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P4‐360: Three in One: Coexistence of Essential Tremor, Idiopathic Parkinson's Disease and Dementia
Author(s) -
Gulsen BabacanYildiz,
Mehmet Aydin,
Talip Asil
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.08.141
Subject(s) - dementia , parkinsonism , parkinson's disease , disease , medicine , movement disorders , essential tremor , psychology , psychiatry , physical medicine and rehabilitation , pediatrics
Background: ELND005 (Scyllo-inositol), a Myo-inositol stereoisomer, is being developed as a potential disease modifying agent based on its amyloid anti-aggregation effects in preclinicalmodels (McLaurin et al., 2000).Endogenous Myo and Scyllo-inositol concentrations in brain arew 4-5mM and< 1mM, respectively. Myo-inositol, through its phosphorylated derivatives, is involved in the Phospho-inositol (PI) cycle, an important signaling pathway of G protein-coupled receptors (GPCRs). Unlike Myo-inositol, Scyllo-inositol is not thought to be phosphorylated or involved in PI signaling (Fenili et al. 2007).Methods: Study AD201, a 78-week study, included 351 AD patients who received placebo or ELND005 (250, 1000, or 2000 mg, all BID). Brain Scyllo andMyo-inositol levels were assessed in 104 patients by proton-magnetic resonance spectroscopy (MRS), at baseline, 24, 48, and 78weeks.MRS measurements (1.5 or 3 Tesla) were obtained from an 18 cm 3 voxel in posterior medial cingulate cortex. Analyses of inositol levels were performed by a central imaging laboratory (NeuroRx Research, Montreal). Results: Brain levels of Scyllo-inositol showed a dose-dependent increase with ELND005 treatment at 250mg and 1000mg doses, and reached apparent saturation above 1000 mg. Brain levels of Myo-inositol showed a reciprocal decrease at same time points: Percent change from baseline (PCBLs) at the 250mg and 1000mg doses were -36% to -45% and -61% to -64%, respectively, and also reached apparent saturation at doses above 1000 mg. These effects on Scyllo andMyo-inositol were observed from 24 through 78wks, and were similar in Mild and Moderate patients. Total brain inositol levels were generally constant at any given visit, and Scyllo and Myo-inositol were highly inversely correlated (at 24, 48 wks: r1⁄4 0.86, 0.9, both p < 0.0001). Conclusions: ELND005 dose-dependently decreased brain Myo-inositol levels, likely due to competition for active uptake by the Sodium/Myo-inositol transporter, which has similar affinity for Myo and Scyllo-inositol (Fenili et al., 2011). ELND005, through reduction of Myo-inositol levels, may play a regulatory role in the PI pathway and in signal transduction of neurotransmitter and growth factor stimuli.