- Email: [email protected]
The Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) trial
S8
Abstracts / Neurobiology of Aging 39 (2016) S1eS13
Nijmegen, Netherlands 3 Nutricia Research, Nutricia Advanced Medical Nutrition, Utrecht, Netherlands; 4 Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, Netherlands. E-mail: [email protected] The medical food SouvenaidÒ, containing FortasynÒ Connect1, has been formulated to counteract synaptic loss and reduce membrane-related pathology in Alzheimer’s disease (AD) by promoting neuronal membrane formation and function. The present Magnetic Resonance Spectroscopy (MRS) study investigates whether Souvenaid affects brain phospholipid metabolism in AD patients by assessing phosphorus (31P) MRS measures of phospholipid synthesis and breakdown. 34 drug-naïve patients with mild AD (Mini-Mental State Examination [MMSE] 20) were enrolled in this double-blind randomised controlled study (NTR3346) to receive Souvenaid or control product daily for 4 weeks. At baseline and after 4 weeks, 31P-MRS of the whole brain, T1-weighted imaging, proton MRS, safety data and blood were collected. Main outcome parameters were relative levels of phosphomonoesters (PME, i.e. membrane phospholipid precursors), phosphodiesters (PDE, i.e. membrane phospholipid breakdown products) and their ratio from 4 brain regions (left and right hippocampus, and anterior cingulate and retrosplenial cortex). Group differences were analysed using mixed models. 31P-MRS data were collected from 33 subjects (mean MMSE 23.1 [SD ¼ 1.9], mean age 73.7 years [SD ¼ 6.8], 14 males). Main intervention effects are reported, since no significant interactions were observed between intervention and brain region. PME/ PDE was higher after 4 weeks of Souvenaid compared to control product (primary model I: LS mean difference ¼ 0.14, SEM ¼ 0.07, p ¼ 0.061; primary model II: LS mean difference ¼ 0.18, SEM ¼ 0.06, p ¼ 0.005), while no significant intervention effect was found for PME or PDE. The result of increased PME/PDE may indicate enhanced phospholipid formation in the brain after 4 weeks intervention with Souvenaid in patients with mild AD. This extends previous findings in preclinical in vivo studies showing that dietary enrichment of the same specific nutrient combination increased formation of neuronal membranes, and is in line with the hypothesis that Souvenaid enhances the formation of neuronal membranes.1 Souvenaid and Fortasyn are registered trademarks of N.V. Nutricia. Keywords. Alzheimer’s disease, Magnetic Resonance Spectroscopy (MRS), Medical food, Phospholipid metabolism
TRANSMISSION OF MISFOLDED PROTEINS IN NEURODEGENERATIVE DISORDERS: A COMMON MECHANISM OF DISEASE PROGRESSION Virginia Lee. University of Pennsylvania, Philadelphia, PA. E-mail: [email protected] The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation and spreading of these disease proteins in brain are poorly understood. Recent studies demonstrate that misfolded disease proteins including alphasynuclein in Parkinson’s disease and tau in Alzheimer’s disease and frontotemporal degeneration can be propagated from cell-to-cell through the recruitment of their endogenous normal counterparts. Moreover, pathologic misfolded aggregates propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and appear to follow neuroanatomical interconnectomes. This spreading of pathology is progressive and leads to behavior impairments and eventually compromises neuronal survival but immune therapy reduces the spread of pathology, rescue behavior phenotypes and neuron loss. Our findings open up new avenues for understanding the mechanisms of disease progression and for developing novel therapeutics. Keywords. disorders
Alpha-synuclein,
Misfolded
proteins,
Neurodegenerative
COORDINATE-BASED META-ANALYSIS OF RESTING FMRI STUDIES FOR THE IDENTIFICATION OF POTENTIAL TARGETS FOR BRAIN STIMULATION IN AD AND BVFTD Michela Pievani1, Lorenzo Pini1, Clarissa Ferrari1, Francesca Pizzini2, Ilaria Boscolo Galazzo2, Maria Cotelli1, Rosa Manenti1, Giovanni Frisoni1.
1
IRCCS Fatebenefratelli, Brescia, Italy; 2 Neuroradiology, Department of Diagnostics and Pathology, Verona University Hospital, Verona, Italy. E-mail: [email protected]
Introduction. Resting-state functional MRI (rs-fMRI) studies might help to find potential targets for non-invasive brain stimulation (Fox et al., 2014). In Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD), two rs-fMRI networks are specifically affected by pathology, i.e. the default mode (DMN) and the salience (SN) network, respectively (Pievani et al., 2014). Aim of this study was to determine DMN and SN coordinates that might be used to identify targets for brain stimulation in these diseases. Methods. A systematic search was performed for rs-fMRI studies according to PRISMA guidelines and studies reporting DMN and SN patterns in healthy subjects were included. Coordinate-based meta-analyses were conducted to identify (i) DMN and (ii) SN connectivity patterns by GingerALE BrainMap application (v2.3.3) with the activation likelihood estimation (ALE) method. The spatial correspondence between rs-fMRI patterns and EEG system targets was then verified through stereotactic markers (fish-oil capsules) located on the EEG cap of a healthy volunteer undergoing rs-fMRI. Results. Forty-five DMN studies and fourteen SN studies were included, with a total of 2440 and 383 subjects respectively. Consistent DMN coordinates mapped to the posterior cingulate cortex (BA 31), medial anterior cingulate and frontal cortex (BA 24/9), and bilateral angular gyrus (BA 39). Further smaller clusters mapped to the temporal cortex (lateral - BA 21 - and parahippocampus - BA 28/36/35), and the lateral superior frontal cortex (BA 6/8) bilaterally. SN coordinates mapped to the medial anterior cingulate cortex (BA 32), bilateral insula, bilateral supramarginal gyrus (BA 40) and right anterior prefrontal cortex (BA 9/10). Conclusions. Taking into account the properties of non-invasive brain stimulation, which cannot reach deep areas (e.g., cingulate cortex, parahippocampus, insula), superficial candidate targets for DMN stimulation in AD might be the bilateral angular gyrus and for SN stimulation in bvFTD the right anterior prefrontal cortex. The test on the volunteer assured that these ROIs are anatomically adjacent to the stereotactic EEG markers. Keywords. Alzheimer’s disease, Behavioral variant frontotemporal dementia, Brain stimulation, Default mode network, Meta-analysis, Salience network
THE ALZHEIMER’S PREVENTION INITIATIVE (API) AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE (ADAD) TRIAL Jessica Langbaum1, Pierre Tariot2, Eric Reiman2, William Cho2, Robert Paul2, Michael Ward2, Silvia Rios Romenets2, Francisco Lopera2. 1 Banner Alzheimer’s Institute, Phoenix, AZ; 2 N/A, N/A. E-mail: [email protected] The Alzheimer’s Prevention Initiative (API) is a collaborative research program involving the Banner Alzheimer’s Institute (BAI) and key partners that evaluates promising treatments with the ultimate goal to postpone, reduce the risk of, or prevent the clinical onset of Alzheimer’s disease (AD). API’s preclinical treatment studies focus on cognitively unimpaired people who, based on age and genetic background, are at the highest imminent risk of developing AD symptoms. Aims include establishing whether cognitive decline or the emergence of clinical symptoms of dementia can be slowed; relating a treatment’s biomarker effects to clinical outcome; theragnostic biomarker development; robustly testing the amyloid hypothesis; further accelerating prevention therapies; giving persons at highest risk access to investigational treatments; creating large prevention registries for these and other preclinical trials; and complementing other prevention initiatives. The API Autosomal Dominant Alzheimer’s Disease (ADAD) Trial, conducted in full partnership with Genentech and the University of Antioquia (UdeA), is evaluating crenezumab in unimpaired PSEN1 E280A mutation carriers at certain risk for developing early-onset AD. Primary outcome is change on the API ADAD composite cognitive test score. Secondary outcomes include time to progression to mild cognitive impairment or dementia due to AD, and change in several AD biomarker measurements including amyloid PET, FDG PET, volumetric MRI, and CSF tau. The Colombian API Registry, created by the UdeA in conjunction with BAI and Genentech, provides a resource for enrollment into the API ADAD Trial and for biomarker and cognitive studies of ADAD. The Registry includes >4,500 members of the PSEN1 E280A kindred, approximately 25% of whom are mutation carriers. We launched the ADAD Trial in 2013. In parallel, we continue to characterize the preclinical trajectory of ADAD in the Antioquia cohort, refine composite cognitive
Abstracts / Neurobiology of Aging 39 (2016) S1eS13
endpoints; estimate sample sizes using biomarker and cognitive endpoints; expand the Colombian API Registry; engage academic, industry and regulatory stakeholders; and prepare for future API trials. Keywords. Alzheimer’s disease, Clinical trial, Preclinical, Prevention
TIME TO FORGET MICE? USING HUMAN CELLS FOR DRUG TESTING? Manfred Windisch. NeuroScios GmbH, St. Radegund, Austria. E-mail: [email protected] The enormous failure rate of new treatments for Alzheimer’s disease (AD) in clinical development is questioning the translational value of preclinical animal models and is demanding better alternatives. It was shown 2014 (Choi et. al; 2014) that 3 dimensional neuronal from human neuronal stem cell can develop all pathological features of AD including toxic Ab oligomers, extracellular plaque like amyloid depositions, p-tau and finally even neurofibrillary tangle like structures. But it needs to be clarified that this is the result of viral transfection of these cells with mutated APP containing Swedish and London mutation, as well as mutated PS1. So also this model of “AD in the petri dish” utilizes a combination of FAD mutations, but in contrast to mouse models the development of neurofibrillary pathology is based on wild-type human tau. Even first conclusions about the use for drug testing can be drawn from this in vitro model, because b- and g-secretase inhibitors/modulators are reducing the amyloid-, but at the same moment ameliorate also NFTpathology. From that point of view the human cells seem to be a promising approach for predictive drug testing, with few limitations, like many transgenic mice they represent a highly artificial combination of FAD features, the “cognitive performance” is rather limited, and so far no drugs exclusively tested in such a, in vitro system reached the advanced clinical trial phase and had no chance to produce success or failure. This is exactly the weak point, because the translation of drug effects on brain pathology worked well in the in vivo models, just reproducing cognitive improvement did not work out. What’s the problem? Are the models not appropriate, did we not use these model in the right way, did we test not really efficacious drugs, or should we even question the rationale behind some of the most actual targets? The development of “humanized” mice and rats may help, as well as the consideration of advanced cognitive test systems in animals and potentially more relevant cognitive test batteries in human trials. More provocative, can we consider to move compounds into clinic without efficacy testing in mice? Keywords. Stem cells, Tissue culture, Transgenic mice, Translation
SIMULTANEOUS QUANTITATIVE SUSCEPTIBILITY MAPPING-MRI AND 18F-FLUTAMETAMOL-PET INDICATE FUNCTIONAL IMPACT OF CEREBRAL IRON AND AMYLOID-b PLAQUE BURDEN IN COGNITIVELY NORMAL SUPER-AGERS Jiri van Bergen1, Frances-Catherine Quevenco1, Sandra Leh2, Anton Gietl1, Valerie Treyer3, Rafael Meyer3, Roger Nitsch1, Christoph Hock1, Paul Unschuld1. 1 University of Zurich, Zurich, Switzerland; 2 University Zürich, Zürich, Switzerland; 3 University Zürich, Zurich, Switzerland. E-mail: [email protected] Background. The aging brain is characterized by distinct pathological alterations that include extracellular accumulation of Amyloid-b (Ab), increased iron load and altered functional properties. This study aimed to investigate cerebral Ab and iron, as well as associated functional brain network activity in a context of cognitively normal aging. Methods. 25 cognitively normal elderly participants (“super-agers”, mean age ¼ 87.6 (SD 2.97) years), were administered 18F-Flutemetamol-PET for estimating Ab-plaque burden, Quantitative-Susceptibility-Mapping (QSM) MRI for cerebral iron load, and functional MRI (fMRI) at rest for assessing functional connectivity with the posterior cingulate cortex, using a 3T SIGNA GE combined PET-MR instrument. Standardized uptake value ratios (SUVR) for 18F-Flutametamol (85-105 minutes post injection) were calculated by time-of-flight reconstruction (voxel size ¼ 1.2x1.2x2.78mm3) and used for splitting the study sample in two groups: “Ab-positive” (n ¼ 6) and “Ab-negative” (n ¼ 19). QSM images were reconstructed from a 3D multi-
S9
echo GRE sequence (TR/TE/DTE ¼ 40/3/4ms, voxel size ¼ 1x1x1mm3). fMRI resting-state scans were performed using a gradient echo EPI sequence (TR: 2.55s, scan time: 8:32min). Results. Local iron load significantly differed between groups (p-FDR-corrected < 0.05) for the caudate nucleus (right and left), and putamen (right and left). By applying the CONN-toolbox, connectivity patterns associated with high cortical Ab (10361 voxels) and high cortical iron (20112 voxels) could be identified (extent threshold FDR-corrected for p < 0.05), which showed a high degree of spatial overlap (7568 voxels) and also temporal synchronicity (adjusted-R2 ¼ 0.59). Discussion. The co-occurence of cortical Ab-plaque load with iron accumulation in basal ganglia gray-matter nuclei indicates the presence of common age-related brain change in cognitively normal super-agers. Additional research is needed to characterize potential compensatory mechanisms that allow for normal cognitive performance, including a potential role of functional network connectivity for conveying resilience against pathologies accumulating in the aging brain. Keywords. Flutametamol, Functional connectivity, Iron
IMAGING NEUROINFLAMMATION IN ALZHEIMER’S AND OTHER DEMENTIAS: RECENT ADVANCES AND FUTURE DIRECTIONS David Brooks. Aarhus University Denmark, Aarhus N, Mid Jutland. E-mail: [email protected] While the molecular mechanisms causing neuronal loss and synaptic damage in Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Lewy body dementias (LBD) are poorly understood, the presence of neuroinflammation (glial activation) is a common feature. However, the relative timing and relationship between inflammation and the abnormal protein aggregation underlying these disorders remains uncertain. An increasing body of evidence suggests that activated microglia may play a central role in driving AD progression and therapies designed to suppress microglial activation are now being trialed as neuroprotective agents. This talk will review the approaches for imaging neuroinflammation and present their findings in AD, FTD and LBD. It will focus on the relationship between amyloid deposition, microglial activation, and tau aggregation and discuss possible intervention strategies. The different roles of microglial phenotypes will also be debated. Keywords. Alzheimer, Amyloid-PET, Inflammation, Parkinson’s disease, Imaging, Tau
PSP AND SMALL VESSEL DISEASE: MORE THAN OCCASIONAL CO-OCCURENCE? Anne Sieben1, Patrick Santens2, Dimitri Hemelsoet2, Sebastiaan Engelborghs1, Peter De Jonghe3, Jan De Bleecker2, Jen Maes4, Christina Jadoul5, Patrick Cras3, Peter-Paul De Deyn1, Christine Van Jean-Jacques Martin6. 1 Institute Born-Bunge, Antwerp Broeckhoven1, University, Antwerp, Belgium; 2 Gent University Hospital, Gent, Belgium; 3 Antwerp University Hospital, Antwerp, Belgium; 4 N/A, N/A 5 AZ Nikolaas, Sint-Niklaas, Belgium; 6 Institute Born-Bunge, Antwerpen, Belgium. E-mail: [email protected] Progressive supranuclear palsy (PSP) is a neurodegenerative disorder, characterized by Parkinsonism, gaze paresis and progressive cognitive decline. PSP is the most frequent tauopathy with a prevalence of 1,39 per 100 000. New insights in the pathophysiology of Alzheimer’s Disease (AD) show that cerebrovascular risk factors are important in neurodegeneration. The occurrence of cerebrovascular pathology in disorders such as AD, Parkinson’s and recently Pick’s Disease suggests that neuronal loss is not only a problem of proteinopathies, but also of ischemic changes inducing neuronal damage. In the brain bank of neurodegenerative disorders in the Institute Born Bunge at the Antwerp University, we collected in the last 2 years 7 brains of patients suffering from PSP. Age of death was 74 years (66-84). A standardized battery of samples was taken from every patient, including different cortical areas, subcortical nuclei, brain stem and cerebellum, on which extensive histochemistry and immunohistochemical stainings were performed. Neuropathological analyses were in all cases compatible with the typical combined tauopathy of neurons, astrocytes and oligodendrocytes. Lesions were found
Abstracts / Neurobiology of Aging 39 (2016) S1eS13
Nijmegen, Netherlands 3 Nutricia Research, Nutricia Advanced Medical Nutrition, Utrecht, Netherlands; 4 Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, Netherlands. E-mail: [email protected] The medical food SouvenaidÒ, containing FortasynÒ Connect1, has been formulated to counteract synaptic loss and reduce membrane-related pathology in Alzheimer’s disease (AD) by promoting neuronal membrane formation and function. The present Magnetic Resonance Spectroscopy (MRS) study investigates whether Souvenaid affects brain phospholipid metabolism in AD patients by assessing phosphorus (31P) MRS measures of phospholipid synthesis and breakdown. 34 drug-naïve patients with mild AD (Mini-Mental State Examination [MMSE] 20) were enrolled in this double-blind randomised controlled study (NTR3346) to receive Souvenaid or control product daily for 4 weeks. At baseline and after 4 weeks, 31P-MRS of the whole brain, T1-weighted imaging, proton MRS, safety data and blood were collected. Main outcome parameters were relative levels of phosphomonoesters (PME, i.e. membrane phospholipid precursors), phosphodiesters (PDE, i.e. membrane phospholipid breakdown products) and their ratio from 4 brain regions (left and right hippocampus, and anterior cingulate and retrosplenial cortex). Group differences were analysed using mixed models. 31P-MRS data were collected from 33 subjects (mean MMSE 23.1 [SD ¼ 1.9], mean age 73.7 years [SD ¼ 6.8], 14 males). Main intervention effects are reported, since no significant interactions were observed between intervention and brain region. PME/ PDE was higher after 4 weeks of Souvenaid compared to control product (primary model I: LS mean difference ¼ 0.14, SEM ¼ 0.07, p ¼ 0.061; primary model II: LS mean difference ¼ 0.18, SEM ¼ 0.06, p ¼ 0.005), while no significant intervention effect was found for PME or PDE. The result of increased PME/PDE may indicate enhanced phospholipid formation in the brain after 4 weeks intervention with Souvenaid in patients with mild AD. This extends previous findings in preclinical in vivo studies showing that dietary enrichment of the same specific nutrient combination increased formation of neuronal membranes, and is in line with the hypothesis that Souvenaid enhances the formation of neuronal membranes.1 Souvenaid and Fortasyn are registered trademarks of N.V. Nutricia. Keywords. Alzheimer’s disease, Magnetic Resonance Spectroscopy (MRS), Medical food, Phospholipid metabolism
TRANSMISSION OF MISFOLDED PROTEINS IN NEURODEGENERATIVE DISORDERS: A COMMON MECHANISM OF DISEASE PROGRESSION Virginia Lee. University of Pennsylvania, Philadelphia, PA. E-mail: [email protected] The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation and spreading of these disease proteins in brain are poorly understood. Recent studies demonstrate that misfolded disease proteins including alphasynuclein in Parkinson’s disease and tau in Alzheimer’s disease and frontotemporal degeneration can be propagated from cell-to-cell through the recruitment of their endogenous normal counterparts. Moreover, pathologic misfolded aggregates propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and appear to follow neuroanatomical interconnectomes. This spreading of pathology is progressive and leads to behavior impairments and eventually compromises neuronal survival but immune therapy reduces the spread of pathology, rescue behavior phenotypes and neuron loss. Our findings open up new avenues for understanding the mechanisms of disease progression and for developing novel therapeutics. Keywords. disorders
Alpha-synuclein,
Misfolded
proteins,
Neurodegenerative
COORDINATE-BASED META-ANALYSIS OF RESTING FMRI STUDIES FOR THE IDENTIFICATION OF POTENTIAL TARGETS FOR BRAIN STIMULATION IN AD AND BVFTD Michela Pievani1, Lorenzo Pini1, Clarissa Ferrari1, Francesca Pizzini2, Ilaria Boscolo Galazzo2, Maria Cotelli1, Rosa Manenti1, Giovanni Frisoni1.
1
IRCCS Fatebenefratelli, Brescia, Italy; 2 Neuroradiology, Department of Diagnostics and Pathology, Verona University Hospital, Verona, Italy. E-mail: [email protected]
Introduction. Resting-state functional MRI (rs-fMRI) studies might help to find potential targets for non-invasive brain stimulation (Fox et al., 2014). In Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD), two rs-fMRI networks are specifically affected by pathology, i.e. the default mode (DMN) and the salience (SN) network, respectively (Pievani et al., 2014). Aim of this study was to determine DMN and SN coordinates that might be used to identify targets for brain stimulation in these diseases. Methods. A systematic search was performed for rs-fMRI studies according to PRISMA guidelines and studies reporting DMN and SN patterns in healthy subjects were included. Coordinate-based meta-analyses were conducted to identify (i) DMN and (ii) SN connectivity patterns by GingerALE BrainMap application (v2.3.3) with the activation likelihood estimation (ALE) method. The spatial correspondence between rs-fMRI patterns and EEG system targets was then verified through stereotactic markers (fish-oil capsules) located on the EEG cap of a healthy volunteer undergoing rs-fMRI. Results. Forty-five DMN studies and fourteen SN studies were included, with a total of 2440 and 383 subjects respectively. Consistent DMN coordinates mapped to the posterior cingulate cortex (BA 31), medial anterior cingulate and frontal cortex (BA 24/9), and bilateral angular gyrus (BA 39). Further smaller clusters mapped to the temporal cortex (lateral - BA 21 - and parahippocampus - BA 28/36/35), and the lateral superior frontal cortex (BA 6/8) bilaterally. SN coordinates mapped to the medial anterior cingulate cortex (BA 32), bilateral insula, bilateral supramarginal gyrus (BA 40) and right anterior prefrontal cortex (BA 9/10). Conclusions. Taking into account the properties of non-invasive brain stimulation, which cannot reach deep areas (e.g., cingulate cortex, parahippocampus, insula), superficial candidate targets for DMN stimulation in AD might be the bilateral angular gyrus and for SN stimulation in bvFTD the right anterior prefrontal cortex. The test on the volunteer assured that these ROIs are anatomically adjacent to the stereotactic EEG markers. Keywords. Alzheimer’s disease, Behavioral variant frontotemporal dementia, Brain stimulation, Default mode network, Meta-analysis, Salience network
THE ALZHEIMER’S PREVENTION INITIATIVE (API) AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE (ADAD) TRIAL Jessica Langbaum1, Pierre Tariot2, Eric Reiman2, William Cho2, Robert Paul2, Michael Ward2, Silvia Rios Romenets2, Francisco Lopera2. 1 Banner Alzheimer’s Institute, Phoenix, AZ; 2 N/A, N/A. E-mail: [email protected] The Alzheimer’s Prevention Initiative (API) is a collaborative research program involving the Banner Alzheimer’s Institute (BAI) and key partners that evaluates promising treatments with the ultimate goal to postpone, reduce the risk of, or prevent the clinical onset of Alzheimer’s disease (AD). API’s preclinical treatment studies focus on cognitively unimpaired people who, based on age and genetic background, are at the highest imminent risk of developing AD symptoms. Aims include establishing whether cognitive decline or the emergence of clinical symptoms of dementia can be slowed; relating a treatment’s biomarker effects to clinical outcome; theragnostic biomarker development; robustly testing the amyloid hypothesis; further accelerating prevention therapies; giving persons at highest risk access to investigational treatments; creating large prevention registries for these and other preclinical trials; and complementing other prevention initiatives. The API Autosomal Dominant Alzheimer’s Disease (ADAD) Trial, conducted in full partnership with Genentech and the University of Antioquia (UdeA), is evaluating crenezumab in unimpaired PSEN1 E280A mutation carriers at certain risk for developing early-onset AD. Primary outcome is change on the API ADAD composite cognitive test score. Secondary outcomes include time to progression to mild cognitive impairment or dementia due to AD, and change in several AD biomarker measurements including amyloid PET, FDG PET, volumetric MRI, and CSF tau. The Colombian API Registry, created by the UdeA in conjunction with BAI and Genentech, provides a resource for enrollment into the API ADAD Trial and for biomarker and cognitive studies of ADAD. The Registry includes >4,500 members of the PSEN1 E280A kindred, approximately 25% of whom are mutation carriers. We launched the ADAD Trial in 2013. In parallel, we continue to characterize the preclinical trajectory of ADAD in the Antioquia cohort, refine composite cognitive
Abstracts / Neurobiology of Aging 39 (2016) S1eS13
endpoints; estimate sample sizes using biomarker and cognitive endpoints; expand the Colombian API Registry; engage academic, industry and regulatory stakeholders; and prepare for future API trials. Keywords. Alzheimer’s disease, Clinical trial, Preclinical, Prevention
TIME TO FORGET MICE? USING HUMAN CELLS FOR DRUG TESTING? Manfred Windisch. NeuroScios GmbH, St. Radegund, Austria. E-mail: [email protected] The enormous failure rate of new treatments for Alzheimer’s disease (AD) in clinical development is questioning the translational value of preclinical animal models and is demanding better alternatives. It was shown 2014 (Choi et. al; 2014) that 3 dimensional neuronal from human neuronal stem cell can develop all pathological features of AD including toxic Ab oligomers, extracellular plaque like amyloid depositions, p-tau and finally even neurofibrillary tangle like structures. But it needs to be clarified that this is the result of viral transfection of these cells with mutated APP containing Swedish and London mutation, as well as mutated PS1. So also this model of “AD in the petri dish” utilizes a combination of FAD mutations, but in contrast to mouse models the development of neurofibrillary pathology is based on wild-type human tau. Even first conclusions about the use for drug testing can be drawn from this in vitro model, because b- and g-secretase inhibitors/modulators are reducing the amyloid-, but at the same moment ameliorate also NFTpathology. From that point of view the human cells seem to be a promising approach for predictive drug testing, with few limitations, like many transgenic mice they represent a highly artificial combination of FAD features, the “cognitive performance” is rather limited, and so far no drugs exclusively tested in such a, in vitro system reached the advanced clinical trial phase and had no chance to produce success or failure. This is exactly the weak point, because the translation of drug effects on brain pathology worked well in the in vivo models, just reproducing cognitive improvement did not work out. What’s the problem? Are the models not appropriate, did we not use these model in the right way, did we test not really efficacious drugs, or should we even question the rationale behind some of the most actual targets? The development of “humanized” mice and rats may help, as well as the consideration of advanced cognitive test systems in animals and potentially more relevant cognitive test batteries in human trials. More provocative, can we consider to move compounds into clinic without efficacy testing in mice? Keywords. Stem cells, Tissue culture, Transgenic mice, Translation
SIMULTANEOUS QUANTITATIVE SUSCEPTIBILITY MAPPING-MRI AND 18F-FLUTAMETAMOL-PET INDICATE FUNCTIONAL IMPACT OF CEREBRAL IRON AND AMYLOID-b PLAQUE BURDEN IN COGNITIVELY NORMAL SUPER-AGERS Jiri van Bergen1, Frances-Catherine Quevenco1, Sandra Leh2, Anton Gietl1, Valerie Treyer3, Rafael Meyer3, Roger Nitsch1, Christoph Hock1, Paul Unschuld1. 1 University of Zurich, Zurich, Switzerland; 2 University Zürich, Zürich, Switzerland; 3 University Zürich, Zurich, Switzerland. E-mail: [email protected] Background. The aging brain is characterized by distinct pathological alterations that include extracellular accumulation of Amyloid-b (Ab), increased iron load and altered functional properties. This study aimed to investigate cerebral Ab and iron, as well as associated functional brain network activity in a context of cognitively normal aging. Methods. 25 cognitively normal elderly participants (“super-agers”, mean age ¼ 87.6 (SD 2.97) years), were administered 18F-Flutemetamol-PET for estimating Ab-plaque burden, Quantitative-Susceptibility-Mapping (QSM) MRI for cerebral iron load, and functional MRI (fMRI) at rest for assessing functional connectivity with the posterior cingulate cortex, using a 3T SIGNA GE combined PET-MR instrument. Standardized uptake value ratios (SUVR) for 18F-Flutametamol (85-105 minutes post injection) were calculated by time-of-flight reconstruction (voxel size ¼ 1.2x1.2x2.78mm3) and used for splitting the study sample in two groups: “Ab-positive” (n ¼ 6) and “Ab-negative” (n ¼ 19). QSM images were reconstructed from a 3D multi-
S9
echo GRE sequence (TR/TE/DTE ¼ 40/3/4ms, voxel size ¼ 1x1x1mm3). fMRI resting-state scans were performed using a gradient echo EPI sequence (TR: 2.55s, scan time: 8:32min). Results. Local iron load significantly differed between groups (p-FDR-corrected < 0.05) for the caudate nucleus (right and left), and putamen (right and left). By applying the CONN-toolbox, connectivity patterns associated with high cortical Ab (10361 voxels) and high cortical iron (20112 voxels) could be identified (extent threshold FDR-corrected for p < 0.05), which showed a high degree of spatial overlap (7568 voxels) and also temporal synchronicity (adjusted-R2 ¼ 0.59). Discussion. The co-occurence of cortical Ab-plaque load with iron accumulation in basal ganglia gray-matter nuclei indicates the presence of common age-related brain change in cognitively normal super-agers. Additional research is needed to characterize potential compensatory mechanisms that allow for normal cognitive performance, including a potential role of functional network connectivity for conveying resilience against pathologies accumulating in the aging brain. Keywords. Flutametamol, Functional connectivity, Iron
IMAGING NEUROINFLAMMATION IN ALZHEIMER’S AND OTHER DEMENTIAS: RECENT ADVANCES AND FUTURE DIRECTIONS David Brooks. Aarhus University Denmark, Aarhus N, Mid Jutland. E-mail: [email protected] While the molecular mechanisms causing neuronal loss and synaptic damage in Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Lewy body dementias (LBD) are poorly understood, the presence of neuroinflammation (glial activation) is a common feature. However, the relative timing and relationship between inflammation and the abnormal protein aggregation underlying these disorders remains uncertain. An increasing body of evidence suggests that activated microglia may play a central role in driving AD progression and therapies designed to suppress microglial activation are now being trialed as neuroprotective agents. This talk will review the approaches for imaging neuroinflammation and present their findings in AD, FTD and LBD. It will focus on the relationship between amyloid deposition, microglial activation, and tau aggregation and discuss possible intervention strategies. The different roles of microglial phenotypes will also be debated. Keywords. Alzheimer, Amyloid-PET, Inflammation, Parkinson’s disease, Imaging, Tau
PSP AND SMALL VESSEL DISEASE: MORE THAN OCCASIONAL CO-OCCURENCE? Anne Sieben1, Patrick Santens2, Dimitri Hemelsoet2, Sebastiaan Engelborghs1, Peter De Jonghe3, Jan De Bleecker2, Jen Maes4, Christina Jadoul5, Patrick Cras3, Peter-Paul De Deyn1, Christine Van Jean-Jacques Martin6. 1 Institute Born-Bunge, Antwerp Broeckhoven1, University, Antwerp, Belgium; 2 Gent University Hospital, Gent, Belgium; 3 Antwerp University Hospital, Antwerp, Belgium; 4 N/A, N/A 5 AZ Nikolaas, Sint-Niklaas, Belgium; 6 Institute Born-Bunge, Antwerpen, Belgium. E-mail: [email protected] Progressive supranuclear palsy (PSP) is a neurodegenerative disorder, characterized by Parkinsonism, gaze paresis and progressive cognitive decline. PSP is the most frequent tauopathy with a prevalence of 1,39 per 100 000. New insights in the pathophysiology of Alzheimer’s Disease (AD) show that cerebrovascular risk factors are important in neurodegeneration. The occurrence of cerebrovascular pathology in disorders such as AD, Parkinson’s and recently Pick’s Disease suggests that neuronal loss is not only a problem of proteinopathies, but also of ischemic changes inducing neuronal damage. In the brain bank of neurodegenerative disorders in the Institute Born Bunge at the Antwerp University, we collected in the last 2 years 7 brains of patients suffering from PSP. Age of death was 74 years (66-84). A standardized battery of samples was taken from every patient, including different cortical areas, subcortical nuclei, brain stem and cerebellum, on which extensive histochemistry and immunohistochemical stainings were performed. Neuropathological analyses were in all cases compatible with the typical combined tauopathy of neurons, astrocytes and oligodendrocytes. Lesions were found