effect size was large (OR, 8.89; 95% CI, 5.19–15.22; P<0.001), indicating a strong drug effect for improvement with active treatment.^35,36 These authors concluded that the cognitive effects of citicoline are clearly evident at the behavioral level and can be easily appreciated with a clinical observation of patients irrespective of the functional paradigm used to measure them. Citicoline is remarkably well-tolerated and more side effects were seen with the placebo than with the active treatment groups.^35,36

Experimental and clinical studies have shown that citicoline effects may result from its contribution to several mechanisms of neuroplasticity and neurorepair. Regarding plasticity, Hurtado et al²⁸ showed that chronic treatment with citicoline improved functional recovery after experimental stroke and, more importantly, demonstrated that a potential neuronal substrate for the improvement of function could be the enhancement of dendritic complexity and spine density compared with the saline control group. Citicoline treatment may then increase neuronal plasticity that might be linked with clinical improvement after stroke.

Regarding potential mechanisms of neurorepair, it has been shown that citicoline enhances neuroprotection by redistributing the main glutamate transporter EAAT2 to lipid raft microdomains, thereby improving glutamate uptake.³⁷ Treatment with neurotrophic factors (ie, basic fibroblast growth factor) enhances cognitive function in an ischemic model of ischemic encephalopathy by increasing the number of cholinergic neurons in the CA region of the hippocampus.³⁷ Interestingly, several cell-based therapies, such as the administration of exogenous endothelial progenitor cells, might increase the level of a number of growth factors secreted by those cells. Recently, Sobrino et al³⁸ showed that citicoline treatment may mobilize endothelial progenitor cells from bone marrow of stroke patients, thus improving functional recovery after acute ischemic stroke. Therefore, the increase of endothelial progenitor cells in peripheral blood induced by citicoline is associated with better functional outcome in ischemic stroke patients.

Currently, however, there is no data on the efficacy and safety of citicoline treatment used for >6 weeks in patients with ischemic stroke, or on the potential benefits of citicoline on prevention of poststroke VCI. Thus, Alvarez-Sabin et al³⁹ conducted a study designed to answer these issues. This study suggests that citicoline treatment within 24 hours of stroke onset, followed by continuous treatment for 6 months, is safe and demonstrates benefits such as prevention of poststroke VCI compared to placebo. The results showed an improvement in temporal orientation, attention, and executive functions. Furthermore, continuous citicoline treatment in patients after stroke for up to 12 months showed excellent tolerability, safety, and continued improvement in poststroke VCI, especially in temporal orientation, executive functions, and attention (Figure).

Conclusion

In summary, it has been shown that patients with cognitive sequelae from acute cerebral infarction may benefit from long-term citicoline treatment and achieve better functional, cognitive, and neurological recovery.³⁹ Citicoline treatment appears to be safe and well-tolerated.^39–43

Disclosures

J.A.S. received a research grant from Ferrer and he is a member of Ferrer’s speakers bureau. G.R. is a member of Ferrer’s speakers bureau. The concepts presented in this review are those of the authors and are independent from Ferrer’s official views.

https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.110.606509