P2‐246: Effects of rivastigmine on brain white matter volume in Mild Cognitive Impairment (MCI)
Steven H. Ferris, Taher Darreh‐Shori, Roger Lane · Alzheimer s & Dementia · 2009
Prospective long-term trials using various cholinesterase inhibitors failed to demonstrate significant effects on conversion from MCI to Alzheimer's disease (AD). However, a retrospective analysis by gender and butyrylcholinesterase genotype (BuChE) demonstrated that female subjects with wild-type BuChE genotype (e.g. BuChE wt/wt, ~70% of the population) showed significantly reduced functional decline and conversion to AD, less whole brain atrophy and ventricular expansion, when treated with rivastigmine, an inhibitor of acetylcholinesterase and BuChE. The largest pool of BuChE in the human brain is in glia, particularly in deep cortical and subcortical structures that map to the distribution of white matter. We hypothesized that rivastigmine-induced increases in the extracellular anti-inflammatory signalling of acetylcholine, lowered in female BuChE wt/wt subjects due to excess BuChE, may reduce white matter damage. Retrospective analysis from a 3-4 year, randomized, placebo-controlled study of rivastigmine (3-12 mg/day) in a sub-population of MCI subjects who consented to pharmacogenetic testing and underwent MRI scans. For assessment of white matter volume, MRI segmentation was performed using an atlas-based approach. To assess differences in change from baseline to endpoint on white matter volume, rivastigmine-treated subjects were compared with placebo-treated subjects using an ANCOVA model. The analysis used a classical intent-to-treat last observation carried forward (ITT-LOCF) population. The current database included 241 MCI subjects. Decline in white matter volume was significantly reduced in rivastigmine-treated female BuChE wt/wt (3.0 versus 6.8%, p = 0.027). Interestingly, rivastigmine was also associated with a numerically greater reduction in white matter volume decline in female BuChE-K carriers but this did not reach statistical significance (4.4 versus 9.1%, p = 0.155). Dual cholinesterase inhibition may influence white matter volume in MCI subjects. The current study also suggests a gender interaction. Greater age-related deterioration of white matter has been shown in women. White matter changes in old age and neurodegenerative disease have been traditionally attributed to Wallerian degeneration of axonal fibres caused by neuronal loss, but white matter changes may be a primary pathophysiological event, with secondary grey matter degeneration.