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

Abstract

Cholinesterase inhibitors (ChE-Is) are used for symptomatic treatment of mild-to-moderate Alzheimer's disease (AD), but long-term effects of these compounds are mild and not always obvious. Preclinical studies have shown that combination of ChE-Is and the cholinergic precursor choline alphoscerate increases brain acetylcholine levels more effectively than single compounds alone. ASCOMALVA (Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in AD associated with cerebrovascular injury) is a double-blind trial investigating if the ChE-I donepezil and choline alphoscerate in combination are more effective that donepezil alone. The trial has recruited AD patients suffering from ischemic brain damage documented by neuroimaging and has completed 2 years of observation in 113 patients of the 210 planned. Patients were randomly allotted to an active treatment group (donepezil + choline alphoscerate) or to a reference group (donepezil + placebo). Cognitive functions were assessed by the Mini-Mental State Evaluation and Alzheimer's Disease Assessment Scale Cognitive subscale. Daily activity was evaluated by the basic and instrumental activities of daily living tests. Behavioral symptoms were assessed by the Neuropsychiatric Inventory. Over the 24-month observation period, patients of the reference group showed a moderate time-dependent worsening in all the parameters investigated. Treatment with donepezil plus choline alphoscerate significantly slowed changes of the different items analyzed. These findings suggest that the combination of choline alphoscerate with a ChE-I may prolong/increase the effectiveness of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury.

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

“…For clarity, the main characteristics of the ASCO-MALVA study are detailed below. Further details are reported in previous studies of our group [34][35][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).…”

“…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 [34][35][36].…”

“…This paper refers to the same patient population already described [34][35][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 symptoms cluster was influenced by the therapy.…”

Unexpected Effects of Acetylcholine Precursors on Pilocarpine Seizure- Induced Neuronal Death

“…One core pathway that impinges on the pathophysiology of epilepsy is that of acetylcholine biosynthesis and neurotransmission, which has only recently been investigated in the field of epilepsy research [ 5 , 7 ]. Since cholinergic decline is known to be involved in the pathogenesis of Alzheimer’s disease and cognitive dysfunction after trauma or cerebrovascular attack, both acetylcholinesterase inhibitors and acetylcholine precursors are being readily used in the aforementioned fields [ 21 - 25 ]. Therefore, the use of choline precursors in Alzheimer’s disease requires special attention if the patients also have epilepsy.…”

“…Acetylcholine precursors such as choline alfoscerate (α-GPC) and cytidine 5’-diphosphocholine (CDP-Choline) are important intermediates in the synthesis of both acetylcholine and cell membrane phospholipids. The ability of acetylcholine precursors to reduce or prevent neuronal insult has been tested both in clinical and animal studies in the field of stroke and Alzheimer’s disease [ 21 , 23 , 26 , 27 ]. Clinical studies have demonstrated that cholinergic precursors improved from cognitive impairment in Alzheimer’s disease and vascular dementia [ 28 , 29 ].…”