The Effect of the Association between Donepezil and Choline Alphoscerate on Behavioral Disturbances in Alzheimer’s Disease: Interim Results of the ASCOMALVA Trial

Abstract

Background: Behavioral and psychological symptoms of dementia (BPSD) are a group of psychological reactions, psychiatric symptoms, and behaviors commonly found in Alzheimer’s disease (AD). Four clusters of BPSD have been described: mood disorders (depression, anxiety, and apathy), psychotic symptoms (delusions and hallucinations), aberrant motor behaviors (pacing, wandering, and other purposeless behaviors), and inappropriate behaviors (agitation, disinhibition, and euphoria). Most of them are attributed to acetylcholine deficiency.

Objective: To evaluate if a higher amount of acetylcholine obtained by associating donepezil and choline alphoscerate might have a favorable effect on BPSD.

Methods: BPSD were measured at baseline and after 24 months in 113 mild/moderate AD patients, included in the double-blind randomized trial ASCOMALVA, by the Neuropsychiatric Inventory (NPI). Two matched groups were compared: group A treated with donepezil (10 mg/day) plus choline alphoscerate (1200 mg/day), and group B treated with donepezil (10 mg/day) plus placebo.

Results: Data of NPI revealed a significant decrease of BPSD severity and distress of the caregiver in patients of group A compared with group B. Mood disorders (depression, anxiety and apathy) were significantly decreased in subjects treated with donepezil and choline alphoscerate, while their severity and frequency was increased in the other group.

Conclusions: Patients treated with donepezil plus choline alphoscerate showed a lower level of behavioral disturbances than subjects treated with donepezil only, suggesting that the association can have beneficial effects.

Keywords

Alzheimer’s disease behavioral and psychological symptoms of dementia choline alphoscerate donepezil neuropsychiatric symptoms

INTRODUCTION

Behavioral and psychological symptoms of dementia (BPSD) are a group of psychological reactions, psychiatric symptoms, and behaviors often occurring in dementia patients [1, 2]. BPSD prevalence is of about 30% in the subjects living in the general community [3, 4] and rises to 80% in those living in nursing facilities [5]. Up to 90% of Alzheimer’s disease (AD) patients have at least one BPSD [6].

The impact of BPSD on direct and indirect costs of AD [7] leads to higher institutionalization rate [8, 9]. BPSD impair the quality of life of the caregivers [10], contributing to AD intangible costs, an aspect which is still overlooked, but which deserves attention and should thus be accurately evaluated [7]. On the other hand, BPSD raise ethical questions about care, autonomy, safety, and treatment. For instance, a reasonable question is what interventions and treatments could be recommended for dementia-related behaviors and if anti-psychotic medications are an acceptable therapy for the treatment of dementia-related behavioral disturbances. This due to the reported increased risk of mortality associated with antipsychotics in patients with BPSD [8 –10]. Several other ethical concerns come from the use of electronic tracking for AD individuals at risk for wandering [11].

Four clusters of BPSD have been described: mood disorders (depression, anxiety, and apathy/indifference), psychotic symptoms (delusions and hallucinations), aberrant motor behaviors (pacing, wandering, and other purposeless behaviors), and inappropriate behaviors (agitation, disinhibition, and euphoria), the last two more associated to faster cognitive and functional decline [12]. Genetic factors are related to each cluster [13, 14]. BPSD causes are still unclear. Besides the contribution of psychological and social aspects, including the premorbid personality, the environmental modifications, and the caregiving style, alterations of several neurotransmitters (GABA, serotonin, noradrenaline) and of the related pathways are certainly involved. Among them, the main role is attributed to acetylcholine reduction and consequent dysfunctions of the brain cholinergic system [15].

The treatment of BPSD [16] is essentially based on antipsychotics, antidepressants, and benzodiazepines. Antipsychotics can ameliorate the symptoms in the short term [17], but older subjects are very sensitive to their undesirable effects that may lead to a further functional decline and the risk of pharmacological interactions [18]. The safety profile of these compounds is also questionable in elderly people, having been reported that these compounds may increase the risk of cerebrovascular events [19 –21]. Antidepressants are effective essentially on depressive aspects [16]. Benzodiazepines, which are used if other agents have failed [22], may lead to increased confusion and falls, and rarely to a paradoxical increase of agitation in the elderly [23].

BPSD treatment is therefore unsatisfactory, and the anticholinergic propriety of many drugs used for treating various disorders, occurring often in the elderly, represents a further limitation [24]. Cholinergic dysfunctions are not only associated with cognitive impairment, but probably also with BPSD [25, 26]. This hypothesis is further supported by the reported benefits of treatment with cholinesterase inhibitors on BPSD [25, 26]. Rivastigmine, in fact, has been shown to reduce apathy, anxiety, depression, and delusions [27] and donepezil and galantamine to decreased delusion, hallucinations, agitation [28, 29], depression, apathy, and anxiety [27, 28].

From a theoretical point of view, symptoms caused directly or indirectly by impaired brain cholinergic neurotransmission could benefit from an enhanced cholinergic neurotransmission and by increasing acetylcholine bioavailability. In this study, we have explored this hypothesis by evaluating BPSD in two matched groups of AD subjects, treated for 24 months with a cholinesterase inhibitor alone (group A) or with the association of the same cholinesterase inhibitor to the cholinergic precursor choline alphoscerate (alpha-glyceryl-phosphorylcholine) (group B). Preclinical studies have shown that choline alphoscerate alone or in association with an acetylcholinesterase-inhibitor (AChE-I) has an enhancing effect on cholinergic transmission [30 –33]. Starting from these observations, we have investigated in a clinical trial the effect of association of choline alphoscerate with the AChE-Idonepezil on BPSD in AD. The activity of the association was compared to that of donepezil alone.

METHODS

Patients and study type

Patients described here were all included in the double blind randomized trial ASCOMALVA (Association between the Cholinesterase Inhibitor Donepezil and the Cholinergic Precursor Choline Alphoscerate in Alzheimer’s Disease). This trial was aimed to compare the cognitive effects of the treatment with donepezil plus the cholinergic precursor choline alphoscerate versus donepezil only in subjects with mild/moderate AD.

For clarity, the main characteristics of the ASCOMALVA study are detailed below. Further details are reported in previous studies of our group [34 –36]. Patients, diagnosed according to NINCDS-ADRDA criteria, were all in a mild/moderate-stage, showed brain ischemic lesions (in CT or MRI), and had at least two vascular risk factors (such as hypertension, diabetes, obesity, ischemic heart disease, hypercholesterolemia, hyperhomocysteinemia, smoking, previous cerebrovascular events, or family history of cardio-cerebrovascular diseases). This to confirm the diagnosis of cerebrovascular impairment [37, 38].Two matched groups were analyzed: one (group A) treated with donepezil 10 mg/day plus choline alphoscerate 1,200 mg/day (associative therapy), the other (group B) with donepezil 10 mg/day + placebo (mono therapy). 175 subjects out of the originally planned 210 were recruited and 29 dropped out (12 in the donepezil only group, and 17 in the associative therapy group) for different causes, indicated in Table 1. The interim results reported in this paper involved 113 subjects treated for 24 months. It was found, at 24 months of treatment, that group A subjects performed significantly better than group B on cognitive [Mini Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale Cognitive subscale (ADAS-Cog)], functional [Basic Activities of Daily Living (BADL), Instrumental Activities of Daily Living (IADL)], and behavioral scales [Neuropsychiatric Inventory (NPI)] [34 –36].

This paper refers to the same patient population already described [34 –36] and was aimed to provide a more accurate evaluation of the behavioral effect observed on the different sub-items of the NPI. This to assess if any specific symptom or symptomscluster was influenced by the therapy. BPSD presence and severity was investigated at the baseline, after 12 months and after 24 months by the NPI relatively to each of its sub-items. The severity of the caregiver distress by the NPI-Distress of caregiver was assessed as well. The sample consists of 113 subjects, whose demographic characteristics are reported in Table 2. All subjects were community dwelling, were enrolled in the study at least 6 months after the diagnosis, and none had received any specific previous treatment. The other psychoactive drugs assumed by each patient at the baseline and the follow up were registered together with their eventual dosage changes. These drugs were classified into three categories: antipsychotics, antidepressants, andanxiolytics.

Procedures

BPSD presence and severity were measured by the subscales of the Neuropsychiatric Inventory NPI [39]. The NPI assesses the frequency and the severity of the symptoms and the caregiver distress in 12 behavioral domains (delusions, hallucinations, depression/dysphoria, anxiety, agitation/aggression, elation/euphoria, disinhibition, irritability/lability, apathy/indifference, aberrant motor activity, sleep/night time behavior, and appetite/eating) [39]. NPI is given as an interview questionnaire, and neuropsychiatric manifestations within each domain are rated by the caregiver in terms of both frequency (1–4) and severity (1–3), yielding a composite symptom domain score (frequency×severity: NPI-F). The caregiver distress (NPI-D) is rated for each positive neuropsychiatric symptom domain by scores from 0 (no distress) to 5 (extreme distress). The total composite score is obtained by summing up the single item score, which may range from 0 to 144, with higher scores indicating more behavioral problems. In addition, a score for the caregiver stress is assigned for each type of the abnormal behavior found. The total distress score may range from 0 to 60, with higher scores indicating more severe distress suffered by thecaregiver.

Statistics

The correlation between the age and gender of the whole sample and the severity of behavioral symptoms (NPI-F) was assessed by the test of Pearson.

NPI-F, NPI-D, and each sub-item was evaluated at baseline and each follow up. Analysis of variance of variance (ANOVA) and multivariate ANOVA were used. A two tailed Student “t” test was then used to evaluate the significance of differences between each group. To assess if the use of antidepressants, anxiolytics, and antipsychotics modified significantly the severity of symptoms, chi square test (χ²) wasemployed.

RESULTS

The 113 patients investigated (43 M), were treated with donepezil (10 mg/day) + choline alphoscerate (1200 mg/day) (n = 57, group A) or with donepezil +placebo (10 mg/day) (n = 56, group B). Groups were matched for age (76±8 y in group A, 78±5 y in group B) and sex (23 males in group A, 20 in group B) and MMSE at baseline. The distribution of mild/moderate cases within the two groups are detailed in Table 2. Vascular risk factors were found in both groups. Arterial hypertension was the most common (87.4%), followed by a family history of cardio-cerebrovascular diseases (74.8%), hypercholesterolemia (61.4%), diabetes (29.9%), smoking (28.3%), obesity (26.8%), hypertriglyceridemia (24.4%), previous ischemic stroke (20.5%), transient ischemic attack (17.3%), ischemic heartdisease (14.2%), and hyperhomocysteinemia (0.8%). No differences between groups in the total number of vascular factors were noticeable (Table 3). Composite cardiovascular [40] and cerebrovascular [41] burden were also calculated, and showed no significant differences within the two groups (data notshown).

The correlation between the age of the whole sample and the severity of behavioral symptoms (NPI-F) showed no differences at the baseline nor after 24 months (Fig. 1). At baseline, the severity of behavioral symptoms (NPI-F) was greater in females (NPI-F = 22) than in males (NPI-F = 16). After 24 months, the NPI-F female averaged 24.9 and the NPI-F male 24.2 (Fig. 2), indicating that baseline differences did no longer occur at the end of the observation time. Among the different neuropsychiatric symptoms, agitation (13%), depression (21%), anxiety (15%), apathy (18%), and irritability (12%) were mostly found (Fig. 3).

At the baseline, the global NPI severity and frequency (NPI-F) and the caregiver distress (NPI-D) were not different between groups (Table 4), whereas after two years of treatment the NPI-F and NPI-D in group A subjects were significantly lower than in group B (Table 4). Variations from baseline of NPI-F and NPI-D are shown in Fig. 4a and 4b, respectively. Assessment of each single NPI item showed that, after treatment, group A subjects had less depression and apathy than group B subjects (Table 4), whereas anxiety was reduced significantly in group A and not in group B subjects (Table 5).

Table 6 summarizes data on patients taking psychoactive drugs (antidepressants, anxiolytics, and antipsychotics), including the mean doses of different compounds used. After 24 months, the global assumption of antidepressants and anxiolytics decreased, whereas administration of antipsychotics increased (Fig. 5). On comparing the two treatment groups investigated, after 24 months, the use of antipsychotic drugs increased and the use of anxiolytics decreased in both groups. Antidepressants use remained the same as in the group A, but decreased in the group B (Fig. 6).

Consumption of antidepressants and anxiolytics was compared versus the improvement in apathy and anxiety by the chi square test (χ²) (Fig. 7). Among subjects in which depression was improved, 56% were in group A and only the 12% of those used antidepressants for 24 months. In subjects in which apathy improved, one half was in group A, and none of them were treated with antidepressants. In subjects with anxiety improved, 62.1% belonged to the group A, and only 6.9% used anxiolytics at the 24th month of observation (Fig. 7).

DISCUSSION

The BPSD, a group of very common symptoms in AD [39], can be assessed by standardized instruments such as the NPI [39, 42]. Leading to high disability and poor quality of life [43], BPSD are a further cause of distress in caregivers [44, 45] and the main reason of the early institutionalization of patients [46]. The occurrence of BPSD raises several ethical and legal medical problems such as to establish the level of remaining autonomy, such as if patients are still able to have enough understanding/knowledge about their disease to decide on their treatment and make plans for the future [47, 48]. Another relevant ethical problem is the opportunity of treating BPSD with antipsychotic drugs. These compounds are at high risk of adverse events, even at modest doses, and may interfere with the progression of cognitive impairment. Moreover, they could interact with several drugs including anti-arrhythmics andAChE-I [49].

Causes and pathophysiology of BPSD are incompletely understood. These problems have been associated with the imbalance of several neurotransmitters and particularly to a cholinergic dysfunction in several brain regions including the limbic system (hippocampus, amygdala, anterior thalamus, hypothalamus, basal forebrain, mammillary bodies, and septal area) and the cingulated, orbitofrontal, and parahippocampal cortices[42 , 51]. The high levels of acetylcholinesterase (AChE), found in the hippocampus, amygdala, and thalamus, have suggested that the inhibition of this enzyme might be useful for treating BPSD [52]. This hypothesis was supported from studies showing a beneficial effect of ChEI on BPSD reduction[27 , 56] and specific activity of donepezil in particular on some symptoms, such as apathy, anxiety, agitation, and depression [28, 57].

In this work, we have evaluated the BPSD burden in 113 mild/moderate AD subjects, all included in the double-blind trial ASCOMALVA. We have found that subjects treated with the association of donepezil and choline alphoscerate had a lower NPI score. The caregiver stress of these subjects was, accordingly, lower. A significant difference was found in the cluster “mood disorders” of the BPSD, which refers to depression, anxiety, and apathy/indifference. This cluster of symptoms has been attributed to the disconnection between the neocortex and the basal nuclei, which would deprive the cortex of its major source of acetylcholine. Consequently, the ability to properly process the emotional significance of stimuli would be impaired [58], leading to apathy [19]. Theoretically, apathy would improve if higher levels of acetylcholine would be available, an aspect we have already described [36]. Beneficial effects of donepezil on depression and anxiety have already been reported [28 , 59]. This study has shown that the association of donepezil to choline alphoscerate has greater efficacy on symptoms of mood disorders such as apathy, depression, and anxiety, improving them more than when donepezil was administered alone.

It might be hypothesized that the occurrence of vascular lesions and risk factors in our sample may represent a limit to the generalization of the results to the whole AD population. However, it should be considered that the presence of cerebrovascular injury occurs in the majority of AD subjects [37]. Hence, AD degeneration plus vascular damages probably is the prevalent phenotype of these subjects [37]. It may be worthy, furthermore, to underline that the vascular burden did not show differences between thegroups.

AD patients’ treatment obviously included other drugs, whose potential interference has been considered. We have therefore evaluated if any significant difference in the assumption of psychoactive drugs (antipsychotics, antidepressant, and anxiolytics) occurred in the two treatment groups. This analysis has shown that the percentage of patients assuming antipsychotics was higher in both groups after 24 months, compared to the baseline. Thesefindings indicate the progression of AD. However, most patients with improved mood symptoms after 24 months did not take antidepressants and anxiolytics, suggesting that this improvement can be related to the cholinergic effect. The antidepressants and anxiolytics administered to our patients probably have a weak, if any, cholinergic effect as only trazodone has some anti-cholinergic activity [60], whereas duloxetine, the most used, has no effect at all. Among the antipsychotics neither quetiapine nor risperidone interfere with the cholinergic neurotransmission [61].

This study has strengths and weaknesses: the longtime of observation and treatment (24 months) represent strengths, while the size of the sample and the nature of the post hoc type of data are weaknesses. We are also aware that the NPI score, being dependent from the caregiver input, is influenced by the caregiver mood, his burden, and belief system [62, 63].However, this test is, up to now, one of the most widely used in clinical trials on the BPSD. Finally, we are aware that the prescription of psychiatric drugs usually cuts across their specific categories, i.e., antipsychotics are frequently used as “tranquillizers” and antidepressants to treat anxiety [64]. Future developments of this research should include a longer observation period and the stratification of the sample according to the severity of the neuropsychiatric symptoms.

In conclusion, globally our findings suggest that the association of donepezil (10 mg/day) to choline alphoscerate (1200 mg/day) may be a beneficial option in reducing BPSD of mild/moderate AD patients and should be considered especially when BPSD are unresponsive to donepezil only, or when the caregivers are unsatisfied with donepezil alone. Beneficial effects should also be evaluated in terms of the reduction of other potentially dangerous drugs given for the BPSD. A larger clinical trial is obviously warranted to further determine the efficacy and the advantages of the treatment.

Footnotes

ACKNOWLEDGMENTS

Authors are indebted to MDM SpA (Milan, Italy) for the complimentary supply of choline alphoscerate (test drug, Delecit^® , and placebo) used in this study and for the fellowships to the PhD students Anna Carotenuto and Raffaele Rea.

Authors’ disclosures available online ()

References

Benoit

, Brocker

, Clement

, Cnockaert

, Hinault

, Nourashemi

, Pancrazi

, Portet

, Robert

, Thomas

, Verny

, Groupe de consensus Théma 2 (2005) Behavioral and psychological symptoms in dementia: Description and management. Rev Neurol (Paris) 161, 357–366.

(1996) Behavioral and psychological signs and symptoms of dementia: Implications for research treatment. Proceedings of an international consensus conference. Lansdowne, Virginia, April 1996. Int Psychogeriatr 8(Suppl 3), 215–552.

Lawlor

(2002) Managing behavioural and psychological symptoms in dementia. Br J Psychiatry 181, 463–465.

Lyketsos

, Steinberg

, Tschanz

, Norton

, Steffens

, Breitner

(2000) Mental and behavioral disturbances in dementia: Findings from the Cache County Study on Memory in Aging. Am J Psychiatry 157, 708–714.

Margallo-Lana

, Swann

, O’Brien

, Fairbairn

, Reichelt

, Potkins

, Mynt

, Ballard

(2001) Prevalence and pharmacological management of behavioural and psychological symptoms amongst dementia sufferers living in care environments. Int J Geriatr Psychiatry 16, 39–44.

Fernández

, Gobartt

, Balañá

, the COOPERA Study Group (2010) Behavioural symptoms in patients with Alzheimer’s disease and their association with cognitive impairment. BMC Neurol 10, 87.

Colucci

, Bosco

, Fasanaro

, Gaeta

, Ricci

, Amenta

(2014) Alzheimer’s disease costs: What we know and what we should take into account. J Alzheimers Dis 42, 1311–1324.

Johnson

, Karlawish

(2015) A review of ethical issues in dementia. Int Psychogeriatr 27, 1635–1647.

Christensen

, Lin

(2007) Practical treatment strategies for patients with Alzheimer’s disease. J Fam Pract 56(12 Suppl New), S17–S23.

10.

Greenblatt

, Greenblatt

(2016) Use of antipsychotics for the treatment of behavioral symptoms of dementia. J Clin Pharmacol 56, 1048–1057.

11.

Faucounau

, Riguet

, Orvoen

, Lacombe

, Rialle

, Extra

, Rigaud

(2009) Electronic tracking system and wandering in Alzheimer’s disease: A case study. Ann Phys Rehabil Med 52, 579–587.

12.

Miller

, Tinklenberg

, Brooks

3rd , Fenn

, Yesavage

(1993) Selected psychiatric symptoms associated with rate of cognitive decline in patients with Alzheimer’s disease. J Geriatr Psychiatry Neurol 6, 235–238.

13.

Harvey

, Ellison

, Hardy

, Hutton

, Roques

, Collinge

, Fox

, Rossor

(1998) Chromosome 14 familial Alzheimer’s disease: The clinical and neuropathological characteristics of a family with a leucine–>serine (L250S) substitution at codon 250 of the presenilin 1 gene. J Neurol Neurosurg Psychiatry 64, 44–49.

14.

Sukonick

, Pollock

, Sweet

, Mulsant

, Rosen

, Klunk

, Kastango

, DeKosky

, Ferrell

(2001) The 5-HTTPR*S/*L Polymorphism and aggressive behavior in Alzheimer disease. Arch Neurol 58, 1425–1428.

15.

Pinto

, Lanctot

, Herrmann

(2011) Revisiting the cholinergic hypothesis of behavioral and psychological symptoms dementia of the Alzheimer’s type. Ageing Res Rev 10, 404–412.

16.

Kozman

, Wattis

, Curran

(2006) Pharmacological management of behavioral and psychological disturbance in dementia. Hum Psychopharmacol Clin Exp 21, 1–12.

17.

Ballard

, Waite

(2006) The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev, CD003476.

18.

Eggermont

, de Vries

, Scherder

(2009) Psychotropic medication use and cognition in institutionalized older adults with mild to moderate dementia. IntPsychogeriatr 21, 286–294.

19.

Douglas

, Smeeth

(2008) Exposure to antipsychotics and risk of stroke: Self controlled case series study. BMJ 337, a1227.

20.

Wang

, Schneeweiss

, Avorn

, Fischer

, Mogun

, Solomon

, Brookhart

(2005) Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 353, 2335–2341.

21.

Kales

, Valenstein

, Kim

, McCarthy

, Ganoczy

, Cunningham

, Blow

(2007) Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medication. Am J Psychiatry 164, 1568–1576.

22.

Profenno

, Tariot

(2004) Pharmacologic management of agitation in Alzheimer’s disease. Dement Geriatr Cogn Disord 17, 65–77.

23.

Hersch

, Falzgraf

(2007) Management of the behavioral and psychological symptoms of dementia. Clin Interv Aging 2, 611–621.

24.

Beier

(2007) Treatment strategies for the behavioral symptoms of Alzheimer’s disease: Focus on early pharmacologic intervention. Pharmacotherapy 27, 399–411.

25.

Lemstra

, Eikelenboom

, van Gool

(2003) The cholinergic deficiency syndrome and its therapeutic implications. Gerontology 49, 55–60.

26.

Brousseau

, Rourke

, Burke

(2007) Acetylcholinesterase inhibitors, neuropsychiatric symptoms, and Alzheimer’s disease subtypes: An alternate hypothesis to global cognitive enhancement. Exp Clin Psychopharmacol 15, 546–554.

27.

Rösler

(2002) The efficacy of cholinesterase inhibitors in treating the behavioural symptoms of dementia. Int J Clin Pract Suppl 127, 20–36.

28.

Cummings

, McRae

, Zhang

, Donepezil-Sertraline Study Group (2006) Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders. Am J Geriatr Psychiatry 14, 605–612.

29.

Herrmann

, Rabheru

, Wang

, Binder

(2005) Galantamine treatment of problematic behavior in Alzheimer disease: Post-hoc analysis of pooled data from three large trials. Am J Geriatr Psychiatry 13, 527–534.

30.

Sigala

, Imperato

, Rizzonelli

, Casolini

, Missale

, Spano

(1992) L-alpha-glycerylphosphorylcholine antagonizes scopolamine-induced amnesia and enhances hippocampal cholinergic transmission in the rat. Eur J Pharmacol 211, 351–358.

31.

Amenta

, Tayebati

, Vitali

, Di Tullio

(2006) Association with the cholinergic precursor choline alphoscerate and the cholinesterase inhibitor rivastigmine: An approach for enhancing cholinergic neurotransmission. Mech Ageing Dev 127, 173.

32.

Tayebati

, Di Tullio

, Tomassoni

, Amenta

(2009) Neuroprotective effect of treatment with galantamine and choline alphoscerate on brain microanatomy in spontaneously hypertensive rats. J Neurol Sci 283, 187–194.

33.

Traini

, Bramanti

, Amenta

(2013) Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline- containing phospholipid with a still interesting profile as cognition enhancing agent. Curr Alzheimer Res 10, 1070–1079.

34.

Amenta

, Carotenuto

, Fasanaro

, Rea

, Traini

(2014) The ASCOMALVA (Association between the Cholinesterase Inhibitor Donepezil and the Cholinergic Precursor Choline Alphoscerate in Alzheimer’s Disease) Trial: Interim results after two years of treatment. J Alzheimers Disease 42, S281–S288.

35.

Amenta

, Carotenuto

, Fasanaro

, Rea

, Traini

(2012) The ASCOMALVA trial: Association between the cholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate in Alzheimer’s disease with cerebrovascular injury: Interim results. J Neurol Sci 322, 96–101.

36.

Rea

, Carotenuto

, Traini

, Fasanaro

, Manzo

Valentino

, Amenta

(2015) Apathy treatment in Alzheimer’s disease. Interim results of the ASCOMALVA Trial. J Alzheimers Dis 48, 377–83.

37.

Agüero-Torres

, Kivipelto

, von Strauss

(2006) Rethinking the dementia diagnoses in a population-based study: What is Alzheimer’s disease and what is vascular dementia? A study from the Kungsholmen project. Dement Geriatr Cogn Disord 22, 244–249.

38.

Carotenuto

, Rea

, Colucci

, Ziello

, Molino

, Carpi

, Traini

, Amenta

, Fasanaro

(2012) Late and early onset dementia: What is the role of vascular factors? A retrospective study. J Neurol Sci 322, 170–175.

39.

Mega

, Cummings

, Fiorello

, Gornbein

(1996) The spectrum of behavioral changes in Alzheimer’s disease. Neurology 46, 130–135.

40.

D’Agostino

, Wolf

, Belanger

, Kannel

(1994) Stroke risk profile: Adjustment for antihypertensive medication. The Framingham Study. Stroke 25, 40–43.

41.

Kivipelto

, Ngandu

, Laatikainen

, Winblad

, Soininen

, Tuomilehto

(2006) Risk score for the prediction of dementia risk in 20 years among middle aged people: A longitudinal, population-based study. Lancet Neurol 5, 735–741.

42.

Cummings

, Mega

, Gray

, Rosenberg-Thompson

, Carusi

, Gornbein

(1994) The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 44, 2308–2314.

43.

González-Salvador

, Lyketsos

, Baker

, Hovanec

, Roques

, Brandt

, Steele

(2000) Quality of life in dementia patients in long-term care. Int J Geriatr Psychiatry 15, 181–189.

44.

Swearer

, Drachman

, O’Donnell

, Mitchell

(1988) Troublesome and disruptive behaviors in dementia. Relationships to diagnosis and disease severity. J Am Geriatr Soc 36, 784–790.

45.

Black

, Almeida

(2004) A systematic review of the association between the behavioral and psychological symptoms of dementia and burden of care. Int Psychogeriatr 16, 295–315.

46.

Steele

, Rovner

, Chase

, Folstein

(1990) Psychiatric symptoms and nursing home placement of patients with Alzheimer’s disease. Am J Psychiatry 147, 1049–1051.

47.

Colijn

MA1

, Nitta

, Grossberg

(2015) Psychosis in later life: A review and update. Harv Rev Psychiatry 23, 354–367.

48.

Bronner

, Perneczky

, McCabe

, Kurz

, Hamann

(2016) Which medical and social decision topics are important after early diagnosis of Alzheimer’s disease from the perspectives of people with Alzheimer’s disease, spouses and professionals? BMC Res Notes 9, 149.

49.

Pasqualetti

, Tognini

, Calsolaro

, Polini

, Monzani

(2015) Potential drug-drug interactions in Alzheimer patients with behavioral symptoms. Clin Interv Aging 10, 1457–1466.

50.

Cummings

, Back

(1998) The cholinergic hypothesis of neuropsychiatric symptoms in Alzheimer’s disease. Am J Geriatr Psychiatry 6(2 Suppl 1), 64–78.

51.

Callen

DJA

, Black

, Caldwell

(2002) Limbic system perfusion in Alzheimer’s disease measured by MRI-coregistered HMPAO SPET. Eur J Nucl Med Mol Imaging 29, 899–906.

52.

Rodda

, Morgan

, Walker

(2009) Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer’s disease? A systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr 21, 813–824.

53.

Sasakia

, Yoshiharu

(2014) The effects of an uninterrupted switch from donepezil to galantamine without dose titration on behavioral and psychological symptoms of dementia in Alzheimer’s disease. Dement Geriatr Cogn Dis Extra 4, 131–139.

54.

Tariot

, Solomon

, Morris

, Kershaw

, Lilienfeld

, Ding

(2000) A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology 54, 2269–2276.

55.

Holmes

, Wilkinson

, Dean

, Vethanayagam

, Olivieri

, Langley

, Pandita-Gunawardena

, Hogg

, Clare

, Damms

(2004) The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 63, 214–219.

56.

Lockhart

, Orme

, Mitchell

(2011) The efficacy of licensed-indication use of donepezil and memantine monotherapies for treating behavioural and psychological symptoms of dementia in patients with Alzheimer’s disease: Systematic review and meta-analysis. Dement Geriatr Cogn Dis Extra 1, 212–227.

57.

Gauthier

, Feldman

, Hecker

, Vellas

, Ames

, Subbiah

, Whalen

, Emir

, Donepezil MSAD Study Investigators Group (2002) Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr 14, 389–404.

58.

Cummings

, Kaufer

(1996) Neuropsychiatric aspects of Alzheimer’s disease: The cholinergic hypothesis revisited. Neurology 47, 876–883.

59.

Feldman

, Gauthier

, Hecker

, Vellas

, Subbiah

, Whalen

, Donepezil

MSAD Study Investigators Group

(2001) A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 57, 613–620.

60.

Haria

, Fitton

, McTavish

(1994) Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging 4, 331–355.

61.

Bymaster

, Lee

, Knadler

, Detke

, Iyengar

(2005) The dual transporter inhibitor duloxetine: A review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des 11, 1475–1493.

62.

Cummings

, Mackell

, Kaufer

(2008) Behavioral effects of current Alzheimer’s disease treatments: A descriptive review. Alzheimers Dement 4, 49–60.

63.

Grimmer

, Kurz

(2006) Effects of cholinesterase inhibitors on behavioural disturbances in Alzheimer’sdisease: A systematic review. Drugs Aging 23, 957–967.

64.

Rang

, Ritter

, Flower

, Henderson

(2015) Rang and Dale’s Pharmacology, 8th Edition 2015. Churchill Livingstone/Elsevier.