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.

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.

Dose-dependent effects of the selective serotonin reuptake inhibitor citalopram: A combined SPECT and phMRI study.

BACKGROUND: Serotonin transporter blockers, like citalopram, dose-dependently bind to the serotonin transporter. Pharmacological magnetic resonance imaging (phMRI) can be used to non-invasively monitor effects of serotonergic medication. Although previous studies showed that phMRI can measure the effect of a single dose of serotoninergic medication, it is currently unclear whether it can also detect dose-dependent effects. AIMS: To investigate the dose-dependent phMRI response to citalopram and compared this with serotonin transporter occupancy, measured with single photon emission computed tomography (SPECT). METHODS: Forty-five healthy females were randomized to pre-treatment with placebo, a low (4 mg) or clinically standard (16 mg) oral citalopram dose. Prior to citalopram, and 3 h after, subjects underwent SPECT scanning. Subsequently, a phMRI scan with a citalopram challenge (7.5 mg intravenously) was conducted. Change in cerebral blood flow in response to the citalopram challenge was assessed in the thalamus and occipital cortex (control region). RESULTS: Citalopram dose-dependently affected serotonin transporter occupancy, as measured with SPECT. In addition, citalopram dose-dependently affected the phMRI response to intravenous citalopram in the thalamus (but not occipital cortex), but phMRI was less sensitive in distinguishing between groups than SPECT. Serotonin transporter occupancy showed a trend-significant correlation to thalamic cerebral blood flow change. CONCLUSION: These results suggest that phMRI likely suffers from higher variation than SPECT, but that these techniques probably also assess different functional aspects of the serotonergic synapse; therefore phMRI could complement positron emission tomography/SPECT for measuring effects of serotonergic medication.

Investigating the origin and evolution of cerebral small vessel disease: The RUN DMC - InTENse study.

BACKGROUND: Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. AIMS: (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD; (2) to assess to which extent these lesions explain progression of SVD imaging markers; (3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance; and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. DESIGN/METHODS: The RUN DMC - InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. DISCUSSION: Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies.