The Treatment Of Vascular Cognitive Impairment With Fluoxetine

Vascular cognitive impairment (VCI) is a spectrum of cognitive impairments caused by or associated with vascular risk factors, including vascular cognitive impairment no dementia, vascular dementia and mixed dementia. Vascular risk factors have played a very important role in the pathogenesis of vascular cognitive impairment. In China, up to30%of stroke patients develop post-stroke cognitive impairment or delayed dementia after stroke. However, no drugs are licensed for the treatment of VCI, and treatment of VCI is limited to controlling known vascular risk factors. Recently, selective serotonin reuptake inhibitors (SSRIs) have been shown to improve motor function and cognition in patients with stroke. A small retrospective clinical study of selective serotonin reuptake inhibitor showed benefits on the Executive Interview in patients with VCI. A preclinical study found that SSRIs had direct effects on brain functions associated with plasticity, neurogenesis, and neuronal differentiation.Brain-derived neurotrophic factor (BDNF) is abundant in the brain and periphery, an important member of the neurotrophin family of growth factors and plays a key role in regulating survival, maintenance and growth of neurons. In addition to its involvement in neuronal survival, growth, and differentiation, BDNF also plays a crucial role in learning and memory. Evidence shows that BDNF can cross the blood-brain barrier, and a positive correlation was found between serum and cortical BDNF levels. However, there are no related research about effect of fluoxetine on the cognition and serum BDNF of patients with vascular cognitive impairment. In light of the observed beneficial effects of SSRIs, we hypothesized that SSRIs would improve cognition and increase the serum level of BDNF in patients with VCI. PART ONECorrelation between Serum BDNF levels and Cognitive functions in Patients with Vascular Cognitive ImpairmentObjective Correlation analysis about serum BDNF levels and cognitive functions in patients with vascular cognitive impairment.Method100patients with vascular cognitive impairment (50vascular dementia and50vascular cognitive impairment no dementia) were collected according to the inclusion criteria and exclusion criteria. Serum BDNF levels of patients with VCI were measured with an enzyme-linked immuno sorbent assay (ELISA) according to the manufacturer’s protocol. The participants’cognitive function were examined, including mini-mental state examination (MMSE), verbal fluency test (VFT), digit span test (DST) and ten point clock drawing test (TPC). Then the correlation between serum BDNF levels and cognitive function was examined.Result Between June9,2012, and June10,2013, a total of100patients with VCI were enrolled in the study.95participants had the history of stroke and the history of stroke was more than3months. Serum BDNF level (across groups) was significantly correlated with MMSE score (R=0.480, P<0.0001), VFT (R=0.464, P<0.0001), DST (R=0.339, P=0.001), TPC (R=0.443, P<0.0001) and hypertention (R=0.280, P=0.005). However, baseline serum BDNF level was not significantly correlated with gender (R=-0.024, P=0.810), age (R=-0.178, P=0.076), body mass index (R=0.107, P=0.289), hypercholesterolaemia (R=-0.073, P=0.469), Diabetes Mellitus (R=0.002, P=0.983), smoking (R=-0.011, P=0.916), Cardiovascular disease (R=0.102, P=0.311) and years of education (R=0.241, P=0.216) in patients with vascular cognitive impairment.Conclusion Cognitive function was positive correlated with serum BDNF levels in patients with vascular cognitive impairment significantly. PART TWOEffects of Fluoxetine on Brain-derived Neurotrophic Factor Serum Concentration and Cognition in Patients with Vascular DementiaObjective Selective serotonin reuptake inhibitors (SSRIs) improve cognition in patients with stroke, and increase the expression of BDNF in the rat hippocampus. However, the effects of SSRIs on cognition and serum BDNF level in vascular dementia (VaD) patients are largely unknown. We performed an open-label study to investigate the effects of fluoxetine on cognition and serum BDNF level in VaD patients.Method Fifty VaD patients were randomly allocated to receive fluoxetine (20mg/d; n=25) or no fluoxetine (control group; n=25) for12weeks. Further more, both groups received secondary prevention of stroke. Serum BDNF level, MMSE score, Ten-Point Clock Drawing (TPC) score, and Digit Span Test (DST) score and Verbal Fluency Test (VFT) score were measured at baseline and week12in the both groups.Results Between June9,2012, and June10,2013, a total of50patients were enrolled in the study. Twenty-five patients were assigned to the fluoxetine group and25patients were assigned to the control group. All of patients completed the12-week follow-up. We found no statistically significant differences between the two groups with respect to age (P=0.562), gender (P=0.777), body mass index (P=0.734), years of education (P=0.306), smoking(P=0.771), hypertention(P=0.564), diabetes mellitus(P=0.258), hypercholesterolaemia(P=0.571), cardiovascular disease(P=0.564), TPC score(P=0.330), and DST score(P=0.251), VFT score(P=0.231), MMSE score (P=0.490), or BDNF level (P=0.885). MMSE score (P=0.031), TPC score (P=0.007) and serum BDNF level (P<0.0001) increased significantly in the fluoxetine group but not in the control group. However the DST score (P=0.342) and VFT score (P=0.660) did not change significantly in the both groups, after12weeks treatment. Furthermore, the increase in serum BDNF level correlated significantly with the increase in MMSE score (R=0.413, P=0.04) and TPC (R=0.460, P=0.001) but did not correlated with VFT (R=0.172, P=0.233) and DST (R=0.123, P=0.394) in the fluoxetine group.Conclusion SSRIs may potentially improve cognition in VaD patients and requires further investigation. BDNF may play an important role in cognitive recovery in patients with VaD. PART THREEEffects of Fluoxetine on Cognition and Brain-derived Neurotrophic Factor Serum Concentration in Patients with Vascular Cognitive Impairment noDementiaObjective We performed an open-label study to investigate the effects of fluoxetine on cognition and serum BDNF level in VCIND patients.Method It was an open label study. Fifty VCIND patients were randomly allocated to receive fluoxetine (20mg/d; n=25) or no fluoxetine (control group; n=25) for12weeks. The patients also received secondary prevention of stroke in the both groups. The primary outcome and secondary outcome was of assessment of MMSE score, Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog) score, TPC, VFT, Trail Making Test form a (TMTa), Trail Making Test form b (TMTb), DST score and serum BDNF level at baseline and week12in the both groups.Results Between June9,2012, and June10,2013, a total of50VCIND patients were enrolled in the study. Twenty-five patients were assigned to the fluoxetine group and25patients were assigned to the control group. We found no statistically significant differences between the two groups with respect to age (P=0.800), gender (P=0.571), body mass index (P=0.640), years of education (P=0.796), smoking(P=0.083), hypertention(P=0.564), diabetes mellitus(P=0.254), hypercholesterolaemia(P=0.571), cardiovascular disease(P=0.777), TPC score(P=0.326), and DST score(P=0.330), VFT score(P=0.827), TMTa score(p=0.125), TMTb score(p=0.171), ADAS-Cog score(p=0.759), MMSE score (P=0.947), or BDNF level (P=0.176). There were significant differences in mean change from baseline in serum BDNF levels (P=0.023), MMSE score (P=0.013), TPC score (P=0.017), TMTa score (P=0.03) and TMTb score (P<0.0001) in the fluoxetine group compared with control group. However, we found no significant differences in mean change from baseline between fluoxetine and control in the primary endpoints of ADAS-Cog score (P=0.08), DST score (P=0.442) and VFT score (P=0.595). Furthermore, the increase in serum BDNF level correlated significantly with the increase in MMSE score (R=0.442, P=0.035), TPC (R=0.538, P=0.008), TMTa (R=-0.646, P=0.001), TMTb (R=-0.590, P=0.003) but did not correlated with VFT (R=0.013, P=0.954), ADAS-Cog (R=-0.403, P=0.056) and DST (R=0.227, P=0.297) in the fluoxetine group.Conclusion Fluoxetine may be an alternative treatment for improving cognitive impairment in patients with VCIND. BDNF may play an important role in cognitive recovery in patients with VCIND.