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Alteration of A beta-1-42 binding in red blood cells: a potential marker for Alzheimer's disease
Poster Presentations P1 Conclusions: We identified candidate genes involved in AD pathogenesis depending on the brain regions. Several genes responsible for clinical manifestation of AD could be elucidated through gene expression profiling.
P1-136
MULTICENTER STUDY ON PROCEDURE, FEASIBILITY AND SAFETY OF LUMBAR PUNCTURE IN 18 FRENCH MEMORY CENTERS
Olivier Hanon1, Jacques Hugon2, Florence Latour3, Isabelle Saulnier4, 1 Centre Memoire de Ressources et de Recherche Paris Sud Ile de France, APHP, Paris; 2Centre Memoire de Ressources et de Recherche Paris Nord Ile de France, APHP, Paris; 3Centre Memoire de Ressources et de Recherche Paris Sud Ile de France, APHP, Paris; 4Centre Hospitalier Universitaire de Limoges, LIMOGES. Background: Cerebrospinal fluid (CSF) biomarkers have been extensively studied as diagnostic marker for Alzheimer’s disease (AD). However, results are variable probably due to lumbar puncture (LP) procedure, CSF collection and transport. This inter-center variability highlights the need for an efficient standardization of clinical procedures and techniques. The aims of this study were firstly to compare the LP procedure and CSF transport process between in all French Memory Centers and secondly to evaluate the incidence of LP side effects in 100 patients with cognitive disturbances. Methods: LP practice and side effect prospective questionnaires were sent to all French Memory Centers in May 2010. All data were collected until the end of July 2010. Results: 18 out of 26 Memory Centers replied with filled questionnaires. Although, these centers did not have the same LP procedure and CSF transport, the majority of them proceeded according to Innogenetics’s advices concerning the use of polypropylene tubes, transport duration and sample conditioning. Polypropylene tubes were different from one center to the other. CSF volume, pharmacological premedication and prevention of post-LP syndrome were variable in all responding center. The prospective study carried out in 100 patients revealed a very good LP acceptability (93/100 patients). LP feasibility was 97 % (90/93) and failed LP were consequently performed with success using radiological scopes. We observed 3 minor complications were observed. Conclusions: All French Centers complied with Innogenetics’ recommendations for pretechnical CSF procedures; however each Center put in place its own procedure that was different between centers. It will be very interesting to compare cutt-off and result values for Abeta tau and p181 tau between several centers that used their own procedures. Acceptability and safety were very good in our short but significant prospective study. These results confirm the data of Zetterberg et al 2010.
P1-137
ALTERATION OF A BETA-1-42 BINDING IN RED BLOOD CELLS: A POTENTIAL MARKER FOR ALZHEIMER’S DISEASE
Corinne Liegeois, Innovative Health Diognostic. Background: Beta-amyloid peptides (A-beta) bind to nerve and peripheral cells and induce alterations in Ca2+ homeostasis and protein kinase C (PKC) activation. In the search of a peripheral biomarker for Alzheimer’s disease (AD) we decided to better characterize the effect of chronically applied A-beta at low concentrations and to develop a method suitable for detection of small peptide amounts bound to the surface of these cells. Methods: Intracellular Ca2+ was measured by Fura 2 imaging to estimate the effects of A-beta-1-42. A new fluorescent probe derived from A-beta was developed. This probe was used on cultured cells and on red blood cells from transgenic TASTPM mice. Results: We show that preincubation with low A-beta concentrations induces a priming effect on primary cultures of hippocampal or cortical neurons. This priming effect is only revealed when the cells
S155
are challenged with an acute application of A-beta at high concentration. A similar priming effect was observed in human peripheral red blood cells from AD patients. Using a new fluorescent probe we were able to detect Abeta bound to the cellular membrane of preincubated cells in culture. We then developed an experimental protocol to distinguish double transgenic TASTPM mice from wild type mice. Used as a test on red blood cells from 4 month old animals, when the pathology is not yet developed, this protocol showed no significant difference between transgenic and wild type mice. However the test was positive on 14 month old mice, when the disease is almost fully developed. The statistical analysis of the results revealed a sensitivity of 77% and a specificity of 91%. Conclusions: Abeta chronically applied to nerve cells induces a priming effect, which suggests that low A-beta concentrations do not significantly alter the basal Ca2+ homeostasis but favour later applied A-beta interaction with the cellular membrane. Using this hypothesis we developed a blood test, which appears efficient in detecting AD in an animal model. This test is currently applied to human samples. It remains to be assessed whether it has a predictive value for disease progression.
P1-138
ALZHEIMER’S DISEASE AND THE ABILITY TO SPEAK OF SELF-AS-AGENT IN FUTURE CONTEXTS: DESCRIPTION AND ANALYSIS
Elissa Asp1, Kenneth Rockwood2, Sherri Fay2, 1Saint Mary’s University; 2 Capital Health/Dalhousie University, Halifax, Nova Scotia. Background: Alzheimer’s disease (AD) can impair agency, reflected in, for instance, reduced ability to plan and carry out (instrumental) activities of daily living. Several related neural systems may contribute to impaired agency in AD: episodic memory impairments may affect recall of plans; degradation of semantic systems may alter representations of component activities for carrying out plans; executive function deficits may compromise forming or carrying out plans. Relatedly, people with AD seldom speak of themselves as agents in future contexts (e.g. "Tomorrow I’m going to visit my daughter"). To aid understanding everyday behavioural correlates of neural dysfunction in AD, we investigated whether treatment response correlates with ability to respond to simple questions about plans for the future. Methods: This is a retrospective analysis of videos recorded in a placebo-controlled, double-blind trial of galantamine [CMAJ 2006; 174(8): 1099-105]. Participants had mild/moderate AD. A novel “evaluation of memory and temporality” (EMT) test was recorded for a subset (74 at baseline, 63 with follow-up). To investigate participants’ ability to speak of themselves as agents in the future, we coded whether responses to eight simple, future-directed questions were unequivocally informative, negative or confabulated. We correlated EMT responses with the trial’s outcome measures, ADAS-cog 11, CIBIC-plus, and GAS, and also with sub-components of these measures to investigate the contributions of episodic and semantic memory and executive function to response patterns. Results: In the 35 participants examined to date, all responded positively to at least one question in one interview. Although there does not appear to be an absolute inability to conceptualize oneself as a future agent, the time frames may affect responses: at baseline, 32 participants answered “what are you going to do in the next few minutes ?” positively. By contrast, 21 responded positively to “What are you going to do the day after tomorrow?”. Half of positive responses were equivocal. At eight months, there were 15% fewer positive responses. Conclusions: Simple questions about future activities may be sensitive to change in AD and might help measure treatment response. P1-139
ACCURATE NON-INVASIVE DIAGNOSES OF ALZHEIMER’S DISEASE USING EYE SCANNING
Stephan Bandelow1, Angela Clifford1, Veronika van der Wardt1, Eef Hogervorst1, Mark Madden1, James Lindesay2, Alastair Gale1, 1 Loughborough University, Loughborough; 2University of Leicester, Leicester. Background: Early and accurate non-invasive diagnosis with an earlier initiation of treatment could possibly delay progression of Alzheimer’s
P1-136
MULTICENTER STUDY ON PROCEDURE, FEASIBILITY AND SAFETY OF LUMBAR PUNCTURE IN 18 FRENCH MEMORY CENTERS
Olivier Hanon1, Jacques Hugon2, Florence Latour3, Isabelle Saulnier4, 1 Centre Memoire de Ressources et de Recherche Paris Sud Ile de France, APHP, Paris; 2Centre Memoire de Ressources et de Recherche Paris Nord Ile de France, APHP, Paris; 3Centre Memoire de Ressources et de Recherche Paris Sud Ile de France, APHP, Paris; 4Centre Hospitalier Universitaire de Limoges, LIMOGES. Background: Cerebrospinal fluid (CSF) biomarkers have been extensively studied as diagnostic marker for Alzheimer’s disease (AD). However, results are variable probably due to lumbar puncture (LP) procedure, CSF collection and transport. This inter-center variability highlights the need for an efficient standardization of clinical procedures and techniques. The aims of this study were firstly to compare the LP procedure and CSF transport process between in all French Memory Centers and secondly to evaluate the incidence of LP side effects in 100 patients with cognitive disturbances. Methods: LP practice and side effect prospective questionnaires were sent to all French Memory Centers in May 2010. All data were collected until the end of July 2010. Results: 18 out of 26 Memory Centers replied with filled questionnaires. Although, these centers did not have the same LP procedure and CSF transport, the majority of them proceeded according to Innogenetics’s advices concerning the use of polypropylene tubes, transport duration and sample conditioning. Polypropylene tubes were different from one center to the other. CSF volume, pharmacological premedication and prevention of post-LP syndrome were variable in all responding center. The prospective study carried out in 100 patients revealed a very good LP acceptability (93/100 patients). LP feasibility was 97 % (90/93) and failed LP were consequently performed with success using radiological scopes. We observed 3 minor complications were observed. Conclusions: All French Centers complied with Innogenetics’ recommendations for pretechnical CSF procedures; however each Center put in place its own procedure that was different between centers. It will be very interesting to compare cutt-off and result values for Abeta tau and p181 tau between several centers that used their own procedures. Acceptability and safety were very good in our short but significant prospective study. These results confirm the data of Zetterberg et al 2010.
P1-137
ALTERATION OF A BETA-1-42 BINDING IN RED BLOOD CELLS: A POTENTIAL MARKER FOR ALZHEIMER’S DISEASE
Corinne Liegeois, Innovative Health Diognostic. Background: Beta-amyloid peptides (A-beta) bind to nerve and peripheral cells and induce alterations in Ca2+ homeostasis and protein kinase C (PKC) activation. In the search of a peripheral biomarker for Alzheimer’s disease (AD) we decided to better characterize the effect of chronically applied A-beta at low concentrations and to develop a method suitable for detection of small peptide amounts bound to the surface of these cells. Methods: Intracellular Ca2+ was measured by Fura 2 imaging to estimate the effects of A-beta-1-42. A new fluorescent probe derived from A-beta was developed. This probe was used on cultured cells and on red blood cells from transgenic TASTPM mice. Results: We show that preincubation with low A-beta concentrations induces a priming effect on primary cultures of hippocampal or cortical neurons. This priming effect is only revealed when the cells
S155
are challenged with an acute application of A-beta at high concentration. A similar priming effect was observed in human peripheral red blood cells from AD patients. Using a new fluorescent probe we were able to detect Abeta bound to the cellular membrane of preincubated cells in culture. We then developed an experimental protocol to distinguish double transgenic TASTPM mice from wild type mice. Used as a test on red blood cells from 4 month old animals, when the pathology is not yet developed, this protocol showed no significant difference between transgenic and wild type mice. However the test was positive on 14 month old mice, when the disease is almost fully developed. The statistical analysis of the results revealed a sensitivity of 77% and a specificity of 91%. Conclusions: Abeta chronically applied to nerve cells induces a priming effect, which suggests that low A-beta concentrations do not significantly alter the basal Ca2+ homeostasis but favour later applied A-beta interaction with the cellular membrane. Using this hypothesis we developed a blood test, which appears efficient in detecting AD in an animal model. This test is currently applied to human samples. It remains to be assessed whether it has a predictive value for disease progression.
P1-138
ALZHEIMER’S DISEASE AND THE ABILITY TO SPEAK OF SELF-AS-AGENT IN FUTURE CONTEXTS: DESCRIPTION AND ANALYSIS
Elissa Asp1, Kenneth Rockwood2, Sherri Fay2, 1Saint Mary’s University; 2 Capital Health/Dalhousie University, Halifax, Nova Scotia. Background: Alzheimer’s disease (AD) can impair agency, reflected in, for instance, reduced ability to plan and carry out (instrumental) activities of daily living. Several related neural systems may contribute to impaired agency in AD: episodic memory impairments may affect recall of plans; degradation of semantic systems may alter representations of component activities for carrying out plans; executive function deficits may compromise forming or carrying out plans. Relatedly, people with AD seldom speak of themselves as agents in future contexts (e.g. "Tomorrow I’m going to visit my daughter"). To aid understanding everyday behavioural correlates of neural dysfunction in AD, we investigated whether treatment response correlates with ability to respond to simple questions about plans for the future. Methods: This is a retrospective analysis of videos recorded in a placebo-controlled, double-blind trial of galantamine [CMAJ 2006; 174(8): 1099-105]. Participants had mild/moderate AD. A novel “evaluation of memory and temporality” (EMT) test was recorded for a subset (74 at baseline, 63 with follow-up). To investigate participants’ ability to speak of themselves as agents in the future, we coded whether responses to eight simple, future-directed questions were unequivocally informative, negative or confabulated. We correlated EMT responses with the trial’s outcome measures, ADAS-cog 11, CIBIC-plus, and GAS, and also with sub-components of these measures to investigate the contributions of episodic and semantic memory and executive function to response patterns. Results: In the 35 participants examined to date, all responded positively to at least one question in one interview. Although there does not appear to be an absolute inability to conceptualize oneself as a future agent, the time frames may affect responses: at baseline, 32 participants answered “what are you going to do in the next few minutes ?” positively. By contrast, 21 responded positively to “What are you going to do the day after tomorrow?”. Half of positive responses were equivocal. At eight months, there were 15% fewer positive responses. Conclusions: Simple questions about future activities may be sensitive to change in AD and might help measure treatment response. P1-139
ACCURATE NON-INVASIVE DIAGNOSES OF ALZHEIMER’S DISEASE USING EYE SCANNING
Stephan Bandelow1, Angela Clifford1, Veronika van der Wardt1, Eef Hogervorst1, Mark Madden1, James Lindesay2, Alastair Gale1, 1 Loughborough University, Loughborough; 2University of Leicester, Leicester. Background: Early and accurate non-invasive diagnosis with an earlier initiation of treatment could possibly delay progression of Alzheimer’s