Citicoline: A Cholinergic Precursor with a Pivotal Role in Dementia and Alzheimer's Disease.

Background: Citicoline is a naturally occurring compound with pleiotropic effects on neuronal function and cognitive processes. Objective: Based on previous studies, which shed light on the positive effects of citicoline 1 g when combined with acetylcholinesterase inhibitors (AChEIs) and/or memantine, we further investigated the benefits of citicoline in combination therapy in Alzheimer's disease and mixed dementia. Methods: We integrated the datasets of CITIMEM and CITIDEMAGE, increasing the overall sample size to enhance statistical power. We analyzed data from these two investigator-initiated studies involving 295 patients. The primary outcome was the assessment over time of the effects of combined treatment versus memantine given alone or AChEI plus memantine on cognitive functions assessed by Mini-Mental State Examination (MMSE). The secondary outcomes were the influence of combined treatment on daily life functions, mood, and behavioral symptoms assessed by activities of daily life (ADL) and instrumental ADL, Geriatric Depression Scale, and Neuropsychiatric Inventory Scale. One-hundred-forty-three patients were treated with memantine and/or AChEI (control group), and 152 patients were treated with memantine and/or AChEI plus citicoline 1 g/day orally (Citicoline group). Results: A significant difference in MMSE score was found in the average between the two groups of treatment at 6 and 12 months. Conclusions: This study confirmed the effectiveness of combined citicoline treatment in patients with mixed dementia and Alzheimer's disease, with a significant effect on the increase of MMSE score over time. The treated group also showed a significant reduction in the Geriatric Depression Scale and a significant increase in the instrumental ADL scale.

An algorithm for the early diagnosis and correct approach to dementia management: results of a multiprofessional team.

BACKGROUNG: The early identification of cognitive disorder is a primary scope, because it could reduce the rate of severe cognitive impairment and thus contribute to reduce healthcare costs in the next future. AIMS: The present paper aimed to build a virtuous diagnostic path of cognitive impairment, highlighting all the professionalism that can serve this purpose. METHODS: The Delphi method was used by the experts, who reviewed the information available during each meeting related to the following topics: early diagnosis of cognitive impairment, definition of Mild Cognitive Impairment, unmet needs in post-stroke patients, critical decision-making nodes in complex patients, risk factors, neuropsychological, imaging diagnosis, blood tests, the criteria for differential diagnosis and the possible treatments. RESULTS: The discussion panels analyzed and discussed the available evidences on these topics and the related items. At each meeting, the activities aimed at the creation of a diagnostic-welfare flow chart derived from the proposal of the board and the suggestions of the respondents. Subsequently, the conclusions of each panel were written, and the study group reviewed them until a global consensus was reached. Once this process was completed, the preparation of the final document was carried out. CONCLUSIONS: Eventually, we built an algorithm for the early diagnosis and treatment, the risk factors, with the possible differences among the different kinds of dementia.

An Overview of Combination Treatment with Citicoline in Dementia.

INTRODUCTION: The present article reports an overview of the studies about combination treatment with citicoline of Alzheimer's (AD) and mixed dementia (MD). METHODS: A Medline search was carried out by using the keywords Alzheimer's dementia, mixed dementia, older people, treatment with citicoline, memantine, and acetylcholinesterase inhibitors (AchEIs). RESULTS: Six studies were found to match the combination treatment of citicoline with AcheIs and/or memantine. The CITIRIVAD and CITICHOLINAGE studies were the first to report the potential benefits of adding citicoline to acetylcholinesterase inhibitors (AchEIs). Then, we added citicoline to memantine in the CITIMEM study, and finally, we demonstrated benefits in terms of delay in cognitive worsening with the triple therapy (citicoline + AchEIs + memantine). Other authors also reinforced our hypothesis through two further studies. CONCLUSION: Open, prospective studies are advised to confirm the utility of combination therapy with citicoline for the treatment of AD and MD.

The risk of polypharmacy and potentially inappropriate drugs in residential care dementia patients: tips from the PharE study.

AIMS: The aims of the present study, conducted in two regions of Italy, Calabria and Piedmont, were to assess the use of inappropriate drugs according to the Beers Criteria and to study the possible drug-drug interactions. METHODS: Data were obtained retrospectively from 972 residential care patients between 2016 and 2018. Mean age was 82.4 ± 8.4 years, with a prevalence of women (64.8%). Activities of daily living, instrumental activities of daily living, Mini-Mental State Examination, Cumulative Illness Rating Scale, Neuropsychiatric Inventory Scale and number and kind of drugs were recorded. A classification of potential inappropriate drugs was made according to the Beers criteria. Data were collected through an Excel file able to gather the main information. In the case of suspected adverse event, Naranjo Scale was applied. The study of possible drug-drug interactions was made by Micromedex 2.0. RESULTS: Functional and cognitive impairments, comorbidities and number of drugs were assessed. The bivariate relationship between number of drugs and glomerular filtration rate assessed by CKD-EPI showed that the higher was the number of drugs used, the worst was kidney function assessment (p = 0.0001). The most frequent inappropriate drugs were anticholinergic drugs, tricyclics antidepressants, long-half-life benzodiazepines, antipsychotics and proton pump inhibitors. CONCLUSIONS: These data are very interesting and show the need for an accurate choice of drugs in elderly people and for starting a wise deprescribing procedure.

The Importance of Citicoline in Combined Treatment in Dementia: What did the Citimem Study Teach us?

BACKGROUND: Citicoline is a drug used both in degenerative and in vascular cognitive decline; memantine is a drug used for the treatment of mild to moderate Alzheimer's disease (AD). Our hypothesis is that their combined use could have enhanced action in patients having AD and mixed dementia (MD). We report the main tips from a recent study on the use of these drugs, the CITIMEM study. METHODS: The study was retrospective and was performed on 126 patients aged 65 years old or older affected with AD or MD (mean age 80.7 ± 5.2 years old) who had been visited between 2015 and 2017 in four different centers for dementia all over Italy. Neuropsychological and functional tests were administered at baseline (T0), after 6 (T1), and 12 months (T2). The effects of combined treatment versus memantine alone on cognitive functions assessed by Mini-Mental State Examination (MMSE) and the possible onset of side effects or adverse events, as well as the influence on daily life functions and behavioral symptoms, were investigated. RESULTS: Patients undergoing combined treatment showed a significant increase in MMSE vs. memantine alone, both at T1 (p=0.003) and T2 (p =0.000). CONCLUSION: The CITIMEM study confirms our hypothesis that the combined administration of memantine plus citicoline is safe and more effective than memantine alone on cognition in patients suffering from AD or MD.

The Art of Safe and Judicious Deprescribing in an Elderly Patient: A Case Report.

Prescription for inappropriate drugs can be dangerous to the elderly due to the increased risk of adverse drug reactions and drug-interactions. In this manuscript, we report the complexity of polypharmacy and the possible harmful consequences in an old person. An 81-year-old man with a clinical history of diabetes, blood hypertension, non-valvular atrial fibrillation, chronic obstructive pulmonary disease, osteoarthritis, anxiety, and depression, was admitted to our attention for cognitive disorders and dementia. Brain magnetic resonance imaging showed parenchymal atrophy with lacunar state involving thalami and internal capsules. Neuropsychological tests revealed cognitive impairment and a depressed mood. History revealed that he was taking 11 different drug severy day with a potential risk of 55 drug-drug interactions. Therefore, risperidone, chlorpromazine, N-demethyl-diazepam, and L-DOPA/carbidopa were gradually discontinued and citicoline (1g/day), cholecalciferol (50,000 IU once a week), and escitalopram (5 mg/day) were started. Furthermore, he started a program of home rehabilitation. During the follow-up, three months later, we recorded an improvement in both mood and cognitive tests, as well as in walking ability. The present case report shows the need for a wise prescription and deprescribing in older people.

The CITIMEM study: A pilot study. Optimizing pharmacological treatment in dementia.

INTRODUCTION: Citicoline can have beneficial effects both in degenerative and in vascular cognitive decline; it works through an increase in acetylcholine intrasynaptic levels and promoting phospholipid synthesis, (chiefly phosphatidylcholine), cellular function, and neuronal repair. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist used for the treatment of mild to moderate Alzheimer's disease (AD). When co-administered they could have a synergistic action in patients affected with AD and mixed dementia (MD) too. SCOPE: The aim of the present study was to show the effectiveness of oral citicoline plus memantine in patients affected with AD and MD. PATIENTS AND METHODS: This was a retrospective study between 2015 and 2017 on 126 patients aged 65 years old or older affected with AD or MD (mean age 80.7 ± 5.2 years old). The study involved four different centers for dementia all over Italy. Diagnosis of AD was made according to clinical symptoms, neuropsychological tests and brain imaging. Diagnosis of MD was made when symptoms typical of AD such as memory loss were associated to symptoms due to cerebrovascular deficits, i.e., impaired judgement, ability to make decisions, plan or organize, and brain imaging. 58 patients were treated with memantine (group A), 68 patients with memantine plus citicoline 1 g/day given orally (group B). In both groups memantine dosage was 10-20 mg/day according to its tolerability. 24 patients of group A and 29 patients of group B were affected with MD. Cognitive functions were assessed by MMSE, daily life functions by ADL and IADL, behavioral symptoms by NPI, comorbidities by CIRS, and mood by GDS-short form. Tests were administered at baseline (T0), after 6 (T1), and 12 months (T2). The primary outcomes were the effects of combined treatment versus memantine alone on cognitive functions assessed by MMSE. The secondary outcomes were the possible side effects or adverse events of combination therapy versus memantine alone, influence on daily life functions and behavioral symptoms. RESULTS AND CONCLUSIONS: Patients treated with citicoline plus memantine showed an increase in MMSE between T0 and T1 (16.6 ± 2.9 vs 17.4 ± 2.7) and between T1 and T2 (17.4 ± 2.7 vs 17.7 ± 2.8). The difference in MMSE score was significant when comparing the two groups, both at T1 (p = 0.003) and T2 (p = 0.000). Since it is important to maximize the pharmacological means in AD and MD, the present study encourages the role of combined administration of memantine plus citicoline in disease management and in slowing down the progression of disease.

The Citicholinage Study: Citicoline Plus Cholinesterase Inhibitors in Aged Patients Affected with Alzheimer's Disease Study.

BACKGROUND: Citicoline can have beneficial effects both in degenerative and in vascular cognitive decline in a variety of ways (apoptosis inhibition, neuroplasticity potentiation, phospholipid, and acetylcholine (ACh) synthesis). Acetylcholinesterase inhibitors (AChEIs) have been used for treatment of Alzheimer's disease (AD). When co-administered with cholinergic precursors, they are able to increase the intrasynaptic levels of ACh more than when the single drugs given alone. OBJECTIVE: The aim of the present study was to show the effectiveness of oral citicoline plus AChEIs in patients affected with AD. METHODS: This was a retrospective multi-centric case-control study, involving seven Centers for Cognitive Impairment and Dementia in Italy, on 448 consecutive patients aged 65 years old or older affected with AD. 197 patients were treated with an AChEI while 251 were treated with an AchEI + citicoline 1000 mg/day given orally. Cognitive functions were assessed by MMSE, daily life functions by ADL and IADL, behavioral symptoms by NPI, comorbidities by CIRS, and mood by GDS-short form. Tests were administered at baseline (T0), after 3 (T1), and 9 months (T2). The primary outcomes were effects of combined administration versus AChEIs given alone on cognitive functions assessed by MMSE. The secondary outcomes were possible side effects or adverse events of combination therapy versus AChEIs alone. RESULTS: Patients treated with citicoline plus an AChEI showed a statistically significant increase in MMSE between T0 and T1 (16.88±3.38 versus 17.62±3.64; p = 0.000) and between T1 and T2 (17.62±3.64 versus 17.89±3.54; p = 0.000). CONCLUSION: The present study encourages the role of combined administration in disease management by slowing disease progression.

The CITIRIVAD Study: CITIcoline plus RIVAstigmine in Elderly Patients Affected with Dementia Study.

BACKGROUND: Acetylcholinesterase inhibitors (AchEIs), such as rivastigmine, coadministered with cholinergic precursors, such as citicoline, could be effective in Alzheimer's disease (AD) and in mixed dementia (MD), because they are able to increase the intrasynaptic levels of acetylcholine more than the single drugs given alone. OBJECTIVE: The aim of the present study was to show the effectiveness of oral citicoline plus rivastigmine in patients with AD and MD. METHODS: The CITIRIVAD study was a retrospective case-control study on 174 consecutive outpatients aged ≥65 years, affected with AD or MD, mean age 81.3 ± 4.5 years. Of the 174 patients, 92 had been treated with rivastigmine + citicoline 1000 mg/day given orally (group A); 82 patients had been treated with rivastigmine (group B). In both groups rivastigmine patch had been used for at least six months at the highest tolerated dosage. Group A comprised 62 patients affected with AD and 30 patients with MD. Group B comprised 53 patients affected with AD and 29 with MD. Cognitive functions had been assessed by Mini Mental State Examination (MMSE), daily life functions by activities of daily living (ADL) and instrumental activities (IADL), behavioral symptoms by neuropsychiatric inventory (NPI), comorbidities by the Cumulative Illness Rating Scale and mood by geriatric depression scale (GDS)-short form tests, which had been administered at baseline, 3 and 9 months. RESULTS AND CONCLUSIONS: Data show the effectiveness of combined administration versus the AchEI alone, mainly in slowing disease progression and consequently in disease management, both in AD and in MD. No differences regarding the combined treatment were found between the two groups. Treatment with citicoline plus rivastigmine was safe and well tolerated.

[Relationship between 25-hydroxy vitamin D and cognitive status in older adults: the COGNIDAGE study]. / Livelli di 25(OH)D e performance cognitive in una popolazione di anziani: lo studio COGNIDAGE.

AIM: The aim of the COGNIDAGE study was to examine the association between 25(OH)D and cognitive status in a group of elderly patients with vitamin D deficiency and high burden of comorbidities attending Geriatric Outpatient Clinics. MATERIALS AND METHODS: We studied the relationship between 25(OH)D and cognitive functions taking into account comorbidities and cognitive functions assessed by MMSE (Mini Mental State Examination), CDT (Clock Drawing Test) and CIRS (Cumulative Illness Rating Scale), in 132 consecutive elderly patients with low levels of 25(OH)D (<10 ng/ml) compatible with the condition of vitamin deficiency. The association among 25(OH)D levels, MMSE score, CDT score and CIRS scores were analyzed using Pearson correlation. All the elderly patients received an adequate vitamin D supplementation and were reassessed after 6 months. RESULTS: At baseline, mean MMSE and CIRS scores were: 21.8+5.56 and 2.96 +1.63 respectively. Mean CDT score was 3,66+-2.05. No associations were found between 25(OH)D levels and global cognitive function. A significant relationship was observed between the total CIRS score and 25(OH)D levels (r=0.305; p=0.000) as well as between total CIRS score and MMSE (r=-0.375; p=0.000). After 6 months, 83.9 % had 25(OH)D levels >20 ng/ml. Mean MMSE and CDT scores were 22.20+-5.76 and 3.90+-2.06 respectively. There was no significant correlation among 25(OH)D, MMSE and CDT scores while a significant correlation was found between 25(OH)D and CIRS- severity score (r=0.275; p=0.001) and between MMSE and total CIRS scores (r=-0.247; p=0.005 for CIRS-comorbidities; r=-0.184; p=0.04 for CIRS-severity). A post hoc evaluation on two subgroups of elderly patients (the first with vitamin D deficiency without cognitive impairment, the second with vitamin D deficiency and dementia) showed a statistically significant difference (p=0.00001) regarding the CIRS-comorbidities scores. CONCLUSIONS: In our cohort of elderly patients with a high burden of comorbidities, 25(OH)D low levels (<10 ng/ml) are not associated with MMSE and CDT scores. There is no statistically difference among the levels of 25(OH)D and MMSE and CDT scores after 6 months. The strong correlation we found regarding CIRS-comorbidities in the two sub-groups suggests that vitamin D deficiency may play a role in promoting cognitive impairment only with comorbidities.

The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives.

BACKGROUND: Citicoline is able to potentiate neuroplasticity and is a natural precursor of phospholipid synthesis, or rather serves as a choline source in the metabolic pathways for biosynthesis of acetylcholine. Several studies have shown that it can have beneficial effects both in degenerative and in vascular cognitive decline. The aim of the present study was to review the pharmacokinetics and pharmacodynamics of this drug and its role in cognitive impairment according to the present medical literature. METHODS: A MEDLINE(®) search was made using the following key words: citicoline, pharmacokinetics, pharmacodynamics, elderly, cognitive impairment, vascular dementia, and Alzheimer's disease. Recent studies on the possible role of citicoline in increasing sirtuin 1 (SIRT1) expression were assessed. Some personal studies were also considered, such as the VITA study and the IDEALE study. RESULTS: Administered by both oral and intravenous routes, citicoline is converted into two major circulating metabolites, cytidine and choline. It is metabolized in the gut wall and liver. Pharmacokinetic studies suggested that it is well absorbed and highly bioavailable with oral dosing. A number of studies have clearly shown the possible role of citicoline in cognitive impairment of diverse etiology. It can also modulate the activity/expression of some protein kinases involved in neuronal death and increases SIRT1 expression in the central nervous system. The VITA study and the IDEALE study suggested that both parenteral and oral citicoline are effective and safe. Other studies have clearly demonstrated citicoline's effects on several cognitive domains. Conversely, some studies did not point out any evidence of efficacy of this drug. CONCLUSION: Citicoline appears to be a promising agent to improve cognitive impairment, especially of vascular origin. In fact, so far it appears as a drug with the ability to promote "safe" neuroprotection, capable of enhancing endogenous protective. Large clinical trials are needed to confirm its benefits.

Retrospective study on the benefits of combined Memantine and cholinEsterase inhibitor treatMent in AGEd Patients affected with Alzheimer's Disease: the MEMAGE study.

BACKGROUND: Combined therapy of memantine and acetylcholinesterase inhibitors (AChEIs) in patients with Alzheimer's disease (AD) may be associated with higher benefits than either monotherapy. OBJECTIVE: This retrospective multicentric study conducted in seven Italian Ambulatory Centers for Dementia assessed the efficacy and safety of memantine 20 mg/day administered for 6 months in addition to an AChEI in AD patients with worsened cognitive functions and behavioral disorders. METHODS: A total number of 240 patients (61.7% of women, 38.3% men, mean age 77.9 ± 7.32 years old) who had started treatment with the combination therapy were recruited. At baseline (T0), Month 3 (T1), and Month 6 (T2), cognitive functions were assessed by Mini-Mental State Examination (MMSE), functional dependence by activities of daily living (ADL) and instrumental ADL, behavioral disturbances by the Neuropsychiatric Inventory (NPI), and comorbidities by Cumulative Illness Rating Scale. Adverse events were reported during the study. RESULTS: MMSE total score significantly increased at Month 6 (p = 0.029 versus month 3) and IADL total score significantly decreased from baseline to endpoint (p = 0.033). There were no significant changes from baseline in mean ADL, despite significant improvements in NPI total score. The mean MMSE total score significantly increased with the combination donepezil + memantine compared to rivastigmine + memantine. The adverse events profile was in line with the expected range of the drugs studied and concomitant therapies. Overall, 17 patients discontinued treatment in the observation time. CONCLUSION: Combined treatment with memantine and AChEIs was effective in patients with AD, particularly in slowing cognitive impairment and preventing the onset of agitation and aggression in elderly AD patients.

Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study.

BACKGROUND: The studio di intervento nel decadimento vascolare lieve (IDEALE study) was an open multicenter Italian study, the aim of which was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment. METHODS: The study was performed in 349 patients. The active or citicoline group was composed of 265 patients and included 122 men and 143 women of mean age 79.9 ± 7.8 years selected from six Italian regions. Inclusion criteria were age ≥ 65 years, Mini-Mental State Examination (MMSE) score ≥ 21, subjective memory complaints but no evidence of deficits on MMSE, and evidence of vascular lesions on neuroradiology. Those with probable Alzheimer's disease were excluded. The control group consisted of 84 patients, including 36 men and 48 women of mean age 78.9 ± 7.01 (range 67-90) years. Patients included in the study underwent brain computed tomography or magnetic resonance imaging, and plasma dosage of vitamin B12, folate, and thyroid hormones. Functional dependence was investigated by scores on the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales, mood was assessed by the Geriatric Depression Scale (GDS), and behavioral disorders using the Neuropsychiatric Inventory scale. Comorbidity was assessed using the Cumulative Illness Rating Scale. An assessment was made at baseline (T0), after 3 months (T1), and after 9 months (T2, ie, 6 months after T1). The main outcomes were an improvement in MMSE, ADL, and IADL scores in the study group compared with the control group. Side effects were also investigated. The study group was administered oral citicoline 500 mg twice a day throughout the study. RESULTS: MMSE scores remained unchanged over time (22.4 ± 4 at T0; 22.7 ± 4 at T1; 22.9 ± 4 at T2), whereas a significant difference was found between the study and control groups, both in T1 and in T2. No differences were found in ADL and IADL scores between the two groups. A slight but not statistically significant difference was found in GDS score between the study and control groups (P = 0.06). No adverse events were recorded. CONCLUSION: In this study, citicoline was effective and well tolerated in patients with mild vascular cognitive impairment. Citicoline activates biosynthesis of phospholipids in neuronal membranes, increases brain metabolism as well as norepinephrine and dopamine levels in the central nervous system, and has neuroprotective effects during hypoxia and ischemia. Therefore, citicoline may be recommended for patients with mild vascular cognitive impairment.

Retrospective and observational study to assess the efficacy of citicoline in elderly patients suffering from stupor related to complex geriatric syndrome.

A significant percentage of elderly subjects (50%-80%) suffering from sub-acute ischemic cerebrovascular disease, with or without moderate or severe cognitive memory decline and with or without associated behavioral and psychological symptoms, shows a complex syndrome. This syndrome is related to the progressive impairment of health conditions and/or stressing events (ie, hospitalization), characterized by confusion and/or stupor, which are consequently difficult to manage and require a great deal of care. Geriatric patients often suffer from multiple chronic illnesses, may take numerous medications daily, exhibit clinical instability, and may experience worsening of medical conditions following cerebral ischemic events and thus have an increased risk of disability and mortality. There are several studies in literature which demonstrate the efficacy of citicoline, thanks to its neuroprotective function, for the recovery and in postischemic cerebral rehabilitation. It has been shown that, even soon after an ischemic stroke, administration of oral citicoline (500-4000 mg/day) improves the general conditions evaluated with the Rankin scale and the National Institute of Health Stroke Scale 12. In particular, it has been shown that the CDP-choline improves the cognitive and mental performance in Alzheimer's dementia and vascular dementia. We have evaluated the administration of citicoline in geriatric patients following a protocol of intravenous study on improvement of individual performances.