- Email: [email protected]
Behavioral disturbances in early familial Alzheimer's disease
Poster Presentations P1 Demirel University Hospital, Department of Neurology, Isparta, Turkey. Contact e-mail: [email protected] Background: In MMST test the attention, calculation and working memory are being tested by making the patients count from 100 down 7 by 7. Alternatively by testing them to spell the ‘WORLD’ backward. The aim of this study is to compare the two methods for finding the relation of age, sex and education on the total MMST score. Methods: The subjects were chosen among dementia patients coming from 9 centers (TAC-Turquaz Alzheimer Study Group) which had come to be examined for for the first time. Fourhundred fortynine subjects (165 male, 284 female) older than 55 years were analyzed whose MMSE scores are in between 10 to 24. All the participants answered the questions of MMST and the evaluation are made over total score of 30. The subjects were asked to count 100 down 7 by 7 and also to spell the word ‘World’ backwards. Results: The mean MMSE score is 22.2664.76 in spelling the word ‘‘WORLD’’ backwards, the mean MMSE score is 18.964.29 in counting 100 down 7 by 7. We found statisticaly significant set as p¼0.0001 between two tests, there is a negative correlation between the age and the test scores (p¼0.001, r¼0.168) were established, We found also there is no affect of gender on the test scores (p>0.05). Conclusions: While making the clinical diagnosis, standardized alternative tests according to age and education give out more precise information. P1-071
FAMILIAL AND SPORADIC ALZHEIMER’S DISEASE: A CLINICAL LONGITUDINAL STUDY
Giuseppina Talarico1, Giuseppe Tosto1, Elisa Piacentini1, Marco Canevelli1, Marco Pignatelli1, Paola Piscopo2, Alessio Crestini2, Lorenzo Malvezzi Careggi2, Annamaria Confaloni2, Marina Gasparini1, Manuela Salati1, Gian Luigi Lenzi1, Nicola Vanacore3, Giuseppe Bruno1, 1 Dept of Neurological Science, University "Sapienza", Rome, Italy; 2Dept of Cell Biology and Neurosciences, Istituto Superiore di Sanita`, Rome, Italy; 3 Dept of Epidemiology, Istituto Superiore di Sanita`, Rome, Italy. Contact e-mail: [email protected] Background: Alzheimer’s disease(AD) is a progressive neurodegenerative disease with a complex pathogenesis. Four gene mutations have been unequivocally confirmed to be linked to AD to date. Mutations in the APP gene on chromosome 21, the PSEN1 gene on chromosome 14, the PENS2 gene on chromosome 1, and the Apolipoprotein E4 (ApoE4) gene on chromosome 19. The first three are mainly linked to the early-onset autosomal dominant familial AD while the ApoE4 allele inheritance is a recognized risk factor for late-onset familial (and sporadic) AD. Genetic heterogeneity might therefore sustain clinical heterogeneity. A few studies have clinically compared familial and sporadic AD patients without definite conclusions. Methods: 86 patients who fulfilled NINCDS-ADRDA criteria for probable AD and family history of AD (at least 2 first-relative affected plus the proband) were matched for sex, age of onset and years of follow-up with 215 sporadic AD patients. The subjects were recruited at the ‘‘Memory Clinic’’ of the Department of Neurological Sciences and followed for a period of up to 6 years by means of clinical assessments that included neurological examination, morphological neuroimaging (MRi/CT) and/or functional (SPECT/PET), Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), NeuroPsychiatric Inventory (NPI) and neuropsychological evaluation. Results: The maternal inheritance is the commonest (52.4%) line of transmission. FAD and SAD patients do not show significant difference in the clinical presentation while the neurological examination (extrapyramidal signs z¼-3.04 p¼0.002; cerebellar signs z¼-2.80 p¼0.005) and the NPI (t¼3.71 p¼0.001; subitems anxiety, apathy and sleep) were remarkably different. At scheduled follow-ups NPI-subitems only maintained a statistically significant difference. Conclusions: This is the first longitudinal study that compares a relevant number of FAD and SAD patients on cognitive and non cognitive variables. Behavioural disturbances appear to be differently represented in the two populations. P1-072
BEHAVIORAL DISTURBANCES IN EARLY FAMILIAL ALZHEIMER’S DISEASE
Deborah L. Flores1, Li-Jung Liang2, Luis D. Medina3, Yaneth Rodriguez Agudelo4, Barbara Schaffer5, Miguel Angel Macias-
P193
Islas6, L. Jaime Fitten3, Freddy Ortiz3, Jeffrey L. Cummings3, John M. Ringman3, 1Department of Psychiatry, Harbor-UCLA Medical Center, Los Angeles, CA, USA; 2UCLA Department of Medicine, Los Angeles, CA, USA; 3Easton Center for Alzheimer’s Disease Research, UCLA Department of Neurology, Los Angeles, CA, USA; 4National Institute of Neurology and Neurosurgery, Mexico City, Mexico; 5UCLA Department of Neurology, Los Angeles, CA, USA; 6Neurosciences Department, University of Guadalajara, Zapopan, Mexico. Contact e-mail: [email protected] Background: Psychiatric symptoms may precede overt cognitive impairment in Alzheimer’s disease (AD). Persons carrying mutations causing familial AD (FAD) provide the opportunity to study this with sensitivity. The goal of this study is to evaluate premorbid psychiatric state using various instruments in this population. Methods: Subjects were 36 Mexican and Mexican-American non-demented persons (81% female) at-risk for familial AD due to PSEN1 (n ¼ 28) or APP (n ¼ 8) mutations. Only one subject was aware of their mutation status. Subjects underwent evaluation with self-rated scales (BDI, BAI, CESD), interview-based assessments (CDR, HAM-A, HAM-D, and QIDS), and the informant-based Neuropsychiatric Inventory (NPI). Total scores on each scale were compared between mutation carriers (MCs) and non-carriers (NCs) by t-tests. Comparisons were made for all subjects (CDR scores < 1) and for cognitively asymptomatic subjects (CDR score ¼ 0). For subjects for whom complete data was available (N ¼ 31), psychiatric scale scores were compared using mixed-effects regression models accounting for gender, country of residence (U.S. vs. Mexico), degree of U.S. acculturation, age, and perceived genetic status. Results: Twenty-two subjects were MCs and 14 NCs. Seven MCs had CDR scores of 0.5 and the remainder had CDR scores of 0. There were no differences between groups in gender or MMSE scores though NCs tended to be older (39 vs. 32 years, p ¼ 0.026). MCs had higher total NPI scores (5.7 vs. 1.3, p ¼ 0.038). When MCs with CDR scores of 0.5 were excluded, total NPI scores did not differ between the groups. Scores on other scales did not differ between MCs and NCs. In mixed-effects regression analyses living in the U.S., being less acculturated, and thinking that one had inherited an FAD mutation were associated with significantly higher NPI scores. Conclusions: Behavioral changes are evident at the earliest stage of cognitive impairment in FAD and are better detected using informant-based than subject-based scales. Substantial psychopathology was not evident in the years prior to cognitive changes but studies involving larger numbers of subjects are necessary to confirm this and to evaluate the contribution of other factors towards behavioral abnormalities in FAD. P1-073
SPECIFIC DETECTION OF SOLUBLE AMYLOID BETA OLIGOMERS USING CONFORMATIONALLY DYNAMIC PRONUCLEONTM PEPTIDES
Jonathan R. Moll, Serguei Soukharev, Craig Nelson, Roxanne Duan, Alan Rudolph, Adlyfe, Inc., Rockville, MD, USA. Contact e-mail: jmoll@ adlyfe.com Background: We have previously reported the use of small conformationally dynamic peptides (PronucleonTM peptides) that enable the detection of beta sheet amyloid proteins associated with Alzheimer’s disease (AD). These fluorescently-labeled peptides undergo a sequence-specific conformational rearrangement in the presence of Abeta aggregates, resulting in a change in their fluorescence profile that can be monitored using standard laboratory instrumentation (Adlyfe’s ‘‘misfolded’’ protein detection [MPD] assay). The development of PronucleonTM peptides to detect soluble amyloid beta (Abeta) oligomers (which are reported to be the neurotoxic species likely to be the cause of AD), would be a unique and valuable contribution to the field. Methods: To aid in development of an effective in vitro diagnostic test to measure neurotoxic Abeta species, we produced two distinct types of soluble oligomers: SDS-derived and DMEM/F12 media-induced oligomers. We have developed a formulation to maximize their stability, and extensively characterized them with respect to size distribution, ThT reactivity, and structural properties. We have also optimized the design of our Pronucleon peptides to enhance solubility, and alter the pH and salt-sensitivity of their conformational states in order to optimize their ability to detect oligomers under clinically relevant conditions. The ability of Pronucleon peptides to detect oligomers was assessed using Adlyfe’s MPD assay as well
FAMILIAL AND SPORADIC ALZHEIMER’S DISEASE: A CLINICAL LONGITUDINAL STUDY
Giuseppina Talarico1, Giuseppe Tosto1, Elisa Piacentini1, Marco Canevelli1, Marco Pignatelli1, Paola Piscopo2, Alessio Crestini2, Lorenzo Malvezzi Careggi2, Annamaria Confaloni2, Marina Gasparini1, Manuela Salati1, Gian Luigi Lenzi1, Nicola Vanacore3, Giuseppe Bruno1, 1 Dept of Neurological Science, University "Sapienza", Rome, Italy; 2Dept of Cell Biology and Neurosciences, Istituto Superiore di Sanita`, Rome, Italy; 3 Dept of Epidemiology, Istituto Superiore di Sanita`, Rome, Italy. Contact e-mail: [email protected] Background: Alzheimer’s disease(AD) is a progressive neurodegenerative disease with a complex pathogenesis. Four gene mutations have been unequivocally confirmed to be linked to AD to date. Mutations in the APP gene on chromosome 21, the PSEN1 gene on chromosome 14, the PENS2 gene on chromosome 1, and the Apolipoprotein E4 (ApoE4) gene on chromosome 19. The first three are mainly linked to the early-onset autosomal dominant familial AD while the ApoE4 allele inheritance is a recognized risk factor for late-onset familial (and sporadic) AD. Genetic heterogeneity might therefore sustain clinical heterogeneity. A few studies have clinically compared familial and sporadic AD patients without definite conclusions. Methods: 86 patients who fulfilled NINCDS-ADRDA criteria for probable AD and family history of AD (at least 2 first-relative affected plus the proband) were matched for sex, age of onset and years of follow-up with 215 sporadic AD patients. The subjects were recruited at the ‘‘Memory Clinic’’ of the Department of Neurological Sciences and followed for a period of up to 6 years by means of clinical assessments that included neurological examination, morphological neuroimaging (MRi/CT) and/or functional (SPECT/PET), Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), NeuroPsychiatric Inventory (NPI) and neuropsychological evaluation. Results: The maternal inheritance is the commonest (52.4%) line of transmission. FAD and SAD patients do not show significant difference in the clinical presentation while the neurological examination (extrapyramidal signs z¼-3.04 p¼0.002; cerebellar signs z¼-2.80 p¼0.005) and the NPI (t¼3.71 p¼0.001; subitems anxiety, apathy and sleep) were remarkably different. At scheduled follow-ups NPI-subitems only maintained a statistically significant difference. Conclusions: This is the first longitudinal study that compares a relevant number of FAD and SAD patients on cognitive and non cognitive variables. Behavioural disturbances appear to be differently represented in the two populations. P1-072
BEHAVIORAL DISTURBANCES IN EARLY FAMILIAL ALZHEIMER’S DISEASE
Deborah L. Flores1, Li-Jung Liang2, Luis D. Medina3, Yaneth Rodriguez Agudelo4, Barbara Schaffer5, Miguel Angel Macias-
P193
Islas6, L. Jaime Fitten3, Freddy Ortiz3, Jeffrey L. Cummings3, John M. Ringman3, 1Department of Psychiatry, Harbor-UCLA Medical Center, Los Angeles, CA, USA; 2UCLA Department of Medicine, Los Angeles, CA, USA; 3Easton Center for Alzheimer’s Disease Research, UCLA Department of Neurology, Los Angeles, CA, USA; 4National Institute of Neurology and Neurosurgery, Mexico City, Mexico; 5UCLA Department of Neurology, Los Angeles, CA, USA; 6Neurosciences Department, University of Guadalajara, Zapopan, Mexico. Contact e-mail: [email protected] Background: Psychiatric symptoms may precede overt cognitive impairment in Alzheimer’s disease (AD). Persons carrying mutations causing familial AD (FAD) provide the opportunity to study this with sensitivity. The goal of this study is to evaluate premorbid psychiatric state using various instruments in this population. Methods: Subjects were 36 Mexican and Mexican-American non-demented persons (81% female) at-risk for familial AD due to PSEN1 (n ¼ 28) or APP (n ¼ 8) mutations. Only one subject was aware of their mutation status. Subjects underwent evaluation with self-rated scales (BDI, BAI, CESD), interview-based assessments (CDR, HAM-A, HAM-D, and QIDS), and the informant-based Neuropsychiatric Inventory (NPI). Total scores on each scale were compared between mutation carriers (MCs) and non-carriers (NCs) by t-tests. Comparisons were made for all subjects (CDR scores < 1) and for cognitively asymptomatic subjects (CDR score ¼ 0). For subjects for whom complete data was available (N ¼ 31), psychiatric scale scores were compared using mixed-effects regression models accounting for gender, country of residence (U.S. vs. Mexico), degree of U.S. acculturation, age, and perceived genetic status. Results: Twenty-two subjects were MCs and 14 NCs. Seven MCs had CDR scores of 0.5 and the remainder had CDR scores of 0. There were no differences between groups in gender or MMSE scores though NCs tended to be older (39 vs. 32 years, p ¼ 0.026). MCs had higher total NPI scores (5.7 vs. 1.3, p ¼ 0.038). When MCs with CDR scores of 0.5 were excluded, total NPI scores did not differ between the groups. Scores on other scales did not differ between MCs and NCs. In mixed-effects regression analyses living in the U.S., being less acculturated, and thinking that one had inherited an FAD mutation were associated with significantly higher NPI scores. Conclusions: Behavioral changes are evident at the earliest stage of cognitive impairment in FAD and are better detected using informant-based than subject-based scales. Substantial psychopathology was not evident in the years prior to cognitive changes but studies involving larger numbers of subjects are necessary to confirm this and to evaluate the contribution of other factors towards behavioral abnormalities in FAD. P1-073
SPECIFIC DETECTION OF SOLUBLE AMYLOID BETA OLIGOMERS USING CONFORMATIONALLY DYNAMIC PRONUCLEONTM PEPTIDES
Jonathan R. Moll, Serguei Soukharev, Craig Nelson, Roxanne Duan, Alan Rudolph, Adlyfe, Inc., Rockville, MD, USA. Contact e-mail: jmoll@ adlyfe.com Background: We have previously reported the use of small conformationally dynamic peptides (PronucleonTM peptides) that enable the detection of beta sheet amyloid proteins associated with Alzheimer’s disease (AD). These fluorescently-labeled peptides undergo a sequence-specific conformational rearrangement in the presence of Abeta aggregates, resulting in a change in their fluorescence profile that can be monitored using standard laboratory instrumentation (Adlyfe’s ‘‘misfolded’’ protein detection [MPD] assay). The development of PronucleonTM peptides to detect soluble amyloid beta (Abeta) oligomers (which are reported to be the neurotoxic species likely to be the cause of AD), would be a unique and valuable contribution to the field. Methods: To aid in development of an effective in vitro diagnostic test to measure neurotoxic Abeta species, we produced two distinct types of soluble oligomers: SDS-derived and DMEM/F12 media-induced oligomers. We have developed a formulation to maximize their stability, and extensively characterized them with respect to size distribution, ThT reactivity, and structural properties. We have also optimized the design of our Pronucleon peptides to enhance solubility, and alter the pH and salt-sensitivity of their conformational states in order to optimize their ability to detect oligomers under clinically relevant conditions. The ability of Pronucleon peptides to detect oligomers was assessed using Adlyfe’s MPD assay as well