Subclinical cognitive deficits are associated with reduced cerebrovascular response to visual stimulation in mid-sixties men.

Reduced cerebrovascular response to neuronal activation is observed in patients with neurodegenerative disease. In the present study, we examined the correlation between reduced cerebrovascular response to visual activation (ΔCBFVis.Act) and subclinical cognitive deficits in a human population of mid-sixties individuals without neurodegenerative disease. Such a correlation would suggest that impaired cerebrovascular function occurs before overt neurodegenerative disease. A total of 187 subjects (age 64-67 years) of the Metropolit Danish Male Birth Cohort participated in the study. ΔCBFVis.Act was measured using arterial spin labelling (ASL) MRI. ΔCBFVis.Act correlated positively with cognitive performance in: Global cognition (p = 0.046), paired associative memory (p = 0.025), spatial recognition (p = 0.026), planning (p = 0.016), simple processing speed (p < 0.01), and with highly significant correlations with current intelligence (p < 10-5), and more complex processing speed (p < 10-3), the latter two explaining approximately 11-13% of the variance. Reduced ΔCBFVis.Act was independent of brain atrophy. Our findings suggest that inhibited cerebrovascular response to neuronal activation is an early deficit in the ageing brain and associated with subclinical cognitive deficits. Cerebrovascular dysfunction could be an early sign of a trajectory pointing towards the development of neurodegenerative disease. Future efforts should elucidate if maintenance of a healthy cerebrovascular function can protect against the development of dementia.

Blood-brain barrier permeability changes in the first year after alemtuzumab treatment predict 2-year outcomes in relapsing-remitting multiple sclerosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), early disease control reduces the risk of permanent disability. The blood-brain barrier (BBB) is compromised in MS, and its permeability is a potential biomarker. OBJECTIVE: To investigate BBB permeability measured by MRI as a marker of alemtuzumab efficacy. METHODS: Patients with RRMS initiating alemtuzumab treatment were recruited prospectively. BBB permeability was assessed as the Patlak-derived influx constant (Ki) by dynamic contrast-enhanced MRI before and 6, 12, and 18 months after the first course of alemtuzumab. No Evidence of Disease Activity-3 (NEDA-3) status was ascertained two years after treatment initiation. RESULTS: Patients who maintained NEDA-3 status at two years (n = 7) had a larger decrease in Ki between baseline and six months (-0.029 ml/100 g/min [CI -0.005 - -0.053]) and between baseline and 12 months in normal appearing white matter (0.043 [CI 0.022 - -0.065]), than those who experienced disease activity (n = 8). ROC curve analysis of the Ki change between baseline and 12 months in NAWM predicted a loss of NEDA status at 2 years with 86% sensitivity and 86% specificity (AUC 0.98, p = 0.002). CONCLUSION: BBB permeability predicted alemtuzumab efficacy at two years, indicating that BBB permeability is a biomarker of treatment response in RRMS.

Natural LacI from E. coli yields faster response and higher level of expression than the LVA-tagged LacI.

The lac promoter is one of the most commonly used promoters for expression control of recombinant genes in E. coli. In the absence of galactosides, the lac promoter is repressed by its repressor protein LacI. Since the lac promoter is regulated by a repressor, overexpression of LacI is necessary for regulation when the promoter is introduced on a high-copy plasmid. For that purpose, a modified variant of LacI, a LVA-tagged LacI, was submitted to the Registry of Standard Biological Parts and has been used for more than 500 constructs since then. We have found, however, that natural LacI is superior to the LVA-tagged LacI as controller of expression.