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Background and Aim: Data on the clinical pharmacokinetics of cannabidiol (CBD) are scanty. We explored the effect of demographic and clinical variables on plasma concentrations of purified CBD in patients with Dravet (DS) and Lennox–Gastaut syndrome (LGS).Methods: The study design was an open, prospective, multicenter expanded access program (EAP). Venous blood samples were drawn from patients between 8 and 9 am, before the CBD morning dose, 12 h apart from the last evening dose, and then 2.5 h after their usual morning dose.Results: We collected 127 plasma samples (67-morning pre-dosing and 60 post-dosing) from 43 patients (24 females, 19 males), 27 with LGS and 16 with DS. Mean ± standard deviation age was 26 ± 15 years. Duration of CBD treatment averaged 4.2 ± 2.9 months at 13.2 ± 4.6 mg/kg/day. CBD median trough plasma concentration was 91 ng/ml; it doubled to 190 ng/ml 2.5 h post-dosing (p < 0.001). Cannabidiol trough plasma concentrations were linearly related to daily doses (r = 0.564, p < 0.001). Median trough CBD plasma concentration-to-weight-adjusted dose ratio (C/D) was 32% higher (p < 0.02) in plasma samples from subjects aged 18 and over than in those under 18. Sex and concomitant antiseizure medications (ASMs) were not associated with significant variations in CBD C/D, but caution is required due to the potential influence of confounders.Conclusion: These are the first data on CBD pharmacokinetics in children and adults with LGS or DS in a real-world setting. The most relevant finding was the higher CBD C/D in adults. In practice, reduced weight-normalized doses might be required with aging to achieve the same CBD plasma levels.

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65–89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid–femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P =0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10 −3 ; P =0.009); only the latter remained significant after adjustment for confounders ( P =0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P =0.006; P =0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34 + cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa −1 ; P =0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34 + cells, and preserved carotid distensibility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01725178.

Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value < 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype. Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value < 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype.

Background and aims: Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. Methods: Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer’s Disease (QOL-AD) scale. Results: After 7months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. Conclusions: Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can ‘live well’ with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline. Background and aims: Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. Methods: Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7 months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer’s Disease (QOL-AD) scale. Results: After 7 months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. Conclusions: Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can ‘live well’ with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline.