Predicting responsiveness to cholinesterase therapy from a challenge with the cholinesterase inhibitor galantamine in patients with Alzheimer’s disease.

Alzheimer’s Disease (AD) is the mostcommon cause of dementia in the Western world. Cholinesteraseinhibitors have been shown to enhance cognitive functioning in AD patients. Onlyapproximately 35% of patients with AD respondfavorably to treatmentwith a CEI. It isdifficult to predictwhich patient willrespond and whichwill not. This leads to many patients who are unnecessarelytreated and exposed to possible adverse drugeffects. Wehypothesizedthatreactivity to an acute cholinergicpharmacological challenge with the cholinesteraseinhibitorgalantaminemaypredictclinicalresponsiveness to cholinergictreatment in AD patients.

This study consists of 1) challenge phase: double-blind, placebo-controlled, randomized crossover study with galantamine in 50 patients with mild to moderate AD (MMSE 18-26), followed by 2) treatment phase: a six-month period with galantamine. In the challenge phase, initiallypatients received galantamine 8mg or placebo, following interim analyses this dose was increased to 16mg. In the treatment phase, patients received galantamine extended release in an escalating dose, starting with 8mg per day for one month, and increasing to 16mg per day. The response to the treatment with galantaminewas examined at 2 months and 6 months after start of treatment, using widely-used clinical outcome measures. Here, results from the challenge phase will be presented. Pharmacodynamic effects during challenge were measured using an a prior specified battery of neuropsychological and neurophysiological tests on the Neuro Cart®, including eyemovements (smooth pursuit and saccadic), simple reaction time (RT), adaptive tracking, visual analogue scales (VAS) Bond and Lader and nausea, n-back (0/1/2-back), visual verbal learning (15 words), face coding and recognition and pharmaco-EEG.

Here, data of 37 AD patients (mean age: 67.1 yrs, range:49-90yrs, 17 males) whom completed the challenge phase with 16mg galantamineare presented. Significant differences between placebo and galantamine were found for saccadic eye movement RT, pEEG alpha, beta and theta power bands (all Fz-Cz) and VAS alertness, calmness, mood and nausea. Here, we highlight several results: a reduction in saccadic RT for galantamine compared to placebo of -.013 (p<0.01, 95%CI=-.022, -.005), where least squared mean (LSM) for galantamine=0.246 msec, and LSM placebo=0.260 msec. A decrease in alpha power of -14% (p<0.01, 95%CI=-22.6%, -4.6%), where LSM galantamine=2.01 µV, LSM placebo=2.34 µV.A reduction of theta power for the galantamine group compared to placebo of -14.8% (p<0.05, 95%CI=-24.9%, -3.3%), where LSM galantamine=1.71 µV and LSM placebo=2.01 µV.

Galantamine 16mg was well tolerated. Decreased mood and increased feelings of nausea were reported for galantamine compared to placebo, which reflect the well-known side-effects of galantamine. Decreased saccadic eye movement RT could reflect increased alertness as saccadic eye movements are seen as a measure of sedation. However, no differences between galantamine and placebo were observed on the adaptive tracking test, which is a sensitive tool for attention/alertness. Interim analyses showed significant improvement for galantamine on this test. P-EEG showed decreased power for theta and alpha bands, both fronto-central. EEG alpha and theta slowing have been shown to be related to AD, more specifically, to diminished cognitive functioning. Moreover, decrease in theta power was found to be greater in responders to rivastigmine treatment, than in non-responders. Analysis of the treatment phase is currently being undertaken, where the group of patients will be divided in responders and non-responders to be able to investigate whether (a profile of) PD results following the acute cholinesterase challenge could predict clinical responsiveness to extensive pro-cholinergic treatment in patient with AD.