Methylphenidate and galantamine in patients with vascular cognitive impairment-the proof-of-principle study STREAM-VCI

Abstract

Background: To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients.

Methods: STREAM-VCI is a single-center, double-blind, three-way crossover trial. We included 30 VCI patients (Mini-Mental State Examination (MMSE) ≥ 16 and Clinical Dementia Rating score 0.5-1.0) with cerebrovascular pathology on MRI. All patients received single doses of methylphenidate (10 mg), galantamine (16 mg), and placebo in random order on three separate study visits. We used the NeuroCart®, a computerized test battery, to assess drug-sensitive cognitive effects. Predefined main outcomes, measured directly after a single dose of a study drug, were (i) change in performance on the adaptive tracker for executive functioning and (ii) performance on the Visual Verbal Learning Test-15 (VVLT-15) for memory, compared to placebo. We performed mixed model analysis of variance.

Results: The study population had a mean age of 67 ± 8 years and MMSE 26 ± 3, and 9 (30%) were female. Methylphenidate improved performance on the adaptive tracker more than placebo (mean difference 1.40%; 95% confidence interval [CI] 0.56-2.25; p = 0.002). In addition, methylphenidate led to better memory performance on the VVLT-15 compared to placebo (mean difference in recalled words 0.59; 95% CI 0.03-1.15; p = 0.04). Galantamine did not improve performance on the adaptive tracker and led to worse performance on delayed recall of the VVLT-15 (mean difference - 0.84; 95% CI - 1.65, - 0.03; p = 0.04). Methylphenidate was well tolerated while galantamine produced gastrointestinal side effects in a considerable number of patients.

Conclusions: In this proof-of-principle study, methylphenidate is well tolerated and improves executive functioning and immediate recall in patients with VCI. Galantamine did not improve memory or executive dysfunction. Results might be influenced by the considerable amount of side effects seen.

Trial registration: http://www.clinicaltrials.gov. Registration number: NCT02098824. Registration date: March 28, 2014.

Keywords: Cognition; Galantamine; MCI; Methylphenidate; Vascular cognitive impairment; Vascular dementia.

Conflict of interest statement

PS has acquired grant support (for the institution) from GE Healthcare, Nutricia Research, Piramal, and MERCK. In the past, he has received consultancy/speaker fees (paid to the institution) from Lilly, Biogen, Novartis, Probiodrug, Roche, and EIP Pharma. FB serves as a consultant for Biogen, Janssen, Bayer, Merck, Roche, Novartis, Lundbeck, and IXICO. He has received sponsoring from EU-H2020, IMDI, SMSR, TEVA, Novartis, Toshiba, and IMI and is supported by NIHR-UCLH Biomedical Research Center. WF performs contract research for Boehringer Ingelheim and has been an invited speaker at Boehringer Ingelheim. Research programs of WF have been funded by ZonMW, NWO, EU-FP7, Alzheimer Nederland, Cardiovasculair Onderzoek Nederland, stichting Dioraphte, Gieskes-Strijbis fonds, Boehringer Ingelheim, Piramal Neuroimaging, Roche BV, Janssen Stellar, and Combinostics. All funding is paid to her institution. NP serves on the advisory board of Boehringer Ingelheim and Probiodrug and on the DSMB of Abbvie’s M15-566 trial. NP is the CEO and co-owner of the Brain Research Center, Amsterdam, The Netherlands. He received research support from Alzheimer Nederland (STREAM-VCI project number WE.03-2012-02). The other authors declare that they have no competing interests.

Figures

Fig. 1

Overview of the activities on a study day. The arrows represent when a test round or test is started. CNS test round encompasses all tests with exception of the VVLT-15 and the FACE. At time point 0, the study medication was administered

Fig. 2

Effect of the study drugs on adaptive tracker. The shaded area represents the 95% CI. The estimated difference in mean change from baseline between methylphenidate and placebo was significant (p = 0.002)