- Email: [email protected]
REPURPOSING A DRUG FOR TREATMENT OF PROSTATE CANCER FOR PREVENTION OF DEMENTIA IN PARKINSON’S DISEASE
Podium Presentations: Sunday, July 24, 2016
dataset measures of genomic inflation of measures were estimated for variants of MAF>0.01. Results: We analyzed an average of 39,216,773 genotyped or imputed SNVs per dataset. Preliminary analyses identified 5 loci with P<5310-8 in known GWAS candidate loci (APOE, BIN1, the MS4A region, PICALM, and CR1), consistent with previously observed associations in these data (PMID: 21460841). An additional 13 loci demonstrated multiple single variant associations with P<10-5, including variants at two IGAP GWAS loci (PMID: 24162737), rs13155750 in MEF2C (OR(95% CI): 1.13(1.08,1.20); P¼5.09310-6) and rs755951 in PTK2B (OR(95% CI): 1.11(1.06,1.16); P¼5.61310-6). Novel associations observed include signals at LILRA5 (19:54821819; OR(95% CI): 1.14(1.08,1.20); P¼4.84310-7), known to be involved in innate immunity; and at SMOX (rs1884732; OR(95% CI): 1.11(1.06,1.17); P¼5.17310-6), which is involved in the catabolism of polyamines, levels of which are altered in AD brains. Score test analyses and replication analyses are underway and these results will be presented. Conclusions: Several novel candidate loci for LOAD have been identified using high-quality imputation of rare and low-frequency variants in the ADGC, demonstrating the utility of rare variant imputation using dense haplotype reference panels in identifying novel disease loci. O1-03-06
POLYGENIC RISK OF ALZHEIMER’S DISEASE AND NEURODEGENERATIVE RELATED TRAITS AND THEIR ASSOCIATION WITH COGNITIVE FUNCTION: UK BIOBANK AND THE DEMENTIAS PLATFORM UK
Chloe Fawns-Ritchie1, Saskia P. Hagenaars1, Sarah E. Harris1, Gail Davies1, David C. Liewald1, W. David Hill1, Jill P. Pell2, John Gallacher3, Daniel J. Smith2, Catharine R. Gale1,4, Ian J. Deary1, 1 University of Edinburgh, Edinburgh, United Kingdom; 2University of Glasgow, Glasgow, United Kingdom; 3University of Oxford, Oxford, United Kingdom; 4University of Southampton, Southampton, United Kingdom. Contact e-mail: [email protected] Background: Genome-wide association studies have identified a number of genes which are associated with increased risk of developing Alzheimer’s disease, a disease characterised by progressive decline in cognitive abilities, including episodic memory and executive functioning. In ageing, scores on cognitive tests vary substantially within the population and there may be shared genetic aetiology between cognitive functions and neurodegenerative diseases. Here, the association between polygenic profile scores for Alzheimer’s disease, as well as measures associated to neurodegeneration, and cognitive function was investigated. Methods: To test for shared genetic aetiology between Alzheimer’s disease and cognitive function, a sample of participants (N ¼ 112 151) from the UK Biobank cohort, one of the largest cohorts in the Dementias Platform UK project, was used. Polygenic profile scores for Alzheimer’s disease, and brain measures such as hippocampal volume, were created using information provided from numerous genome-wide association study consortia. The association between the polygenic profile scores and scores on tests of episodic memory, processing speed, reasoning, and executive functioning were investigated using regression models. Results: Using this large population-based sample, there were significant associations between scores on tests of cognitive function and many of the polygenic profile scores examined. Participants with higher polygenic risk of Alzheimer’s disease showed lower scores on some of the cognitive tests. There were also significant associations be-
P179
tween cognitive scores and brain measures. Conclusions: The present findings suggest that the same genes that are associated with higher risk of Alzheimer’s disease, are also implicated in cognitive functioning in the general population. Further analyses are in progress to investigate associations with other neurodegenerative diseases and related traits. Dementias Platform UK is planning to enhance the cognitive assessment within UK Biobank to include additional cognitive measures sensitive to cognitive decline and dementia. This cohort will be pivotal in researching the genetic architecture of both healthy and pathological cognitive ageing. SUNDAY, JULY 24, 2016 ORAL SESSIONS O1-04 PRECLINICAL THERAPEUTICS: TARGET IDENTIFICATION — NOVEL APPROACHES O1-04-01
REPURPOSING A DRUG FOR TREATMENT OF PROSTATE CANCER FOR PREVENTION OF DEMENTIA IN PARKINSON’S DISEASE
Giulio Maria Pasinetti, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA. Contact e-mail: [email protected] Background: Cognitive deterioration is a common feature of Parkinson’s disease (PD). About one-third of patients show signs of cognitive impairment at diagnosis and cumulative prevalence rates of Alzheimer’s disease (AD)-type dementia in PD range up to 80%. Methods: Using an experimental model of substantial nigra (SN) dopaminergic (DA) lesion, we tested the hypothesis that IRX4204, a nuclear Retinoid X Receptor (RXR) ligand, being currently developed for treatment of prostate cancer, could promote neurotrophic activity and preservation of PD motorfunction. DA lesions were performed by injection of 6-OHDA stereotaxically in the SN followed by drug treatment, and extent of lesion assessed by sterolocigal assessment of TH positive neurons in the SN. Measurement of dopamine and metabolites in the striatum region and apomorphine behavioral testing were used to monitor beneficial effects of IRX4204 treat. HPLC LC/MS/MS analysis was used for further exploring IRX4204 brain bioavailability. A battery of biochemical assays were used to explore the mechanisms by which IRX4204 may interfere with the assembly of a-syn into misfolded aggregates, cause disintegration of a-synuclein aggregates, and increase susceptibility to proteolytic digestion. Results: We found that IRX4204 neuroprotects DA neurons through mechanisms involving the expression of genes associated with dopamine synthesis and neurotrophic activities. However, we also found that IRX4204 may prevent the accumulation of neurotoxic b-amyloid (Ab)-mediated oligomerization in a mouse model of dementia, coincidental with attenuation of AD-type cognitive deterioration. IRX4204 may beneficially attenuate the risk of PD-associated dementia through prevention of Ab neurotoxicity while promoting motor functions through mechanisms involving DA neuroprotection. Ongoing studies are characterizing the role of IRX4204 in PD dementia through mechanisms interfering with abnormal asynuclein fibrillization. Data will be presented to demonstrate that IRX4204 may activate Nurr-1 and promote neuroprotective mechanisms against dementia and DA degeneration through the control of transcription of glial cell line-derived neurotrophic factor (GNDF) signaling pathways that are significantly down regulated in a-synuclein-mediated pathological conditions. Conclusions: The
P180
Podium Presentations: Sunday, July 24, 2016
outcomes of this study will provide novel disease modifying strategies to prevent DA cell death and possibly dementia through attenuation of a-synuclein fibrils induced toxicity and Lewy body formation, pathological features associated with dementia in PD.
O1-04-02
LIFESPAN OF ONE FOCUSED ULTRASOUND MEDIATED BLOOD-BRAIN BARRIER TREATMENT IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
Charissa Poon1,2, Kullervo Hynynen1,2, 1University of Toronto, Toronto, ON, Canada; 2Sunnybrook Research Institute, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Focused ultrasound (FUS) mediated blood-brain barrier opening (BBBO) is a noninvasive and targetable method to cause transient BBBO (Hynynen, 2001). It has been used to successfully deliver an anti-b-amyloid (Ab) antibody, BAM10, through the BBB of a mouse model of Alzheimer’s disease (AD) (Jord~ao, 2010). Surprisingly, three weekly treatments of FUS mediated BBBO without therapeutics has also been shown decrease Ab plaque loads and improve cognitive deficits in an amyloidogenic mouse model of AD (Burgess, 2014). The cognitive improvements after repeated FUS treatments were verified in a different mouse model of AD (Leinenga, 2015). For repeated treatments to be most effective, the lifespan of one FUS treatment in AD must be determined. Methods: Two-photon microscopy allows repeated in vivo imaging of vasculature, plaques, and cells through a cranial window. Imaging began three weeks after implantation of a sterile cranial window to avoid artifacts from inflammation (Holtmaat, 2009). The field of view was chosen to include arterioles, venules, and capillaries. The vasculature was visualized by injecting a fluorescent dextran into the systemic circulation; Ab was labelled with methoxy-X04 (Klunk, 2002). A single-element piezoelectric transducer was used for FUS application. BBBO was confirmed by
leakage of fluorescent dextran into the extravascular space (Cho, 2011). Plaque sizes were tracked for two weeks following FUS treatment. For quantification of soluble Ab, the bilateral hippocampi were treated using magnetic resonance imaging-guided FUS-mediated BBBO. The hippocampus was then isolated, and Ab species were quantified using electrospray ionization mass spectroscopy. Results: The methodology for the two-photon experiments has been optimized. Plaques can be consistently located every imaging session by mapping their distance relative to the surrounding vasculature and cerebral amyloid angiopathy. Mass spectrometry optimization is currently underway. Conclusions: Despite the growing evidence that FUS mediated BBBO without therapeutics improves AD pathology, the mechanism behind this is still not understood. Two-photon microscopy allows longitudinal imaging analyses of how FUS affects the vasculature and Ab plaques. Understanding the lifespan of one FUS treatment will aid in determining the frequency of FUS treatments required and safety considerations, which will be helpful for fine-tuning treatment paradigms for using FUS with AD therapeutics.
O1-04-03
IDENTIFICATION OF A NOVEL LIPID-RELATED DRUG TARGET TO REACTIVATE ADULT NEURAL STEM CELLS IN ALZHEIMER’S DISEASE
Laura K. Hamilton1, Sandra E. Joppe2, Martin Dufresne2, Pierre Chaurand2, Sarah Petryszyn3, Martin Parent4, Karl J. L. Fernandes2, Anne Aumont2, Alexandra Furtos2, Frederic Calon5, 1Universite de Montreal/CRCHUM, Montreal, QC, Canada; 2Universite de Montreal, Montreal, QC, Canada; 3Universite de Laval, Quebec City, QC, Canada; 4 Universite de Montreal, Quebec City, QC, Canada; 5Faculty of Pharmacy, Universite Laval, Quebec, QC, Canada. Contact e-mail: [email protected] Background: Alois Alzheimer originally described five pathologies within the brains of AD patients: blood vessel abnormalities (cerebrovascular amyloidoisis), intraneuronal fibrils (neurofibrillary tangles), focal deposits (amyloid plaques),
dataset measures of genomic inflation of measures were estimated for variants of MAF>0.01. Results: We analyzed an average of 39,216,773 genotyped or imputed SNVs per dataset. Preliminary analyses identified 5 loci with P<5310-8 in known GWAS candidate loci (APOE, BIN1, the MS4A region, PICALM, and CR1), consistent with previously observed associations in these data (PMID: 21460841). An additional 13 loci demonstrated multiple single variant associations with P<10-5, including variants at two IGAP GWAS loci (PMID: 24162737), rs13155750 in MEF2C (OR(95% CI): 1.13(1.08,1.20); P¼5.09310-6) and rs755951 in PTK2B (OR(95% CI): 1.11(1.06,1.16); P¼5.61310-6). Novel associations observed include signals at LILRA5 (19:54821819; OR(95% CI): 1.14(1.08,1.20); P¼4.84310-7), known to be involved in innate immunity; and at SMOX (rs1884732; OR(95% CI): 1.11(1.06,1.17); P¼5.17310-6), which is involved in the catabolism of polyamines, levels of which are altered in AD brains. Score test analyses and replication analyses are underway and these results will be presented. Conclusions: Several novel candidate loci for LOAD have been identified using high-quality imputation of rare and low-frequency variants in the ADGC, demonstrating the utility of rare variant imputation using dense haplotype reference panels in identifying novel disease loci. O1-03-06
POLYGENIC RISK OF ALZHEIMER’S DISEASE AND NEURODEGENERATIVE RELATED TRAITS AND THEIR ASSOCIATION WITH COGNITIVE FUNCTION: UK BIOBANK AND THE DEMENTIAS PLATFORM UK
Chloe Fawns-Ritchie1, Saskia P. Hagenaars1, Sarah E. Harris1, Gail Davies1, David C. Liewald1, W. David Hill1, Jill P. Pell2, John Gallacher3, Daniel J. Smith2, Catharine R. Gale1,4, Ian J. Deary1, 1 University of Edinburgh, Edinburgh, United Kingdom; 2University of Glasgow, Glasgow, United Kingdom; 3University of Oxford, Oxford, United Kingdom; 4University of Southampton, Southampton, United Kingdom. Contact e-mail: [email protected] Background: Genome-wide association studies have identified a number of genes which are associated with increased risk of developing Alzheimer’s disease, a disease characterised by progressive decline in cognitive abilities, including episodic memory and executive functioning. In ageing, scores on cognitive tests vary substantially within the population and there may be shared genetic aetiology between cognitive functions and neurodegenerative diseases. Here, the association between polygenic profile scores for Alzheimer’s disease, as well as measures associated to neurodegeneration, and cognitive function was investigated. Methods: To test for shared genetic aetiology between Alzheimer’s disease and cognitive function, a sample of participants (N ¼ 112 151) from the UK Biobank cohort, one of the largest cohorts in the Dementias Platform UK project, was used. Polygenic profile scores for Alzheimer’s disease, and brain measures such as hippocampal volume, were created using information provided from numerous genome-wide association study consortia. The association between the polygenic profile scores and scores on tests of episodic memory, processing speed, reasoning, and executive functioning were investigated using regression models. Results: Using this large population-based sample, there were significant associations between scores on tests of cognitive function and many of the polygenic profile scores examined. Participants with higher polygenic risk of Alzheimer’s disease showed lower scores on some of the cognitive tests. There were also significant associations be-
P179
tween cognitive scores and brain measures. Conclusions: The present findings suggest that the same genes that are associated with higher risk of Alzheimer’s disease, are also implicated in cognitive functioning in the general population. Further analyses are in progress to investigate associations with other neurodegenerative diseases and related traits. Dementias Platform UK is planning to enhance the cognitive assessment within UK Biobank to include additional cognitive measures sensitive to cognitive decline and dementia. This cohort will be pivotal in researching the genetic architecture of both healthy and pathological cognitive ageing. SUNDAY, JULY 24, 2016 ORAL SESSIONS O1-04 PRECLINICAL THERAPEUTICS: TARGET IDENTIFICATION — NOVEL APPROACHES O1-04-01
REPURPOSING A DRUG FOR TREATMENT OF PROSTATE CANCER FOR PREVENTION OF DEMENTIA IN PARKINSON’S DISEASE
Giulio Maria Pasinetti, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA. Contact e-mail: [email protected] Background: Cognitive deterioration is a common feature of Parkinson’s disease (PD). About one-third of patients show signs of cognitive impairment at diagnosis and cumulative prevalence rates of Alzheimer’s disease (AD)-type dementia in PD range up to 80%. Methods: Using an experimental model of substantial nigra (SN) dopaminergic (DA) lesion, we tested the hypothesis that IRX4204, a nuclear Retinoid X Receptor (RXR) ligand, being currently developed for treatment of prostate cancer, could promote neurotrophic activity and preservation of PD motorfunction. DA lesions were performed by injection of 6-OHDA stereotaxically in the SN followed by drug treatment, and extent of lesion assessed by sterolocigal assessment of TH positive neurons in the SN. Measurement of dopamine and metabolites in the striatum region and apomorphine behavioral testing were used to monitor beneficial effects of IRX4204 treat. HPLC LC/MS/MS analysis was used for further exploring IRX4204 brain bioavailability. A battery of biochemical assays were used to explore the mechanisms by which IRX4204 may interfere with the assembly of a-syn into misfolded aggregates, cause disintegration of a-synuclein aggregates, and increase susceptibility to proteolytic digestion. Results: We found that IRX4204 neuroprotects DA neurons through mechanisms involving the expression of genes associated with dopamine synthesis and neurotrophic activities. However, we also found that IRX4204 may prevent the accumulation of neurotoxic b-amyloid (Ab)-mediated oligomerization in a mouse model of dementia, coincidental with attenuation of AD-type cognitive deterioration. IRX4204 may beneficially attenuate the risk of PD-associated dementia through prevention of Ab neurotoxicity while promoting motor functions through mechanisms involving DA neuroprotection. Ongoing studies are characterizing the role of IRX4204 in PD dementia through mechanisms interfering with abnormal asynuclein fibrillization. Data will be presented to demonstrate that IRX4204 may activate Nurr-1 and promote neuroprotective mechanisms against dementia and DA degeneration through the control of transcription of glial cell line-derived neurotrophic factor (GNDF) signaling pathways that are significantly down regulated in a-synuclein-mediated pathological conditions. Conclusions: The
P180
Podium Presentations: Sunday, July 24, 2016
outcomes of this study will provide novel disease modifying strategies to prevent DA cell death and possibly dementia through attenuation of a-synuclein fibrils induced toxicity and Lewy body formation, pathological features associated with dementia in PD.
O1-04-02
LIFESPAN OF ONE FOCUSED ULTRASOUND MEDIATED BLOOD-BRAIN BARRIER TREATMENT IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
Charissa Poon1,2, Kullervo Hynynen1,2, 1University of Toronto, Toronto, ON, Canada; 2Sunnybrook Research Institute, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Focused ultrasound (FUS) mediated blood-brain barrier opening (BBBO) is a noninvasive and targetable method to cause transient BBBO (Hynynen, 2001). It has been used to successfully deliver an anti-b-amyloid (Ab) antibody, BAM10, through the BBB of a mouse model of Alzheimer’s disease (AD) (Jord~ao, 2010). Surprisingly, three weekly treatments of FUS mediated BBBO without therapeutics has also been shown decrease Ab plaque loads and improve cognitive deficits in an amyloidogenic mouse model of AD (Burgess, 2014). The cognitive improvements after repeated FUS treatments were verified in a different mouse model of AD (Leinenga, 2015). For repeated treatments to be most effective, the lifespan of one FUS treatment in AD must be determined. Methods: Two-photon microscopy allows repeated in vivo imaging of vasculature, plaques, and cells through a cranial window. Imaging began three weeks after implantation of a sterile cranial window to avoid artifacts from inflammation (Holtmaat, 2009). The field of view was chosen to include arterioles, venules, and capillaries. The vasculature was visualized by injecting a fluorescent dextran into the systemic circulation; Ab was labelled with methoxy-X04 (Klunk, 2002). A single-element piezoelectric transducer was used for FUS application. BBBO was confirmed by
leakage of fluorescent dextran into the extravascular space (Cho, 2011). Plaque sizes were tracked for two weeks following FUS treatment. For quantification of soluble Ab, the bilateral hippocampi were treated using magnetic resonance imaging-guided FUS-mediated BBBO. The hippocampus was then isolated, and Ab species were quantified using electrospray ionization mass spectroscopy. Results: The methodology for the two-photon experiments has been optimized. Plaques can be consistently located every imaging session by mapping their distance relative to the surrounding vasculature and cerebral amyloid angiopathy. Mass spectrometry optimization is currently underway. Conclusions: Despite the growing evidence that FUS mediated BBBO without therapeutics improves AD pathology, the mechanism behind this is still not understood. Two-photon microscopy allows longitudinal imaging analyses of how FUS affects the vasculature and Ab plaques. Understanding the lifespan of one FUS treatment will aid in determining the frequency of FUS treatments required and safety considerations, which will be helpful for fine-tuning treatment paradigms for using FUS with AD therapeutics.
O1-04-03
IDENTIFICATION OF A NOVEL LIPID-RELATED DRUG TARGET TO REACTIVATE ADULT NEURAL STEM CELLS IN ALZHEIMER’S DISEASE
Laura K. Hamilton1, Sandra E. Joppe2, Martin Dufresne2, Pierre Chaurand2, Sarah Petryszyn3, Martin Parent4, Karl J. L. Fernandes2, Anne Aumont2, Alexandra Furtos2, Frederic Calon5, 1Universite de Montreal/CRCHUM, Montreal, QC, Canada; 2Universite de Montreal, Montreal, QC, Canada; 3Universite de Laval, Quebec City, QC, Canada; 4 Universite de Montreal, Quebec City, QC, Canada; 5Faculty of Pharmacy, Universite Laval, Quebec, QC, Canada. Contact e-mail: [email protected] Background: Alois Alzheimer originally described five pathologies within the brains of AD patients: blood vessel abnormalities (cerebrovascular amyloidoisis), intraneuronal fibrils (neurofibrillary tangles), focal deposits (amyloid plaques),