Mira Chamoun

Cholinergic Potentiation Improves Perceptual-Cognitive Training of Healthy Young Adults in Three Dimensional Multiple Object Tracking

A large body of literature supports cognitive enhancement as an effect of cholinergic potentiation. However, it remains elusive whether pharmacological manipulations of cholinergic neurotransmission enhance complex visual processing in healthy individuals. To test this hypothesis, we randomly administered either the cholinergic transmission enhancer donepezil (DPZ; 5 mg P.O.) or placebo (lactose) to young adults (n = 17) 3 h before each session of the three-dimensional (3D) multiple object tracking (3D-MOT) task. This multi-focal attention task evaluates perceptual-cognitive learning over five sessions conducted 7 days apart. A significant amount of learning was observed in the DPZ group but not the placebo group in the fourth session. In the fifth session, this learning effect was observed in both groups. Furthermore, preliminary results for a subgroup of participants (n = 9) 4–14 months later suggested the cholinergic enhancement effect was long lasting. On the other hand, DPZ had no effect on basic visual processing as measured by a motion and orientation discrimination task performed as an independent one-time, pre-post drug study without placebo control (n = 10). The results support the construct that cholinergic enhancement facilitates the encoding of a highly demanding perceptual-cognitive task although there were no significant drug effects on the performance levels compared to placebo.

Dose-dependent effect of donepezil administration on long-term enhancement of visually evoked potentials and cholinergic receptor overexpression in rat visual cortex

Stimulation of the cholinergic system tightly coupled with periods of visual stimulation boosts the processing of specific visual stimuli via muscarinic and nicotinic receptors in terms of intensity, priority and long-term effect. However, it is not known whether more diffuse pharmacological stimulation with donepezil, a cholinesterase inhibitor, is an efficient tool for enhancing visual processing and perception. The goal of the present study was to potentiate cholinergic transmission with donepezil treatment (0.5 and 1mg/kg) during a 2-week visual training to examine the effect on visually evoked potentials and to profile the expression of cholinergic receptor subtypes. The visual training was performed daily, 10min a day, for 2weeks. One week after the last training session, visual evoked potentials were recorded, or the mRNA expression level of muscarinic (M1-5) and nicotinic (α/β) receptors subunits was determined by quantitative RT-PCR. The visual stimulation coupled with any of the two doses of donepezil produced significant amplitude enhancement of cortical evoked potentials compared to pre-training values. The enhancement induced by the 1mg/kg dose of donepezil was spread to neighboring spatial frequencies, suggesting a better sensitivity near the visual detection threshold. The M3, M4, M5 and α7 receptors mRNA were upregulated in the visual cortex for the higher dose of donepezil but not the lower one, and the receptors expression was stable in the somatosensory (non-visual control) cortex. Therefore, higher levels of acetylcholine within the cortex sustain the increased intensity of the cortical response and trigger the upregulation of cholinergic receptors.

Cholinergic Potentiation of Restoration of Visual Function after Optic Nerve Damage in Rats

Enhancing cortical plasticity and brain connectivity may improve residual vision following a visual impairment. Since acetylcholine plays an important role in attention and neuronal plasticity, we explored whether potentiation of the cholinergic transmission has an effect on the visual function restoration. To this end, we evaluated for 4 weeks the effect of the acetylcholinesterase inhibitor donepezil on brightness discrimination, visually evoked potentials, and visual cortex reactivity after a bilateral and partial optic nerve crush in adult rats. Donepezil administration enhanced brightness discrimination capacity after optic nerve crush compared to nontreated animals. The visually evoked activation of the primary visual cortex was not restored, as measured by evoked potentials, but the cortical neuronal activity measured by thallium autometallography was not significantly affected four weeks after the optic nerve crush. Altogether, the results suggest a role of the cholinergic system in postlesion cortical plasticity. This finding agrees with the view that restoration of visual function may involve mechanisms beyond the area of primary damage and opens a new perspective for improving visual rehabilitation in humans.

Regulation of the expression of the cholinergic receptors in the visual cortex following long-term enhancement of visual cortical activity by cholinergic stimulation

The muscarinic and nicotinic transmissions in the primary visual cortex (V1) are involved in the enhancement of specific visual stimuli as well as long-term modifications of the neuronal processing, in regards to perceptual learning. We investigated the involvement of the different cholinergic receptors subtypes underlying this long-term functional plasticity using RT-PCR and recording of visual evoked potentials (VEPs). Perceptual learning-like test was performed by exposing awaken rats to a visual stimulation (VS) - a sinusoidal grating (30°, 0.12cpd) - for 10min/day during 14days. This VS was provided alone or coupled to an electrical stimulation of the basal forebrain which sends cholinergic projections to V1 (HDB/VS) or paired with a cholinesterase inhibitor (donepezil, 1mg/kg injected 30min prior to visual exposure) to enhance cholinergic transmission in V1 (DONEP/VS). One week after the last training session, VEPs were recorded and the cortices encompassing V1 were collected to determine the expression level of mRNA of muscarinic (M1-5) and nicotinic (α/β) receptors sub-units by RT-PCR. VS coupled to pharmacological or electrical stimulation of the cholinergic system produced a significant enhancement of the cortical response, as shown by VEP recordings. Two weeks of VS treatment alone caused an increase of the expression of M3 and M5 mRNA suggesting an increase of their production and activity during long-term visual stimulation. In the HDB/VS group, α3 sub-unit was decreased suggesting its involvement in phasic cholinergic stimulation. The DONEP/VS treatment presented a decrease in the expression of M2, suggesting a down regulation of mRNA synthesis. This could indicate an increased cortico-cortical inhibition, as M2 receptors are located massively on the GABAergic neurons. Therefore, even with similar functional enhancement, the cholinergic receptors regulation differs between an electrical and a pharmacological treatment. These results are crucial for determining which receptors are the most involved in the pharmacological cholinergic stimulation to enhance visual perception. Meeting abstract presented at VSS 2015.

Stimulation of Acetylcholine Release and Pharmacological Potentiation of Cholinergic Transmission Affect Cholinergic Receptor Expression Differently during Visual Conditioning

Cholinergic stimulation coupled with visual conditioning enhances the visual acuity and cortical responses in the primary visual cortex. To determine which cholinergic receptors are involved in these processes, qRT-PCR was used. Two modes of cholinergic enhancement were tested: a phasic increase of acetylcholine release by an electrical stimulation of the basal forebrain cholinergic nucleus projecting to the visual cortex, or a tonic pharmacological potentiation of the cholinergic transmission by the acetylcholine esterase inhibitor, donepezil. A daily visual exposure to sine-wave gratings (training) was paired with the cholinergic enhancement, up to 14 days. qRT-PCR was performed at rest, 10 min, one week or two weeks of visual/cholinergic training with samples of the visual and somatosensory cortices, and the BF for determining mRNA expression of muscarinic receptor subtypes (m1, m2, m3, m4, m5), nicotinic receptor subunits (α3, α4, α7, β2, β4), and NMDA receptors, GAD65 and ChAT, as indexes of cortical plasticity. A Kruskal-Wallis test showed a modulation of the expression in the visual cortex of m2, m3, m4, m5, α7, β4, NMDA and GAD65, but only β4 within the basal forebrain and none of these mRNA within the somatosensory cortex. The two modes of cholinergic enhancement induced different effects on mRNA expression, related to the number of visual conditioning sessions and receptor specificity. This study suggests that the combination of cholinergic enhancement and visual conditioning is specific to the visual cortex and varies between phasic or tonic manipulation of acetylcholine levels.

UNBIASED ASSESSMENT OF GLOBAL AMYLOID LOAD AS DETERMINED BY VOXEL-WISE RECEIVER OPERATING CHARACTERISTIC ANALYSIS

the uncinate fasciculus in preclinical autosomal dominant Alzheimer’s disease Note: the interaction group by EC tau pathology on tract diffusivity is plotted and statistical significance for the interaction is provided in the panels (corrected for age, robust regressions). Note the limited range in tau pathology in the noncarriers. Abbreviations: FA 1⁄4 Fractional Anisotropy, MD 1⁄4 Mean Diffusivity, AxD 1⁄4 Axial Diffusivity, RD 1⁄4 Radial Diffusivity, EC 1⁄4 Entorhinal cortex, UF 1⁄4 uncinate fasciculus Poster Presentations: Monday, July 23, 2018 P898

CORRELATION BETWEEN CSF T-TAU AND P-TAU WITH [18F]MK6240 IN THE DIAGNOSIS OF ALZHEIMER’S DISEASE

between stages of AD progression when examined independently. The significance of TI and TSS in combined models dropped substantially, indicating that information used by these metrics is largely redundant (Table 2, Figures 1&3). However, TI remained statistically significant in combined models, suggesting that unique information above TSS information is conveyed with this approach (Table 2). Conclusions:Both TI and TSS can monitor progression of tau pathology in AD individuals. However, TSS could hold advantages in clinical trial settings and atypical dementia identification by retaining much of the information while shifting analytic emphasis to peripheral areas with relatively low binding affinity. Further investigation of TSS with a larger sample sizes is needed.

REGIONAL PATTERNS OF TAU DEPOSITION DRIVEN BY LOCAL AMYLOID ACCUMULATION RECAPITULATE BRAAK STAGES IN AD

QC, Canada; Translational Neuroimaging Laboratory, McGill University, Verdun, QC, Canada; Cerebral Imaging Centre, Douglas Research Centre, Verdun, QC, Canada; Douglas Hospital Research Centre, Verdun, QC, Canada; McGill Centre for Studies in Aging, Verdun, QC, Canada; Douglas Hospital Research Centre, Montreal, QC, Canada; McConnell Brain Imaging Centre, McGill University, Montr eal, QC, Canada; McGill University Research Centre for Studies in Aging, Canada, Verdun, QC, Canada. Contact e-mail: peter.ms.kang@gmail.com

THE SYNERGISTIC INTERACTION BETWEEN AMYLOID AND TAU DISRUPTS LOCAL AND GLOBAL RESTING STATE FMRI CONNECTIVITY

P3-096 THE SYNERGISTIC INTERACTION BETWEEN AMYLOID AND TAU DISRUPTS LOCAL AND GLOBAL RESTING STATE FMRI CONNECTIVITY Melissa Savard, Sulantha Mathotaarachchi, Min Su Kang, Tharick A. Pascoal, Joseph Therriault, Andrea Lessa Benedet, Mira Chamoun, Emilie M. Thomas, Serge Gauthier, Pedro RosaNeto, McGill University Research Centre for Studies in Aging, Verdun, QC, Canada; Translational Neuroimaging Laboratory-McGill University, Verdun, QC, Canada; Douglas Hospital Research Centre, Verdun, QC, Canada. Contact e-mail: melissa_savard2@hotmail.com

THE EFFECT OF PROTON PUMP INHIBITORS AND CYP2C19 ON AMYLOID PATHOLOGY

IC-P-063 THE EFFECT OF PROTON PUMP INHIBITORS AND CYP2C19 ON AMYLOID PATHOLOGY Andrea Lessa Benedet, Sulantha Mathotaarachchi, Tharick A. Pascoal, Yasser Iturria Medina, Melissa Savard, Joseph Therriault, Min-Su Kang, Mira Chamoun, Serge Gauthier, Alan C. Evans, Aurelie Labbe, Pedro RosaNeto, Coordenaç~ao de Aperfeiçoamento de Pessoal de N ıvel Superior Foundation, Brasilia, Brazil; Translational Neuroimaging Laboratory, McGill University, Verdun, QC, Canada; Douglas Hospital Research Centre, Verdun, QC, Canada; McGill Centre for Integrative Neuroscience, McGill University, Montreal, QC, Canada; Douglas Hospital Research Centre, Montreal, QC, Canada; Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada; McGill University Research Centre for Studies in Aging, Verdun, QC, Canada; HEC Montr eal, Montreal, QC, Canada; McGill University Research Centre for Studies in Aging, Canada, Verdun, QC, Canada. Contact e-mail: andrea.benedet@mail.mcgill.ca