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Lower serum antibodies against tau protein and heavy neurofilament in Alzheimer's disease
P280
Poster Presentations: P2
transmembrane domain peptides. CSF and plasma p3-Alc levels, together with Abeta levels, may be useful in selecting subjects that might benefit from therapeutics aimed at modulation of gamma-secretase function. P2-048
VISUAL CONTRAST SENSITIVITY IN MCI AND OLDER ADULTS WITH COGNITIVE COMPLAINTS IS ASSOCIATED WITH ALTERED RESTING CONNECTIVITY IN THE VISUAL NETWORK
Shannon Risacher, Yang Wang, John West, Tamiko Magee, Darrell WuDunn, Li Shen, Brenna McDonald, Martin Farlow, Darren O’Neill, Andrew Saykin, Indiana University School of Medicine, Indianapolis, Indiana, United States. Background: Visual contrast sensitivity is impaired in patients with prodromal and clinical Alzheimer’s disease [1,2]. However, the biological basis for these deficits is unknown and may involve retinal and/or central visual pathway changes. The present study sought to evaluate whether changes in resting connectivity in the primary visual pathway are associated with visual contrast sensitivity deficits. Methods: Visual contrast sensitivity was assessed using frequency doubling technology (FDT) [1] in a cohort of older adults with mild cognitive impairment (MCI; n ¼ 7), cognitive complaints (CC; n ¼ 14) but no psychometric deficits, and healthy controls (HC; n ¼ 11). Resting state fMRI scans were acquired on a Siemens 3T scanner while participants were at rest with eyes closed. Resting connectivity along the primary visual pathway was evaluated using independent component analysis and a dual regression approach as implemented with FSL and AFNI. The association between visual pathway resting connectivity and visual contrast sensitivity impairment was assessed on a voxel-wise basis using SPM8 with age, sex, and education as covariates. Values from the resulting clusters were assessed to further explore the association between FDT measures and visual pathway resting connectivity. Results: Significant associations between visual contrast sensitivity performance and resting connectivity in the visual pathway were observed in the bilateral temporoparietal junctions (Figure 1A; P <0.001 uncorrected, k ¼ 50; observed clusters reach a clusterwise threshold of P <0.05 FDR). Correlations were strong (P <0.0001) for both right (Figure 1B; r ¼ -0.828) and left (Figure 1C; r ¼ -0.781) temporoparietal junction. Results appeared consistent across diagnostic groups. Conclusions: Alterations in functional connectivity in the bilateral temporoparietal cortical components of the visual network may play a role in reduced visual contrast sensitivity in older adults with MCI and CC, as well as in normal aging. References: [1] Risacher et al. ICAD poster (2010). [2] Frost et al. J Alz Dis (2010).
Steven Arnold2, 1University of Pennsylvania, Philadelphia, Pennsylvania, United States; 2University of Pennsylvania, Philadelphia, Pennsylvania, United States; 3Emory University, N.E. Atlanta, Georgia, United States. Background: Depression has been recognized as a risk factor for cognitive decline and represents a significant health concern in its own right. The pathophysiology of depressive symptoms in older adults is complex and poorly understood. We used an unbiased analytic biomarker discovery approach to identify biochemical biomarkers in cerebrospinal fluid (CSF) that are associated with depressive symptoms in older adults with varying degrees of cognitive impairment. Methods: 179 individuals with normal cognition, Alzheimer’s disease (AD) or other dementias underwent clinical evaluation and CSF sampling. Depressive symptoms were assessed by the Geriatric Depression Scale (GDS), four subscales (depression, anxiety, apathy and agitation) of the Neuropsychiatric Inventory Questionnaire ("NPIQ-4") and a combination of the GDS and NPIQ using z-transformation (GN). A large multi-analyte immunochemical panel, the Rules-Based Medicine Human DiscoveryMAP, validly measured 135 CSF proteins and hormones spanning important inflammatory, metabolic, chemokine and growth factor pathways. To construct depressive symptom-related biomarkers, participants were dichotomized into depressed versus non-depressed categories by three schema: 1) GDS3 vs. GDS1; 2) NPIQ-41 vs. NPIQ-4 ¼ 0; and 3) GN0.5€If (GN) vs. GN0.5€If (GN). Five-fold cross-validation evaluated the performance of models. Random Forest was applied on the training portion. Top analytes were chosen based on their variable importance scores. The final model was determined by the best training accuracy obtained, tested on the left-out portion. Results: Six analytes separated subjects with or without depressive symptoms based on GDS, yielding 70% sensitivity, 78% specificity and 76% accuracy. Based on NPIQ-4, 18 analytes were chosen, with 75% sensitivity, 79% specificity and 78% accuracy. Using the combined GN index, 20 analytes were selected, with 85% sensitivity, specificity and accuracy. Selected analytes having reported biological significance for depression included FABP, SORT1, CRP, PRL, IL-8, CCL2, CCL5 and CKB. Canonical pathways related to cytokines and immune system were selected by Ingenuity Pathway Analyses (P <0.001). Conclusions: A focused selection of immune/ inflammatory proteins in CSF accurately predicted depressive symptoms in a mixed sample of older adults. Identification of these proteins and associated pathways prompt additional studies to determine their pathophysiological role in negative affect states and utility in diagnosis and therapeutic response in neuropsychiatric illness in older adults. P2-050
LOWER SERUM ANTIBODIES AGAINST TAU PROTEIN AND HEAVY NEUROFILAMENT IN ALZHEIMER’S DISEASE
Ales Bartos1, Lenka Fialova2, Jana Svarcova2, Daniela Ripova1, 1Prague Psychiatric Center, Prague, Czech Republic; 2Charles University in Prague, First Faculty of Medicine and General University Hospital, Institute of Medical Biochemistry and Laboratory Diagnostics, Prague, Czech Republic.
Figure 1. (A) Association of Visual Contrast Sensitivity and Resting State Connectivity in Visual Pathway on a Voxel-wise Basis. (B) Association in the Right Temporoparietal Cortex. (C) Association in the Left Temporoparietal Cortex P2-049
CEREBROSPINAL FLUID BIOCHEMICAL BIOMARKERS OF DEPRESSIVE SYMPTOMS IN OLDER ADULTS
Yuk Yee Leung1, Li-San Wang2, William T. Hu3, Mitchel Kling2, David Wolk2, John Trojanowski2, Virginia Lee2, Leslie Shaw2,
Background: Unlike antibodies against beta-amyloid, little is known about serum antibodies to neuron- and disease-specific cytoskeletal proteins in patients with Alzheimer disease (AD). Moreover, fluctuations of these antibodies over time are not known, neither. Methods: Antibodies against three targets (tau, light (NFL) and heavy (NFH) neurofilaments) were measured using ELISA in 100 serum samples from 51 cognitively normal elderly controls (NC) and 49 patients with AD fulfilling NINCDS-ADRDA criteria. We also measured all three anti-neurocytoskeletal antibodies in paired serum samples from 48 NC and 11 AD patients after 562 6 161 days in NC and after 441 6 253 days in AD. Results: The AD patients had significantly lower levels of anti-tau antibodies (P ¼ 0.03) and more anti-NFH antibodies (p ¼ 0.005) than those in the control group at baseline. On the contrary, anti-NFL antibodies or total IgG concentrations in serum did not differ. All three antibodies remained stable in both groups except for a selective and significant anti-tau decline in AD patients (P ¼ 0.03). Conclusions: The different responses to these antigens suggest some antibody selectivity in AD. The significant decline was observed for only serum anti-tau antibodies in AD patients over time and it corresponds to lower levels in these patients. Our findings indicate a novel and special feature of disease-relevant antigens and humoral autoimmunity in AD.
Poster Presentations: P2
transmembrane domain peptides. CSF and plasma p3-Alc levels, together with Abeta levels, may be useful in selecting subjects that might benefit from therapeutics aimed at modulation of gamma-secretase function. P2-048
VISUAL CONTRAST SENSITIVITY IN MCI AND OLDER ADULTS WITH COGNITIVE COMPLAINTS IS ASSOCIATED WITH ALTERED RESTING CONNECTIVITY IN THE VISUAL NETWORK
Shannon Risacher, Yang Wang, John West, Tamiko Magee, Darrell WuDunn, Li Shen, Brenna McDonald, Martin Farlow, Darren O’Neill, Andrew Saykin, Indiana University School of Medicine, Indianapolis, Indiana, United States. Background: Visual contrast sensitivity is impaired in patients with prodromal and clinical Alzheimer’s disease [1,2]. However, the biological basis for these deficits is unknown and may involve retinal and/or central visual pathway changes. The present study sought to evaluate whether changes in resting connectivity in the primary visual pathway are associated with visual contrast sensitivity deficits. Methods: Visual contrast sensitivity was assessed using frequency doubling technology (FDT) [1] in a cohort of older adults with mild cognitive impairment (MCI; n ¼ 7), cognitive complaints (CC; n ¼ 14) but no psychometric deficits, and healthy controls (HC; n ¼ 11). Resting state fMRI scans were acquired on a Siemens 3T scanner while participants were at rest with eyes closed. Resting connectivity along the primary visual pathway was evaluated using independent component analysis and a dual regression approach as implemented with FSL and AFNI. The association between visual pathway resting connectivity and visual contrast sensitivity impairment was assessed on a voxel-wise basis using SPM8 with age, sex, and education as covariates. Values from the resulting clusters were assessed to further explore the association between FDT measures and visual pathway resting connectivity. Results: Significant associations between visual contrast sensitivity performance and resting connectivity in the visual pathway were observed in the bilateral temporoparietal junctions (Figure 1A; P <0.001 uncorrected, k ¼ 50; observed clusters reach a clusterwise threshold of P <0.05 FDR). Correlations were strong (P <0.0001) for both right (Figure 1B; r ¼ -0.828) and left (Figure 1C; r ¼ -0.781) temporoparietal junction. Results appeared consistent across diagnostic groups. Conclusions: Alterations in functional connectivity in the bilateral temporoparietal cortical components of the visual network may play a role in reduced visual contrast sensitivity in older adults with MCI and CC, as well as in normal aging. References: [1] Risacher et al. ICAD poster (2010). [2] Frost et al. J Alz Dis (2010).
Steven Arnold2, 1University of Pennsylvania, Philadelphia, Pennsylvania, United States; 2University of Pennsylvania, Philadelphia, Pennsylvania, United States; 3Emory University, N.E. Atlanta, Georgia, United States. Background: Depression has been recognized as a risk factor for cognitive decline and represents a significant health concern in its own right. The pathophysiology of depressive symptoms in older adults is complex and poorly understood. We used an unbiased analytic biomarker discovery approach to identify biochemical biomarkers in cerebrospinal fluid (CSF) that are associated with depressive symptoms in older adults with varying degrees of cognitive impairment. Methods: 179 individuals with normal cognition, Alzheimer’s disease (AD) or other dementias underwent clinical evaluation and CSF sampling. Depressive symptoms were assessed by the Geriatric Depression Scale (GDS), four subscales (depression, anxiety, apathy and agitation) of the Neuropsychiatric Inventory Questionnaire ("NPIQ-4") and a combination of the GDS and NPIQ using z-transformation (GN). A large multi-analyte immunochemical panel, the Rules-Based Medicine Human DiscoveryMAP, validly measured 135 CSF proteins and hormones spanning important inflammatory, metabolic, chemokine and growth factor pathways. To construct depressive symptom-related biomarkers, participants were dichotomized into depressed versus non-depressed categories by three schema: 1) GDS3 vs. GDS1; 2) NPIQ-41 vs. NPIQ-4 ¼ 0; and 3) GN0.5€If (GN) vs. GN0.5€If (GN). Five-fold cross-validation evaluated the performance of models. Random Forest was applied on the training portion. Top analytes were chosen based on their variable importance scores. The final model was determined by the best training accuracy obtained, tested on the left-out portion. Results: Six analytes separated subjects with or without depressive symptoms based on GDS, yielding 70% sensitivity, 78% specificity and 76% accuracy. Based on NPIQ-4, 18 analytes were chosen, with 75% sensitivity, 79% specificity and 78% accuracy. Using the combined GN index, 20 analytes were selected, with 85% sensitivity, specificity and accuracy. Selected analytes having reported biological significance for depression included FABP, SORT1, CRP, PRL, IL-8, CCL2, CCL5 and CKB. Canonical pathways related to cytokines and immune system were selected by Ingenuity Pathway Analyses (P <0.001). Conclusions: A focused selection of immune/ inflammatory proteins in CSF accurately predicted depressive symptoms in a mixed sample of older adults. Identification of these proteins and associated pathways prompt additional studies to determine their pathophysiological role in negative affect states and utility in diagnosis and therapeutic response in neuropsychiatric illness in older adults. P2-050
LOWER SERUM ANTIBODIES AGAINST TAU PROTEIN AND HEAVY NEUROFILAMENT IN ALZHEIMER’S DISEASE
Ales Bartos1, Lenka Fialova2, Jana Svarcova2, Daniela Ripova1, 1Prague Psychiatric Center, Prague, Czech Republic; 2Charles University in Prague, First Faculty of Medicine and General University Hospital, Institute of Medical Biochemistry and Laboratory Diagnostics, Prague, Czech Republic.
Figure 1. (A) Association of Visual Contrast Sensitivity and Resting State Connectivity in Visual Pathway on a Voxel-wise Basis. (B) Association in the Right Temporoparietal Cortex. (C) Association in the Left Temporoparietal Cortex P2-049
CEREBROSPINAL FLUID BIOCHEMICAL BIOMARKERS OF DEPRESSIVE SYMPTOMS IN OLDER ADULTS
Yuk Yee Leung1, Li-San Wang2, William T. Hu3, Mitchel Kling2, David Wolk2, John Trojanowski2, Virginia Lee2, Leslie Shaw2,
Background: Unlike antibodies against beta-amyloid, little is known about serum antibodies to neuron- and disease-specific cytoskeletal proteins in patients with Alzheimer disease (AD). Moreover, fluctuations of these antibodies over time are not known, neither. Methods: Antibodies against three targets (tau, light (NFL) and heavy (NFH) neurofilaments) were measured using ELISA in 100 serum samples from 51 cognitively normal elderly controls (NC) and 49 patients with AD fulfilling NINCDS-ADRDA criteria. We also measured all three anti-neurocytoskeletal antibodies in paired serum samples from 48 NC and 11 AD patients after 562 6 161 days in NC and after 441 6 253 days in AD. Results: The AD patients had significantly lower levels of anti-tau antibodies (P ¼ 0.03) and more anti-NFH antibodies (p ¼ 0.005) than those in the control group at baseline. On the contrary, anti-NFL antibodies or total IgG concentrations in serum did not differ. All three antibodies remained stable in both groups except for a selective and significant anti-tau decline in AD patients (P ¼ 0.03). Conclusions: The different responses to these antigens suggest some antibody selectivity in AD. The significant decline was observed for only serum anti-tau antibodies in AD patients over time and it corresponds to lower levels in these patients. Our findings indicate a novel and special feature of disease-relevant antigens and humoral autoimmunity in AD.