- Email: [email protected]
Cerebrovascular and Alzheimer's disease: A synergistic pathogenesis
P332
Oral Sessions: O2-09: Biomarkers: Differential Diagnosis and Co-morbidities
internationally accepted criteria, and AD cases were further classified for the presence of cerebrovascular disease (CBVD). Controls with no history of stroke and cognitive impairment were selected from the Singapore Epidemiology of Eye Disease program and matched by race, gender and 5year age groups. Retinal vascular parameters (retinal vascular caliber, fractal dimension and tortuosity) were assessed using a semi-automated computer-based program. Due to its skewed distribution, retinal vessel tortuosity was log-transformed. Logistic regression models were constructed adjusting for gender, age, hypertension, diabetes and hypercholesterolemia status. Results: A total of 156 AD cases (98 without CBVD and 58 with CBVD), 27 vascular dementia cases, and 493 controls were included in this preliminary analysis. Narrower arteriolar caliber was associated with VaD (multivariable-adjusted odds ratio (OR) per standard deviation (SD) decrease: 2.41; 95%CI: 1.13-5.14) and AD with CBVD (OR per SD decrease: 1.84; 95%CI: 1.05-3.23). Narrower venular caliber (OR per SD decrease: 1.72; 95%CI: 1.11-2.68), decreased arteriolar fractal dimension (OR per SD decrease: 1.29; 95%CI: 1.03-1.61) and venular fractal dimension (OR per SD increase: 1.36; 95%CI: 1.08-1.72) were associated with only AD without CBVD. However, increased arteriolar and venular tortuosity was associated with all three subtypes of dementia. Conclusions: A sparser retinal microvascular network was associated with AD, whereas narrower arterioles were associated with dementia linked to CBVD, and tortuous retinal vessels were associated with all three subtypes of dementia. This suggests that retinal vascular parameters may potentially useful in assessing the contribution of microvascular pathology to the different subtpyes of dementia. O2-09-02
CEREBROVASCULAR AND ALZHEIMER’S DISEASE: A SYNERGISTIC PATHOGENESIS
Jeroen Goos, Maartje Kester, Charlotte Teunissen, Femke Bouwman, Frederik Barkhof, Philip Scheltens, Wiesje Van der Flier, VU University Medical Center, Department of Neurology and Alzheimer Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: We explored synergism of cerebrovascular disease with Alzheimer’s pathology, by examining effects of MRI white matter hyperintensities (WMH), lacunar infarcts and microbleeds (MBs) on CSF amyloid beta 1-42 (Ab42), total tau (tau) and tau phopshorylated at threonine 181 (ptau-181) in Alzheimer’s disease (AD), Vascular dementia (VaD) and controls with subjective memory complaints. Methods: We included consecutive patients with available CSF and MRI from the memory clinic based Amsterdam Dementia Cohort: 547 AD (54%F, 6768yrs, MMSE 2165), 30 VaD (37%F, 6469yrs, MMSE 2464) and 337 controls (42% F, 5969yrs, MMSE 2862). Beta-amyloid 42, tau and ptau-181 levels were determined and log-transformed, as they were not normally distributed. MRIs were made at 1.5T or 3T, and readings were dichotomized: WMH (0-1 vs. 2-3), lacunar infarcts (0 vs. 1), MBs (0 vs. 1) and medial temporal atrophy (MTA, 0-1 vs. 2). Sex, age and MTA adjusted linear regression analyses with CSF-biomarkers as dependent variables, were performed for each diagnostic group separately. First, with only one MRImeasure as determinant, and secondly, multivariate with all MRI-measures combined. Results: In AD, presence of WMH and microbleeds were associated with lower CSF beta-amyloid 42 (standardized b -0.10, p¼0.03; -0.15, p¼0.001), but we found no associations between lacunes and betaamyloid 42 or between any of the MRI measures and tau or ptau. In controls, presence of WMH was associated with lower CSF beta-amyloid 42 (sb: -0.11, p¼0.04). In VaD there were only trends: WMH, microbleeds and lacunes were associated with lower CSF beta-amyloid 42 (sb: -0.33, -0.36, 0.28, p¼0.1, p¼0.1, p¼0.2). In the multivariate analysis for AD, microbleeds were the strongest predictor for lower Ab42 (sb: -0.13, p¼0.004). For controls, WMH was the strongest predictor (sb: -0.13, p¼0.02), and for VaD lacunes (sb: 0.41, p<0.05). There were no MRI associations with tau or ptau. All effects were independent of sex, age and MTA. Conclusions: The results of this study suggest a direct relationship between cerebral small vessel disease and Alzheimer’s pathology. Amyloid pathology appears aggravated in patients with vascular damage, supporting pathophysiological synergy.
O2-09-03
DETECTION AND QUANTIFICATION OF NOVEL TAU/PHOSPHO-TAU EPITOPES IN CSF USING A MULTIPLEX ASSAY APPROACH
Ann De Vos1, Dirk Jacobs1, Eugeen Vanmechelen1, Joris Winderickx2, Jeff Van den Brande2, Sebastiaan Engelborghs3, Hanne Struyfs3, Kaj Blennow4, Henrik Zetterberg4, 1ADx NeuroSciences, Zwijnaarde, Ghent, Belgium; 2KU Leuven, Leuven, Belgium; 3University of Antwerp, Antwerp, Belgium; 4Sahlgrenska Academy, University of Gothenburg, M€olndal, Sweden. Contact e-mail: [email protected] Background: Tau and phospho-tau (p-tau) isoforms in cerebrospinal fluid (CSF) are considered as diagnostic markers for staging the progression of Alzheimer’s disease (AD) or for differentiating AD from other dementia forms. So far, only four (pS199, pT181, pT231, pS396-404) of the more than 40 abnormally phosphorylated sites in protein tau have been examined as potential biomarker. To the best of our knowledge only one multicenter study has compared different p-tau assays in a clinical setting. The possible clinical value of the p-tau sites for differential dementia diagnosis requires larger studies and the availability of novel tools for their quantification. Methods: Multiplex-assays were developed to study different tau isoforms in CSF simultaneously, based on xMAP Ô -technology (Luminex). Combining the different tau-epitopes in a single peptide sequence allows calibration of two (or more) analytes concurrently, such as pS198-tau or oligomeric tau. One of the novel p-tau sites detected with the assays is pS198, which is abnormally phosphorylated in Paired Helical Filaments (PHFs) in AD but not in PHFs isolated from brains of patients with Progressive Supranuclear Palsy (PSP). By using the same antibody as capture and detector antibody, we are able to quantify tau-oligomers as well. Results: The qualification of the multiplex-assays is based on phosphorylated and aggregated protein tau isolated and characterized from yeast strains expressing such modified tau. The analytical characteristics of the multi-tau assays are similar to ELISA with respect to standard curve accuracy, precision, robustness and parallelism, but superior with respect to analytical sensitivity. Current CSF-studies with the assays confirm the increase of CSF-tau in AD versus controls, but more elaborate studies of clinical diagnostic groups, such as FTD, PSP and/ or VAD will be presented. Conclusions: The assay format for multi-tau/ptau detection and quantification will allow for a more efficient selection of the most relevant tau species in a clinical-diagnostic setting and might be used to monitor tau-mediated disease-modifying therapies. O2-09-04
EEG PHENOTYPING AND SUB-PHENOTYPING OF ALZHEIMER’S DISEASE AND OTHER DEMENTIAS ıs Emilsdottir, Gısli Johannesson, Jon Snædal, Nicolas Blin, Asd Halla Helgadottir, Paula Newmann, Magnus Johannsson, ~ zorkell Guðmundsson, Kristinn Johnsen, Mentis Cura, Reykjavik, A Iceland. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly population. Possibly AD has several subtypes. Lewy body dementia (LBD) and Parkinsons disease dementia (PDD) combined are the second most prevalent cause of neurodegenerative dementia. The only current biomarker for LBD/PDD is dopamine scan but it cannot differentiate between the different extrapyramidal syndromes. Medications are especially challenging in LBD as these patients are extremely sensitive for neuroleptics, a medication that is used for symptoms prevalent in this disease. It has been estimated that up to 50% of patients with LBD treated with any antipsychotic medication may experience severe neuroleptic sensitivity or symptoms resembling neuroleptic malignant syndrome, which can be fatal. It is therefore of importance for the treatment of these patients that they are correctly diagnosed. Methods: In an EEG database, EEGs from 226 healthy (NRM), 239 mild AD subjects, 22 individuals with LBD, and 26 individuals with PDD have been entered. In each pair wise comparison of the groups, 10 classifiers are constructed by applying statistical pattern recognition (SPR) to a large set of EEG features. For each classifier, the SPR finds an optimal combination of the EEG features which separate the two groups under consideration. The accuracy, sensitivity,
Oral Sessions: O2-09: Biomarkers: Differential Diagnosis and Co-morbidities
internationally accepted criteria, and AD cases were further classified for the presence of cerebrovascular disease (CBVD). Controls with no history of stroke and cognitive impairment were selected from the Singapore Epidemiology of Eye Disease program and matched by race, gender and 5year age groups. Retinal vascular parameters (retinal vascular caliber, fractal dimension and tortuosity) were assessed using a semi-automated computer-based program. Due to its skewed distribution, retinal vessel tortuosity was log-transformed. Logistic regression models were constructed adjusting for gender, age, hypertension, diabetes and hypercholesterolemia status. Results: A total of 156 AD cases (98 without CBVD and 58 with CBVD), 27 vascular dementia cases, and 493 controls were included in this preliminary analysis. Narrower arteriolar caliber was associated with VaD (multivariable-adjusted odds ratio (OR) per standard deviation (SD) decrease: 2.41; 95%CI: 1.13-5.14) and AD with CBVD (OR per SD decrease: 1.84; 95%CI: 1.05-3.23). Narrower venular caliber (OR per SD decrease: 1.72; 95%CI: 1.11-2.68), decreased arteriolar fractal dimension (OR per SD decrease: 1.29; 95%CI: 1.03-1.61) and venular fractal dimension (OR per SD increase: 1.36; 95%CI: 1.08-1.72) were associated with only AD without CBVD. However, increased arteriolar and venular tortuosity was associated with all three subtypes of dementia. Conclusions: A sparser retinal microvascular network was associated with AD, whereas narrower arterioles were associated with dementia linked to CBVD, and tortuous retinal vessels were associated with all three subtypes of dementia. This suggests that retinal vascular parameters may potentially useful in assessing the contribution of microvascular pathology to the different subtpyes of dementia. O2-09-02
CEREBROVASCULAR AND ALZHEIMER’S DISEASE: A SYNERGISTIC PATHOGENESIS
Jeroen Goos, Maartje Kester, Charlotte Teunissen, Femke Bouwman, Frederik Barkhof, Philip Scheltens, Wiesje Van der Flier, VU University Medical Center, Department of Neurology and Alzheimer Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: We explored synergism of cerebrovascular disease with Alzheimer’s pathology, by examining effects of MRI white matter hyperintensities (WMH), lacunar infarcts and microbleeds (MBs) on CSF amyloid beta 1-42 (Ab42), total tau (tau) and tau phopshorylated at threonine 181 (ptau-181) in Alzheimer’s disease (AD), Vascular dementia (VaD) and controls with subjective memory complaints. Methods: We included consecutive patients with available CSF and MRI from the memory clinic based Amsterdam Dementia Cohort: 547 AD (54%F, 6768yrs, MMSE 2165), 30 VaD (37%F, 6469yrs, MMSE 2464) and 337 controls (42% F, 5969yrs, MMSE 2862). Beta-amyloid 42, tau and ptau-181 levels were determined and log-transformed, as they were not normally distributed. MRIs were made at 1.5T or 3T, and readings were dichotomized: WMH (0-1 vs. 2-3), lacunar infarcts (0 vs. 1), MBs (0 vs. 1) and medial temporal atrophy (MTA, 0-1 vs. 2). Sex, age and MTA adjusted linear regression analyses with CSF-biomarkers as dependent variables, were performed for each diagnostic group separately. First, with only one MRImeasure as determinant, and secondly, multivariate with all MRI-measures combined. Results: In AD, presence of WMH and microbleeds were associated with lower CSF beta-amyloid 42 (standardized b -0.10, p¼0.03; -0.15, p¼0.001), but we found no associations between lacunes and betaamyloid 42 or between any of the MRI measures and tau or ptau. In controls, presence of WMH was associated with lower CSF beta-amyloid 42 (sb: -0.11, p¼0.04). In VaD there were only trends: WMH, microbleeds and lacunes were associated with lower CSF beta-amyloid 42 (sb: -0.33, -0.36, 0.28, p¼0.1, p¼0.1, p¼0.2). In the multivariate analysis for AD, microbleeds were the strongest predictor for lower Ab42 (sb: -0.13, p¼0.004). For controls, WMH was the strongest predictor (sb: -0.13, p¼0.02), and for VaD lacunes (sb: 0.41, p<0.05). There were no MRI associations with tau or ptau. All effects were independent of sex, age and MTA. Conclusions: The results of this study suggest a direct relationship between cerebral small vessel disease and Alzheimer’s pathology. Amyloid pathology appears aggravated in patients with vascular damage, supporting pathophysiological synergy.
O2-09-03
DETECTION AND QUANTIFICATION OF NOVEL TAU/PHOSPHO-TAU EPITOPES IN CSF USING A MULTIPLEX ASSAY APPROACH
Ann De Vos1, Dirk Jacobs1, Eugeen Vanmechelen1, Joris Winderickx2, Jeff Van den Brande2, Sebastiaan Engelborghs3, Hanne Struyfs3, Kaj Blennow4, Henrik Zetterberg4, 1ADx NeuroSciences, Zwijnaarde, Ghent, Belgium; 2KU Leuven, Leuven, Belgium; 3University of Antwerp, Antwerp, Belgium; 4Sahlgrenska Academy, University of Gothenburg, M€olndal, Sweden. Contact e-mail: [email protected] Background: Tau and phospho-tau (p-tau) isoforms in cerebrospinal fluid (CSF) are considered as diagnostic markers for staging the progression of Alzheimer’s disease (AD) or for differentiating AD from other dementia forms. So far, only four (pS199, pT181, pT231, pS396-404) of the more than 40 abnormally phosphorylated sites in protein tau have been examined as potential biomarker. To the best of our knowledge only one multicenter study has compared different p-tau assays in a clinical setting. The possible clinical value of the p-tau sites for differential dementia diagnosis requires larger studies and the availability of novel tools for their quantification. Methods: Multiplex-assays were developed to study different tau isoforms in CSF simultaneously, based on xMAP Ô -technology (Luminex). Combining the different tau-epitopes in a single peptide sequence allows calibration of two (or more) analytes concurrently, such as pS198-tau or oligomeric tau. One of the novel p-tau sites detected with the assays is pS198, which is abnormally phosphorylated in Paired Helical Filaments (PHFs) in AD but not in PHFs isolated from brains of patients with Progressive Supranuclear Palsy (PSP). By using the same antibody as capture and detector antibody, we are able to quantify tau-oligomers as well. Results: The qualification of the multiplex-assays is based on phosphorylated and aggregated protein tau isolated and characterized from yeast strains expressing such modified tau. The analytical characteristics of the multi-tau assays are similar to ELISA with respect to standard curve accuracy, precision, robustness and parallelism, but superior with respect to analytical sensitivity. Current CSF-studies with the assays confirm the increase of CSF-tau in AD versus controls, but more elaborate studies of clinical diagnostic groups, such as FTD, PSP and/ or VAD will be presented. Conclusions: The assay format for multi-tau/ptau detection and quantification will allow for a more efficient selection of the most relevant tau species in a clinical-diagnostic setting and might be used to monitor tau-mediated disease-modifying therapies. O2-09-04
EEG PHENOTYPING AND SUB-PHENOTYPING OF ALZHEIMER’S DISEASE AND OTHER DEMENTIAS ıs Emilsdottir, Gısli Johannesson, Jon Snædal, Nicolas Blin, Asd Halla Helgadottir, Paula Newmann, Magnus Johannsson, ~ zorkell Guðmundsson, Kristinn Johnsen, Mentis Cura, Reykjavik, A Iceland. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly population. Possibly AD has several subtypes. Lewy body dementia (LBD) and Parkinsons disease dementia (PDD) combined are the second most prevalent cause of neurodegenerative dementia. The only current biomarker for LBD/PDD is dopamine scan but it cannot differentiate between the different extrapyramidal syndromes. Medications are especially challenging in LBD as these patients are extremely sensitive for neuroleptics, a medication that is used for symptoms prevalent in this disease. It has been estimated that up to 50% of patients with LBD treated with any antipsychotic medication may experience severe neuroleptic sensitivity or symptoms resembling neuroleptic malignant syndrome, which can be fatal. It is therefore of importance for the treatment of these patients that they are correctly diagnosed. Methods: In an EEG database, EEGs from 226 healthy (NRM), 239 mild AD subjects, 22 individuals with LBD, and 26 individuals with PDD have been entered. In each pair wise comparison of the groups, 10 classifiers are constructed by applying statistical pattern recognition (SPR) to a large set of EEG features. For each classifier, the SPR finds an optimal combination of the EEG features which separate the two groups under consideration. The accuracy, sensitivity,