Decreased integrity of the monoaminergic tract is associated with a positive response to MPH in patients with vascular cognitive impairment - proof of principle study STREAM-VCI

Abstract

Background: Patients with vascular cognitive impairment (VCI) are very heterogeneous in both symptoms and type of cerebrovascular pathology. This might be an important reason why there is no symptomatic treatment available for VCI patients. In this study, we investigated in patients with VCI, whether there was an association between a positive response to methylphenidate and galantamine and the type of cerebrovascular disease, structural damage to specific neurotransmitter systems, cerebral perfusion, and presence of co-morbid Alzheimer (AD) pathology.

Methods: We included 27 VCI patients (mean age 67 years ± 8,30% female) from the STREAM-VCI trial who received placebo, methylphenidate(10 mg), and galantamine(16 mg) in a single challenge, cross-over design. In this study, we classified patients improving on a task for executive functioning after methylphenidate compared to placebo as methylphenidate responders (MPH+; resp. non-responders, MPH-) and patients improving on a task for memory after galantamine compared to placebo as galantamine responders (GAL+; resp. non-responders, GAL-). On baseline MRI, we visually assessed measures of cerebrovascular disease, automatically segmented white matter hyperintensities, used diffusion tensor imaging to visualize the integrity of monoaminergic and cholinergic neurotransmitter systems with mean diffusivity (MD) and fractional anisotropy (FA). Comorbid AD pathology was assessed using CSF or amyloid-PET. We tested differences between responders and non-responders using ANOVA, adjusting for age and sex.

Results: Nine patients were MPH+ vs 18 MPH-. MPH+ had higher MD (1.22 ± 0.07 vs 0.94 ± 0.05); p = .001) and lower FA (0.38 ± .01 vs 0.43 ± .01); p = .04) in the monoaminergic tract compared to MPH-. Eight patients were GAL+ and 18 GAL-. We found no differences between GAL+ and GAL- in any of the MRI measures. Information on co-morbid AD pathology was present in 17 patients. AD pathology tended to be more frequent in GAL+ vs GAL- (5(71%) vs 2(20%); p = .06).

Conclusions: In patients with VCI, we found that decreased integrity of the monoaminergic tract is associated with a positive response to MPH. Responsiveness to galantamine may be related to co-morbid AD pathology.

Keywords: Clinical trial; Cognition; Dementia; Galantamine; Methylphenidate; Small vessel disease; Vascular cognitive impairment; Vascular disease.