Laksanun Cheewakriengkrai

A 10-year perspective on donepezil.

Introduction: Donepezil is the first cholinesterase inhibitor widely used for the treatment of Alzheimers disease (AD). Its pharmacological actions are straightforward, enhancing cholinergic activity both in the brain and systemically, with a long-enough half-life to allow for once a day dosing. Its efficacy has been approved for use in mild-to-moderate AD stage for improvement of symptoms for 10 years, and now it is also approved for use in severe stage. Areas covered: This review article will offer a 10-year perspective on the use of donepezil in clinical practice against AD and related disorders. In addition to discussing the information from randomized clinical trials and from the drug monograph, this article will seek to facilitate the clinical development and clinical use of the next generation of drugs for AD. Expert opinion: Adjustments about expectations and safe use of donepezil were made over time based on such clinical experiences. Offering a cholinesterase inhibitor to patients with mild-to-moderate AD clearly showed advantages. If well tolerated, donepezil should be continued in the severe stages of AD as long as the patient appears to benefit from a slower clinical decline.

White Matter Abnormalities and Structural Hippocampal Disconnections in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

The purpose of this project was to evaluate white matter degeneration and its impact on hippocampal structural connectivity in patients with amnestic mild cognitive impairment, non-amnestic mild cognitive impairment and Alzheimer’s disease. We estimated white matter fractional anisotropy, mean diffusivity and hippocampal structural connectivity in two independent cohorts. The ADNI cohort included 108 subjects [25 cognitively normal, 21 amnestic mild cognitive impairment, 47 non-amnestic mild cognitive impairment and 15 Alzheimer’s disease]. A second cohort included 34 subjects [15 cognitively normal and 19 amnestic mild cognitive impairment] recruited in Montreal. All subjects underwent clinical and neuropsychological assessment in addition to diffusion and T1 MRI. Individual fractional anisotropy and mean diffusivity maps were generated using FSL-DTIfit. In addition, hippocampal structural connectivity maps expressing the probability of connectivity between the hippocampus and cortex were generated using a pipeline based on FSL-probtrackX. Voxel-based group comparison statistics of fractional anisotropy, mean diffusivity and hippocampal structural connectivity were estimated using Tract-Based Spatial Statistics. The proportion of abnormal to total white matter volume was estimated using the total volume of the white matter skeleton. We found that in both cohorts, amnestic mild cognitive impairment patients had 27-29% white matter volume showing higher mean diffusivity but no significant fractional anisotropy abnormalities. No fractional anisotropy or mean diffusivity differences were observed between non-amnestic mild cognitive impairment patients and cognitively normal subjects. Alzheimer’s disease patients had 66.3% of normalized white matter volume with increased mean diffusivity and 54.3% of the white matter had reduced fractional anisotropy. Reduced structural connectivity was found in the hippocampal connections to temporal, inferior parietal, posterior cingulate and frontal regions only in the Alzheimer’s group. The severity of white matter degeneration appears to be higher in advanced clinical stages, supporting the construct that these abnormalities are part of the pathophysiological processes of Alzheimer’s disease.

NEURODEGENERATION AND CORTICAL ATROPHY IN [18F]FLORBETAPIR ACCUMULATORS AND NON-ACCUMULATORS

BBSI n 18 22 26 23 49 104 LS Mean (SE) 13.17 (2.06) 13.46 (1.91) 15.72 (1.80) 16.03 (1.89) 15.77 (1.25) 14.5 (8.5) VBSI n 20 22 29 24 53 104 LS Mean (SE) 4.46 (0.59) 4.25 (0.57) 5.31 (0.54) 4.36 (0.55) 4.85 (0.35) 4.43 (3.17) LHBSI n 21 22 29 24 53 104 LS Mean (SE) 0.136 (0.020) 0.119 (0.020) 0.186 (0.018) 0.191 (0.019) 0.188 (0.013) 0.340 (0.190) RHBSI n 21 22 29 24 53 LS Mean (SE) 0.135 (0.020) 0.110 (0.020) 0.176 (0.018) 0.171 (0.019) 0.173 (0.013)

Regional distribution of fibrillar amyloid deposition in the brain as a function of CSF beta-amyloid 1-42 and biomarkers of neurodegeneration

polygenetic profilewas predictive of age of AD diagnosis, AD vs control, and MCI conversion to AD over a three-year period. It was alsoweakly correlated to cognitive performance as measured by the modified ADAS-Cog and MMSE scores. As previously shown, imaging data is highly predictive of AD vs control and MCI conversion; we also show that it is correlated to age of AD diagnosis and cognitive performance. When imaging and genetic information is combined, all predictivemeasures improve (Tables 3& 4). Predictions using a polygenetic profile suggest that most of the MCI subjects are AD-like, whichmay indicate increased risk or environmental effects that have delayed the onset ofAD (Figure 1).Conclusions:Wedemonstrate that a polygenetic profile is predictive of AD, both in terms of AD vs control and in the approximate age of AD diagnosis. When combined with imaging data, the polygenetic profile improves prediction accuracy.

Differential impact of amyloidosis and tau pathology on brain metabolism

a small cluster in the frontal area. In contrast, CSF t-tau or p-tau showed correlation with [18F]florbetapir in frontal, temporal and parietal brain regions. No correlation was shown between global [18F]FDGSUVR and the binding of amyloid imaging agents (Figure1). Conclusions: The pattern of regional deposition of fibrillary amyloid in the brain is non-linearly associated with CSF Ab1-42 concentrations. However the link between p-tau, t-tau and fibrillary amyloid deposition seems to be dependent on the amyloid-imaging agent. While imaging and CSF measures of amyloid pathology are equivalent, [18F]FDG uptake seems to provide independent information from regional deposition of fibrillary amyloid.

CORRELATIONS BETWEEN VARIOUS MOCA COGNITIVE DOMAIN ASSESSMENTS AND REGIONAL BRAIN FDG-PET HYPOMETABOLISM

old. Three hundred fourteen (314) subjects have multiple MRIs, 52 have NP data , and 268 have genotype data at ADGC. After restricting to UDS visits within 180 days of a MRI (n1⁄41379), corresponding cognitive diagnoses consisted of 830 (60.2%) normal cognition, 308 (22.3%) mild cognitive impairment, and 241 (17.5%) dementia, among which 222 (92.1%) were primary probable or possible AD. Associated data from standardized assessments of behavioral and motor symptoms, functional activities, neurologic exam, and neuropsychological tests are also available. Conclusions: The NACC MRI Database is a large, freely available sample of MRIs that are linked to the rich, standardized UDS and NP data, as well as genotype data from ADGC.

HYPOMETABOLISM AND CORTICAL ATROPHY IN [18F]FLORBETAPIR ACCUMULATORS AND NON-ACCUMULATORS

O2-03-05 HYPOMETABOLISM AND CORTICAL ATROPHY IN [18F]FLORBETAPIR ACCUMULATORS AND NON-ACCUMULATORS Sara Mohades, Sulantha Sanjeewa Mathotaarachchi, Maxime Parent, Monica Shin, Seqian Wang, Andrea Lessa Benedet, Antoine Leuzy, Thomas Beaudry, Eduardo Rigon Zimmer, Laksanun Cheewakriengkrai, Daliah Farajat, Vladmir Fonov, Simon Eskildsen, Serge Gauthier, Pedro Rosa-Neto, McGill Center for Studies in Aging, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; McGill Centre for Studies in Aging, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; Aarhus University, Aarhus, Denmark; McGill Center for Studies in Aging, Montreal, Quebec, Canada; MCSA, Montreal, Quebec, Canada. Contact e-mail: sara.mohades@gmail.com

WHITE MATTER ABNORMALITIES AND STRUCTURAL PARIETAL DISCONNECTIONS IN ALZHEIMER'S DISEASE

Lucas Porcello Schilling, Eduardo Rigon Zimmer, Antoine Leuzy, Andrea Lessa Benedet, Tharick Pascoal, Sara Mohades, Sulantha Mathotaarachch, Laksanun Cheewakriengkrai, Monica Shin, Maxime Parent, Min Su Kang, Sarinporn Manitsirikul, Daliah Farajat, Seqian Wang, Jessica Di Ciero, Thomas Beaudry, Simon Eskildsen, Jared Rowley, Felix Carbonell, Vladmir Fonov, Serge Gauthier, Pedro Rosa-Neto, McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; PUCRS, Porto Alegre, Quebec, Brazil; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; Aarhus University, Aarhus, Denmark. Canada; Biospective Inc., Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada. Contact e-mail: lucaspschilling@gmail.com

REGIONAL ASSOCIATION MAPS DESCRIBE DYNAMIC ARCHITECTURE OF AMYLOIDOSIS AND HYPOMETABOLISM IN ALZHEIMER'S DISEASE

IC-P-194 REGIONAL ASSOCIATION MAPS DESCRIBE DYNAMIC ARCHITECTURE OFAMYLOIDOSIS AND HYPOMETABOLISM IN ALZHEIMER’S DISEASE Sulantha Sanjeewa Mathotaarachchi, Sara Mohades, Eduardo Rigon Zimmer, Felix Carbonell, Thomas Beaudry, Maxime Parent, Andrea Lessa Benedet, Seqian Wang, Monica Shin, Vladimir S. Fonov, Laksanun Cheewakriengkrai, Antoine Leuzy, Lucas Porcello Schilling, Sarinporn Manitsirikul, Simon Eskildsen, Min Su Kang, Serge Gauthier, Pedro Rosa-Neto, McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Center-McGill Centre for Studies in Aging, Montreal, Quebec, Canada; McGill Center for Studies in Aging, Montreal, Quebec, Canada; Biospective Inc., Montreal, Quebec, Canada; McGill Centre for Studies in Aging, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; McGill University, Porto Alegre, Brazil. Contact e-mail: sulantha.s@gmail.com

NEURODEGENERATION ASSOCIATED WITH LONGITUDINAL CHANGES OF AB1-42 AND FIBRILLARY AMYLOID

Background: Mutations in the Presenilin 1 (PSEN1) gene are associated with autosomal dominant early onset Alzheimer disease (EOAD). Posterior cerebral atrophy (PCA), a progressive neurodegenerative syndrome affecting visual processing accompanied by atrophy and hypometabolism in the parieto-occipital brain, has been associated with AD and certain PSEN1 gene mutations.Methods:Clinical, neuropsychological, and neuroimaging studies were performed. Postmortem neuropathologic studies of the brain were carried out. Histological methods included hematoxylinand eosin-Luxol fast blue and Thioflavin S. For immunohistochemistry, antibodies against b-amyloid, tau, and a-synuclein were used. DNA was extracted from brain or blood for gene sequencing. Results: At 47, the proband developed memory loss, unsteady gait, pyramidal signs, and visual disturbance (loss of depth perception, intermittent visual loss suggestive of a visual apraxia, eventual blindness.) MRI revealed greater atrophy in parietal than frontal lobes. DNA sequencing revealed an ATT to TTT nucleotide mutation, resulting in a phenylalanine for isoleucine substitution (I229F) in the PSEN1 gene. The proband’s daughters enrolled in the Dominantly Inherited Alzheimer Network. At 39, one daughter developed memory loss, unsteady gait, and visual disturbance. DNA sequencing confirmed a PSEN1 I229F mutation. Neuropsychological evaluation revealed inability to copy a simple geometric design, recall visual information, and a WAIS-R Block Design raw score of 0/51, indicating markedly impaired visuospatial abilities. Structural MRI revealed greater bilateral parieto-occipital lobe gray matter volume loss relative to frontal gray matter. FDG-PET confirmed notable hypometabolism in bilateral parietal lobes. PIB-PET showed high signal consistent with amyloid deposition throughout cortex, including parieto-occipital lobes. She died at 44. Histological and immunohistochemical studies confirmed AD in both brains. The proband’s brain showed severe cerebral atrophy of parieto-occipital lobes relative to the frontal and temporal lobes. The daughter’s brain showed disproportionate thinning of occipital cortex relative to other lobes and reduction of occipital white matter. In both brains, b-amyloid and tau burdens were severe in occipital cortex. The proband also had corticospinal tract degeneration. Conclusions: Prominent visual disturbances in EOADmay suggest the PCA syndrome. Our findings suggest that PCA may be associated with the PSEN1 I229F mutation. (Grants: P30AG35982, P30AG 010133, U19AG032438)