Is Citicoline Effective in Preventing and Slowing Down Dementia?—A Systematic Review and a Meta-Analysis

1. Introduction

Mild cognitive impairment (MCI) is defined as an objective decline in cognitive function, reported by a patient or relative, that has no or minimal impact on instrumental activities of daily living [ 1 ]. Some people with MCI will progressively develop dementia while others remain stable or recover full functioning [ 2 ]; it is estimated that about 12% to 36% of people aged 65 and over have MCI [ 3 ] and, as the population of older adults increases, the prevalence of MCI will gradually increase [ 4 ]. People with MCI are at greater risk of dementia than the general population; the mean annual conversion rate of MCI to dementia is approximately 10% [ 5 ], which is far higher than the annual incidence (1–2%) in the general population. According to the existing literature, MCI progresses mostly to Alzheimer’s disease and, less frequently, to vascular dementia [ 6 ].

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for an estimated 60% to 80% of cases (50 million worldwide) [ 7 ], and its prevalence is increasing worldwide. AD is characterized by intraneuronal fibrillary tangles and extracellular deposit of amyloid plaques (Aβ) coupled with reactive microgliosis and loss of neurons and synapses in the cortex [ 8 ]. Deposits of Aβ can lead to cortical dysfunctions resulting in several cognitive impairments such as memory and intellectual disabilities, causing a disability in activities of daily living [ 9 ] and interfering with quality of life.

Another common cause of dementia is vascular dementia (VaD), accounting for about 20% of all cases of dementia [ 10 ]. It is a neurocognitive disorder with significant cognitive impairment that is directly related to vascular injury to the brain; it has several potential contributing factors such as ischemic stroke [ 11 ]. Almost half of stroke survivors have cognitive impairment [ 12 ]; cognitive decline after stroke is even more common than stroke recurrence, and stroke patients with cognitive impairment but no dementia have an increased risk of developing VaD and other dementias at 5 years [ 13 ].

MCI and dementia can also occur in patients with Parkinson’s disease (PD); the prevalence of PD-MCI ranges from 20% to 40% depending on the population studied, and the incidence of PD-dementia increases with the duration of disease, with estimates as high as 30% at 5 years and over 80% at 20 years from diagnosis [ 14 15 ]. Cognitive decline is usually slow and insidious, but may be rapid in some cases [ 16 ].

MCI and dementia pose significant challenges to patients, caregivers and healthcare systems due to their rising prevalence and socioeconomic burden, with the numbers of people living with dementia worldwide projected to triple to 152 million cases by 2050 [ 17 ]; furthermore, MCI [ 18 ] and dementia [ 19 ] seriously affect the quality of life and well-being of older adults. In the face of this staggering impact on personal and societal health of these conditions, the therapeutic options are somewhat limited [ 11 21 ], and there is a strong interest in potential strategies for prevention and treatment interventions.

It has been suggested that dementia may be prevented or slowed down by improving nutritional status. For example, Dominguez et al. [ 22 ] documented that adherence to the Mediterranean dietary pattern and Dietary Approach to Stop Hypertension (DASH) is associated with slower rates of cognitive decline and significant reduction in incidence of AD. In addition, Martinez [ 23 ] suggests in a systematic review that supplementation of B complex vitamins, especially folic acid, may have a positive effect on delaying and preventing the risk of cognitive decline. Given their safety, nutritional supplements have been extensively investigated as an option for treating cognitive disorders [ 24 28 ], especially in the initial stages of the disease to prevent the progression to dementia [ 29 30 ]. A consensus has emerged that intervention strategies must be initiated as early as possible, even before any significant symptoms begin to appear [ 31 32 ].

One of the most promising nutritional supplements is citicoline, the pharmaceutical form of the endogenous compound cytidine-5′-diphosphate (CDP) choline. It increases the intrasynaptic concentration of acetylcholine and promotes phospholipid synthesis and neuronal repair, as shown in different studies in animals [ 33 ]. Moreover, it can inhibit apoptosis associated with cerebral ischemia and several models of neurodegeneration, as demonstrated in studies in vitro or in animals [ 34 ]. It has neuroprotective properties, as shown in studies performed in vitro or in animal models, that have been shown in different patterns of cognitive impairment, Parkinson’s disease or dementia (Alzheimer’s disease or vascular dementia), and that are much more evident when the treatment is administered for an extended period of time [ 35 ]. Citicoline seems to be effective also in provoking cognitive functions in normal healthy people as shown by Al-kuraishy et al. [ 36 ]; it improved human psychomotor vigilance, arousal and visual working memory with significant amelioration of oxidative stress after two weeks of being administered in healthy volunteers (age range 21–22 years).

The current evidence on this supplement has been obtained from studies that for the most part have a small sample size, and has been summarized in previous reviews that have focused on Alzheimer’s disease [ 37 ], or on MCI associated with Parkinson’s disease [ 38 ] or on a wide range of neurological conditions [ 39 ]. The results are heterogeneous; furthermore, there are no reviews that compare and analyze at the same time the efficacy of citicoline in MCI and in different types of dementia.

The aim of this systematic review and meta-analysis is to evaluate whether citicoline, compared with a placebo or standard treatment, is effective in preventing dementia in people with MCI or in improving cognitive functions in people with dementia.